LongForm
Skip to main content
Close

Lung

1. Tumour Site/ Type Demographics

Revised 15 March 2013

Incidence

Lung cancer which includes tumours of the bronchus, trachea and lung, is the second most common cancer diagnosed in British Columbia and also in Canada, for both men and women (National Cancer Institute of Canada, 2012). It accounts for about 12% and 13% of all cancer diagnoses in BC for males and females respectively.  Among women, the incidence rate of lung cancer is stabilizing after a period of rapid increase, while in men, the rate peaked in the mid-1980s and has since consistently declined as indicated on the figure below.


Age Standardized Incidence Rates for Lung Cancer by sex from 1970-2010


Age Standardized Incidence Rates per 100,000 for Lung Case in 2000, 2005, 2010

Diagnosis Year

Male

Female

2000

60.4

44.4

2005

56.9

45.2

2010

49.5

41.2

 

Mortality

Overall, lung cancer causes about 25.5% of all cancer deaths in British Columbia. This death toll is greater than that attributed to colorectal, breast, and prostate cancer (the second through fourth leading causes of cancer mortality) combined.

Age Standardized Mortality Rates for Lung Cancer by sex from 1970-2010



Age Standardized Mortality Rates per 100,000 for Lung Cancer in 2000, 2005, 2010

Diagnosis Year

Male

Female

2000

51.7

33.8

2005

49.3

35.3

2010

39.9

33.3


In 2010, the last year for which data are complete, there were 1,447 cases of lung cancer diagnosed in men, and 1,155 lung cancer deaths recorded. Among women there were 1,357 new cases diagnosed, and 1,098 deaths recorded. Approximately 52% of the diagnoses were among males and 48% among females, but this ratio is rapidly changing as the incidence among women is growing. 

Incident Lung Cancer Cases 1985-2010 with Projection to 2025



Incident Lung Cancer Cases 2000-2025

Diagnosis Year

Male

Female

2000

1273

1101

2005

1398

1275

2010

1447

1357

2015 (projected)

1576

1645

2020 (projected)

1645

1896

2025 (projected)

1698

2171

In 2010, about 88.5% of the new cases were diagnosed with non small cell cancers; the remainder was diagnosed with small cell carcinoma.

Non Small Cell Carcinoma Diagnoses in 2010

Histologies

Male

Female

Total

Non small cell carcinoma

1284

1197

2481

Small cell carcinoma *

163

160

323

Total

1447

1357

2804

* Small cell carcinoma includes ICD-O 80413 small cell carcinoma nos, 80423 oat cell carcinoma, 80433 small cell carcinoma fusiform cell, 80443 small cell carcinoma intermediate cell, 80453 combined small cell carcinoma,

Age Distribution

In BC during the last ten years (2000-2010) three quarters of diagnosed lung cancer patients were 78 years old and older, and half were 71 years and older at diagnosis. The mean age at diagnosis was 70 years.

Age distribution is presented on the histogram below: 

 

Survival

The estimated probability of surviving up to 1, 3, 5 and 7 years after diagnosis with lung cancer are shown in the table below:

Estimated Probability
of Surviving

Years After Diagnosis

1 year

3 years

5 years

7 years

Lung Cancer (only)

40%

19%

15%

13%

Overall Survival (all causes)

35%

14%

10%

7%

 

The trends in 1-, 3- and 5-year Relative Survival for Lung Cancer Patients in BC are shown in the figure below.


The plot below indicates that the vast majority of patients diagnosed with Lung Cancer died from this cancer; few died from other cancers or non-cancer causes. The median lung cancer specific survival is about 8.5 months. The median overall survival for these patients is 7 months.

 

Source: CAIS Patient Information

Date Retrieved: 5 March 2013

Prepared by: Cancer Surveillance and Outcomes dataeval@bccancer.bc.ca

Date Prepared: 6 March 2013

Filename: q11926

 

2. Predisposing Factors/Prevention

​Revised 15 March 2013

Risk Factors
The vast majority of lung cancers (85–90%) are associated with cigarette smoking. Preventing the onset of smoking and bringing about successful smoking cessation in current smokers will most effectively achieve primary prevention of lung cancer. Pooled evidence comparing non-smokers living with smokers indicates that second-hand smoke is associated with a 20–30% increased risk in lung cancer, after controlling for some potential biases and confounding factors.

Other risk factors for lung cancer, predominantly environmental and occupational, include exposure to radon indoors, air pollution, arsenic, asbestos, silica, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, and radon decay products. In addition, fumes from cooking stoves and biomass fires are associated with increased risk in some developing countries. Patients with head and neck cancer (excluding nasopharyngeal carcinoma) and patients with non-small cell lung cancer are at risk of developing second primary cancer in the lung because of field carcinogenesis.

A family history of lung cancer has been frequently found to be associated with lung cancer even after careful adjustment for smoking. Genome-wide association studies have identified inherited susceptibility variants for lung cancer on several chromosomal loci such as15q25 (nicotinic acetylcholine receptor subunit CHRNA5) and 6q23-25. Several additional factors have been associated with lung cancer, but the findings have not been consistent. For example, several studies have suggested that diets rich in fruits and vegetables are protective. In general, the associations between non-smoking factors and lung cancer are substantially smaller than the association between cigarette smoking and lung cancer. However, it should be noted that even if all tobacco smoke induced lung cancers were eliminated, lung cancer would still be the 6th most common cause of cancer deaths.

Prevention
Cessation of cigarette smoking would clearly prevent the majority of lung cancer. Secondary prevention by pharmacological treatment to reverse a recognizable premalignant lesion is under investigation at the British Columbia Cancer Agency. A standard approach does not exist at this time.

Tobacco Control 
Lung cancer is largely preventable as 85% of all cases are related to smoking. For children and adolescents, the focus should be on not starting smoking, whereas for adults, smoking cessation is an effective method of reducing lung cancer risk.

Over the past decade there has been an overall decline in the proportion of Canadians over age 12 who smokes (from 25% to 17%) with the lowest rate in British Columbia although rates for women have leveled off (stopped declining) since 2006. The Northern Health Region has consistently higher smoking rates than other health regions in BC and not surprising the poorest lung cancer outcome.

Percentage of Population (age ≥ 12) who Reported Smoking Cigarettes Every Day, Over Time by Health Regions





Physicians and other health care professionals can help to reduce cigarette smoking and lung cancer in the following ways.

a)

Set an example by not smoking.

b)

Display and promote "anti-smoking" information.

c)

Take a careful smoking history on all patients and counsel smoking patients to stop even if they are well. Physician counseling is one of the most effective interventions.

d)

Be familiar with the methods and pharmacology of nicotine replacement therapies, Buproprion (Zyban) and Varenicline (Champix) as an adjunct to counseling.

e)

Inform the patient how to access government subsidy for smoking cessation drugs by phoning HealthLink BC at 8-1-1 to register for the BC Smoking Cessation Program. Patients have a choice of obtaining nicotine patches or gum through a community pharmacy or through direct mail distribution from the government. Buprobion and varenicline up to 12 weeks are covered under Fair PharmaCare, and Plans B, C and G

f)

Be aware of the non-smoking advice and programs available through the Canadian Cancer Society, British Columbia Lung Association and the British Columbia Medical Association. (http://www.lung.ca)

g)

Assist those who are promoting legislation to restrict all cigarette advertising and increase tobacco taxes.

h)

Be aware of industrial and environmental hazards, which may be related to lung cancer.

The Cancer Risk Management Model developed by the Canadian Partnership Against Cancer shows that if Canadian smoking rates dropped from 21% to 10%, by 2030 an estimated 58,000 new cases of lung cancer could be avoided.


As well, an estimated 46,000 deaths from lung cancer could be avoided in Canada. These projections point to the importance of tobacco control in reducing the societal burden due to lung cancer.


Key References:

  1. Canadian Cancer Society/National Cancer Institute of Canada. Canadian Cancer Statistics 2011. Toronto, ON: CCS/NCIC; 2011

  2. World Health Organization. Research for international tobacco control. WHO report on the global tobacco epidemic, 2008: the MPOWER package. Geneva, Switzerland: World Health Organization; 2008.

  3. Surveillance and Risk Assessment Division, CCDPC, Public Health Agency of Canada; Statistics Canada; Canadian Council of Cancer Registries. Cancer surveillance on-line. Available from: http://dsol-smed.phac-aspc.gc.ca/dsol-smed/.

  4. Coleman MP, Forman D, Bryant H, et al. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet. 2011;377(9760):127–38.

  5. United States Department of Health and Human Services, Office of the Surgeon General. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2006.

  6. International Agency for Research on Cancer. Tobacco Smoke and Involuntary Smoking. Lyon, France: World Health Organization; 2004. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 83.

  7. Tammemagi MC, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction – prostate, lung, colorectal and ovarian cancer screening trial models and validation. J Natl Cancer Inst. 2011;103(13):1058-68.

  8. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008;452(7187):633–7.

  9. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40(5):616–22.

  10. Thorgeirsson TE, Geller F, Sulem P, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452(7187):638–42.

  11. Bailey- Wilson JE, Amos CI, Pinney SM, Petersen GM, de Andrade M, Wiest JS, et al. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet. 2004;75(3):460-74.

3. Screening / Early Detection

​Revised 15 March 2013

The current evidence regarding lung cancer screening using LDCT is recently reviewed by the Canadian Partnership Against Cancer Anticipatory Science Expert Panel. The document is designed to assist health professionals and policy-makers make an informed decision on lung cancer screening in Canada. The key issues are summarized below:

The National Lung Screening Trial (NLST) conducted by the U.S. National Cancer Institute is the first randomized trial of adequate sample size and follow-up to evaluate the efficacy of low dose computed tomography (LDCT) screening to reduce lung cancer mortality in heavy smokers. 53,454 current and former smokers between 55 and 74 years of age with a cigarette smoking history of 30 or more pack-years were randomized to receive a LDCT or chest-X-ray at study entry and annually for two years. Former smokers had to quit smoking within the 15 years prior to study entry. Those with treatment for cancer in the five years before eligibility assessment except non-melanoma skin cancer, history of lung cancer, history of removal of part of the lung (excluding needle biopsy), need for home oxygen supplementation, explained weight loss of more than 15 pounds in the last 12 months, recent hemoptysis, pneumonia or acute respiratory infection treated with antibiotics in the 12 weeks prior to eligibility assessment were excluded from the study. The trial found a shift to earlier stages and a significant 20% reduction in lung cancer mortality with LDCT compared to chest x-ray. There was also a 6.7% reduction in all cause mortality.

The Prostate, Lung, Colorectal, Ovarian (PLCO) trial published shortly after the NLST trial, provides good evidence that Chest X-ray is not effective for lung cancer screening, when compared to no screening. An analysis of only the participants with characteristics that matched eligibility for the National Lung Screening Trial (NLST) also found no significant impact of Chest X-ray screening compared to no screening. Since chest X-ray is not an effective screening test, it is likely that screening with LDCT is efficacious over no screening in high-risk heavy smokers similar to the NLST inclusion criteria.

Aside from NLST, the only large scale randomized trial is the NELSON trial (a Dutch acronym for a Dutch-Belgium lung cancer screening trial) comparing LDCT with no screening. Participants between 50 and 75 years of age, a smoking history of >15 cigarettes/day over 25 years or >10 cigarettes/day over 30 years underwent LDCT screening at baseline, 1 year later (second round), 3 years later (third round) and 5.5 years later (fourth round) or no screening. The study excluded persons who were unable to climb two flights of stairs; had a body weight of 140 kilograms or more; had a history of renal cancer, melanoma or breast cancer; had a history of lung cancer diagnosed less than five years ago; or had received a chest LDCT scan for any reason less than one year prior to enrolment. A total of 15,428 participants have been randomized. When the NELSON participants are pooled with the Danish Randomized Lung Cancer CT Screening Trial (DLCST) involving 4,104 participants, the trial is expected to have 80% power to show a lung cancer mortality reduction of ≥25%, 10 years after randomization. The NELSON trial was launched in April 2004. Recruitment was completed in October 2005. The DLCST enrolment and randomization ran from October 2004 to March 2006. The results of these trials are anticipated around 2015 – 2016.

Although the NLST results are encouraging, it should be recognized that lung cancer screening is a process, not a single event. It requires the use of tests to detect unrecognized cancer to permit timely intervention. For screening to demonstrate effectiveness at a population level, the screening test must be applied systematically on a large scale to distinguish between those apparently unaffected from those who may have lung cancer. A screening test is not intended to be diagnostic. The test results require confirmation through definitive diagnostic tests, followed by treatment of confirmed cases. Screening can only be effective if effective treatment is available for the disease revealed by screening. The potential benefits of screening must be balanced against possible harms of screening tests such as downstream investigations or therapeutic intervention for suspicious pulmonary lesions that turn out to be non-malignant. Such lesions are several times more frequent than true cancers. Implementation of lung cancer screening at the population level would require coordinated and specialized multi-disciplinary professional expertise to ensure the benefits of screening are maximized while the potential risks are minimized. For example, population penetration strategies for large-scale screening would have to be developed. As well, there would be a need for radiologists skilled in interpretation of lung cancer screening LDCT scans, biopsy and localization of small lung nodules; respirologists and thoracic surgeons experienced in management of lung nodules; interventional pulmonologists skilled in diagnosis of peripheral lung lesions and staging of lung cancer using endoscopic ultrasound; thoracic surgeons knowledgeable in staging, resection techniques and treatment methods; and pathologists experienced with interpretation of small biopsy specimens. The development of screening would need to be accompanied by a parallel process of quality assurance including radiologists, medical technologists, medical physicists, picture archiving and communications specialists as well as external evaluators.

Considerable expertise has been developed in BCCA and Vancouver Coastal Health over the last decade through support from the US NCI, the Terry Fox Research Institute and the Canadian Partnership Against Cancer (CPAC) to define the optimal population for screening as well as the management pathway of screen detected lung nodules using a novel lung nodule malignancy potential prediction model and calculator. A Canadian Lung Cancer Screening Network has been established by CPAC to develop Canadian guidelines for radiology, clinical work-up pathway for abnormal CT, pathology reporting, recommendations for surgical and therapeutic interventions and integration of smoking cessation practices. Before lung cancer screening can be adopted at the provincial level, it needs to be introduced in stages to ensure that adequate infrastructure is available as well as a robust program of quality assurance and performance management. Until such pilot programs are introduced, the BC Cancer Agency Lung Tumor Group advises against ad hoc/opportunistic screening by physicians. Ad hoc screening can cause net harm if performed on patients who have only a low risk of lung cancer and therefore low probability of benefit. The patient may receive a full dose/contrast enhanced CT instead of LDCT and hence significantly higher radiation exposure. Lack of expertise in interpreting screening CT can result in both false negative and false positive findings. Non-standardized protocols regarding diagnosis & management of CT detected lung nodules can also lead to unnecessary repeat imaging procedures, invasive diagnostic procedures or surgery with their associated potential for morbidity or even mortality.

Key References:

1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. June 29, 2011; 365:395-409.

2. Oken MM, Hocking WG, Kvale PA et al. Screening by chest radiograph and lung cancer mortality. The Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial. JAMA. 2011;306(17):doi:10.1001/jama.2011.1591.

3. van Iersel CA, de Koning HJ, Draisma G, et al. Risk-based selection from the general population in a screening trial: selection criteria, recruitment and power for the Dutch-Belgian randomised lung cancer multi-slice CT screening trial (NELSON). Int J Cancer. 2007;120:868–74.

4. Pedersen JH, Ashraf H, Dirksen A, et al. The Danish randomized lung cancer CT screening trial—overall design and results of the prevalence round. J Thorac Oncology. 2009;4:608–14.

5. van Klaveren RJ, Oudkerk M, Prokop M, Scholten et al. Management of Lung Nodules Detected by Volume CT Scanning. N Engl J Med 2009;361:2221-9.

6. Tammemagi M, Hormuzd K, Hocking W, et al. Selection Criteria for Lung-Cancer Screening. N Engl J Med, 2013;368:728-36

7. Tammemagi MC, Lam S, McWilliams A, Sin DD. Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction. Cancer Prev Res 2011; 4(4):552-61.

4. Diagnosis

1 Histologic Classification of Lung Tumours

Most lung cancers arise from the bronchial walls rather than the lung alveoli parenchyma. Approximately 80% of lung cancer cases have non-small cell (NSCLC) pathology and 20% have small cell carcinoma (SCLC). Currently, about 40% of NSCLC cases are adenocarcinoma subtypes and about 40% are squamous tumours. The remaining NSCLC cases have large cell anaplastic, less common subtypes and carcinoma NOS. For management decisions, NSCLC including squamous (epidermoid), adenocarcinoma and large cell anaplastic carcinoma are considered together.

Small cell carcinoma includes classic "oat cell" and intermediate size subtypes. There are no convincing clinical data to support treating classic or "oat cell" subtype of small cell carcinoma different than the intermediate subtype. Combined small cell and NSCLC is commonly managed with the SCLC treatment paradigm but non-small cell pathological elements are associated with greater treatment resistance and less durable remissions.

The World Health Organisation's histologic classification of carcinoma of the lung is as follows:

  1. Dysplasia, carcinoma in situ
  2. Squamous cell carcinoma
  3. Small cell carcinoma
    1. Small cell carcinoma 
    2. Intermediate cell type carcinoma
    3. Combined small cell carcinoma
  4. Adenocarcinoma
    1. Acinar adenocarcinoma 
    2. Papillary adenocarcinoma 
    3. Bronchiolo-alveolar carcinoma
    4. Solid carcinoma with mucus formation
  5. Large cell carcinoma 
  6. Adenosquamous carcinoma 
  7. Carcinoid tumour
    1. Classic carcinoid
    2. Atypical carcinoid
  8. Bronchial gland carcinomas
  9. Others

Key References 

  1. Colby TV, Koss MN, Travis WD. Atlas of Tumor Pathology: Tumors of the Lower Respiratory Tract. Armed Forces Institute of Pathology, Washington DC, 1994  

  2. Travis TV, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histologic and graphical text slides for the histologic typing of lung and pleural tumors. In: World Health Organisation Pathology Panel: World Health Organization. International Histological Classification of Tumors. 3rd ed. Springer Verlag, Berlin, 1999 (page 5).

2 Diagnostic Pathology

Definitive Diagnosis of Lung Cancer

A full history and physical examination should precede any investigation. Because clinical lung cancers are sometimes shown to be a benign process and because of the difference in treatment for non-small cell and small cell lung cancer, histological or cytological verification of the diagnosis should be obtained.

Diagnostic procedures should be tailored to the individual patient and may include: 

  1. Review of old chest X-rays to exclude a long-standing benign lesion or determine the rate of progression of a malignant lesion.  
  2. Sputum cytology: three early morning specimens of sputum should be collected in seventy percent alcohol; post-bronchoscopy cytology when the patient is coughing vigorously, may be helpful.  
  3. Bronchoscopy, biopsy of endobronchial lesions, brushings and washings, post-bronchoscopy sputum cytology.  
  4. Mediastinoscopy: to exclude inoperable metastases in mediastinal lymph nodes.  
  5. Percutaneous fine needle biopsy in selected cases.  
  6. Excisional or needle biopsy of readily accessible secondary deposits

Once the diagnosis of non-small cell lung carcinoma has been established, steps are taken to stage clinically and assess the patient for operability. Small-cell lung carcinoma has considerably different staging, treatment and prognostic characteristics from non-small cell lung carcinoma and will be discussed in a later section (5.3.2).

Pathological Evaluation of Resection Specimens
The specimen should be received fresh. Frozen sections of the planned bronchial margin and nodes at this site may be requested. The specimen is inflated with fixative (either endobronchially or via a large bore needle inserted trans-pleurally into each segment) and allowed to fix in the inflated state overnight. Complete slices are then made in the fixed specimen in the desired plane to correspond to a P-A or lateral chest X-ray or CT scan.

Assessment of T Status 

Peripheral tumour 

  1. Tumour size in three dimensions is noted.  
  2. Segment location and distance from pleura is noted.  
  3. Presence of adherent parietal pleural or pericardium is noted.

Central tumour 

  1. Tumour size in three dimensions is noted.  
  2. Location of the involved bronchus, gross depth of invasion, degree of luminal occlusion, distance from pleura are all noted.

Assessment of N Status 
In a pneumonectomy specimen, the nodes around the main bronchus are N2 nodes and should be assessed separately. In all specimens, the nodal station of grossly positive nodes should be specified.

Minimum Sections 

  1. Bronchial resection margin.  
  2. Three or four sections of tumour to include its relationship to pleura and/or parent bronchus; for peripheral tumours less than 3 cm, the entire pleural-tumour interface should be processed.  
  3. Lymph nodes from around the bronchial resection margin should be submitted separately from other nodal tissue.  
  4. The presence of grossly positive nodes must be verified histologically.  
  5. If no grossly positive nodes are identified, all nodal tissue should be processed to exclude microscopic metastases.

5. Staging


​Revised 6 July 2012 

Staging Diagram 

5.1 Classification Criteria for Non Small Cell Lung Cancer

The staging definitions (UICC, TNM, 7th edition) and stage groups are as follows:

T (Tumour) Definitions

T1

Tumor ≤3 cm diameter, surrounded by lung or visceral pleura, without invasion more proximal than lobar bronchus

T1a

Tumor ≤2 cm in diameter

T1b

Tumor >2 cm but ≤3 cm in diameter

T2

Tumor >3 cm but ≤7 cm, or tumor with any of the following features:

 

Involves main bronchus, ≥2 cm distal to carina

 

Invades visceral pleura

 

Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a

Tumor >3 cm but ≤5 cm

T2b

Tumor >5 cm but ≤7 cm

T3

Tumor >7 cm or any of the following:

 

Directly invades any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, main bronchus <2 cm from carina (without involvement of carina)

 

Atelectasis or obstructive pneumonitis of the entire lung

 

Separate tumor nodules in the same lobe

T4

Tumor of any size that invades the mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or with separate tumor nodules in a different ipsilateral lobe

 

N (Node) Definitions

NX

Regional lymph nodes cannot be assessed.

N0

No regional lymph node metastases

N1

Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3

Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

 

M (Metastasis) Definitions

MX

Presence of distant metastasis cannot be assessed.

M0

No known distant metastasis.

M1

Distant metastasis present.

M1a

Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural or pericardial effusion

M1b

Distant metastasis (in extrathoracic organs)

  • *The uncommon superficial tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus is also classified as T1.
  • **Most pleural effusions associated with lung cancer are due to tumour. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid show no tumor. In these cases, the fluid is non-bloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as T1, T2, T3, or T4. Pericardial effusion is classified according to the same rules.
  • The letter P is used to denote classification which is determined histologically after resection. A staging diagram to assist in classification of individual nodes is appended.

 

Stage Groupings:TNM Subsets*

Occult carcinoma:

TX

NO

MO

Stage 0:

TIS

N0

M0

Stage IA

T1a-T1b

N0

M0

Stage IB

T2a

N0

M0

Stage IIA

T1a,T1b,T2a

N1

M0

 

T2b

N0

M0

Stage IIB

T2b

N1

M0

 

T3

N0

M0

Stage IIIA

T1a,T1b,T2a,T2b

N2

M0

 

T3

N1,N2

M0

 

T4

N0,N1

M0

Stage IIIB

T4

N2

M0

 

Any T

N3

M0

Stage IV

Any T

Any N

M1a or M1b

Reference:

Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest 2009; 136(1) 26-71.

5.2 Staging Definitions for Small Cell Lung Cancer (SCLS)

SCLC grows and spreads quickly. It is important to recognise this tumour because it responds readily to both chemotherapy and radiotherapy and in some cases can be cured with appropriate treatment. The Veterans Administration Lung Group system divides SCLC patients into either limited or extensive stages. More recently some cooperative groups have supported to use the TNM staging to define disease. In B.C. practice is still to define as limited or extensive.

Using current staging procedures, 30-40% of SCLC patients have limited stage SCLC. Defining limited versus extensive is important as it impacts treatment and helps predict prognosis. Limited SCLC patients fit enough to receive combined modality therapy are treated with curative inten​t. Extensive stage SCLC patients are generally treated with palliative intent. After the diagnosis of SCLC, accurate staging should be completed as expediently as possible.

Limited Stage Small Cell Lung Cancer

The original operational definition of limited disease was tumour quantity and configuration that could be encompassed by a "reasonable" radiotherapy treatment volume including the primary tumour site and the adjacent hilar, mediastinal and ipsilateral supraclavicular lymph nodes. The presence of massive intrathoracic tumour may preclude a "reasonable" thoracic radiotherapy volume and allow palliative therapy only.

Extensive Stage Small Cell Lung Cancer

Disease beyond the limited stage criteria is defined as extensive stage. Patients with "regional" extensive stage disease (pleural effusion, contralateral supraclavicular nodes or cervical lymph nodes) have a prognosis that is intermediate between limited and extensive and may benefit from a limited stage type treatment plan.

References:

Zelen M. Keynote address on biostatistics and data retrieval, part 3, Cancer Chemo Rep 1973;4(2):31.

Argiris A, Murren JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J. 2001;7(5):437.

Stahel RThatcher NFrüh MLe Péchoux CPostmus PESorensen JBFelip EPanel members.1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer.Ann Oncol. 2011 Sep;22(9):1973-80. Epub 2011 Jul 4.

van Meerbeeck JPFennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1741-55. Epub 2011 May 10.

Investigations for Staging

Revised 6 July 2012

1 Non-Small Cell Lung Cancer 

Diagnostic Evaluation of Patients with Non-small Cell Lung Cancer

A variety of tools assist in the diagnostic evaluation of patients with lung cancer. These tools, when used in conjunction with the history, physical examination and chemistry panel, help determine the patient's cancer stage, prognosis and treatment options according to stage. Aside from a general history and physical it is useful to question regarding overall respiratory function and exercise tolerance, symptoms related to local tumour spread (dysphagia, hoarseness, shortness of breath, facial swelling) and systemic symptoms or symptoms suggestive of paraneoplastic syndromes.

1a. Assessment of the Primary Intrathoracic Extent of Disease Clinical Considerations 

Diagnostic Imaging

Chest x-rays alone are inadequate for staging although they provide initial information on the presence of lung mass and temporal changes in size.

Computed tomography (CT) of the mediastinum with infusion of contrast material is recommended to stage locoregional disease. The CT scan should extend inferiorly to include the liver and the adrenal glands. CT scans are used to characterize the primary tumour. CT scans detect enlarged nodes but have inadequate sensitivity and specificity and thus should be supplemented by mediastinoscopy. A major role of CT is to aid in decisions regarding respectability and to detect synchronous/metastatic cancers that are not visible on the chest radiograph.

Magnetic Resonance Imaging (MRI) is not superior to CT scans for staging of mediastinal nodes but may be of value in selected cases (Pancoast tumours) for assessment of the operability of the primary tumour.

Positron emission tomography (PET) scanning is a newer technology that is not widely available throughout B.C. PET does not aid in accurate staging for T stage. PET is more sensitive and specific then CT in radiologic detection of malignant lymph nodes yet there is still a high false positive rate and there are multiple benign reasons that lymph nodes may be PET positive. As a result PET may not be considered definitive proof of a positive lymph node and definitive biopsy would be recommended. The role of PET in the routine staging of lung cancer has not been established but preliminary reports indicate that it may be useful in selected cases. In B.C. current indications for PET include:

  1. Staging of patients with clinical stage I and IIA lesions being treated with curative intent.
  2. Staging of potentially resectable stage IIB and III disease.
  3. To aid in planning of radical radiotherapy.
  4. Staging prior to resection of solitary lung metastases.

NOTE: No definite indications exist for bronchial carcinoid or small cell lung cancer.

Mediastinoscopy
For patients with clinically operable NSCLC, biopsy is recommended of mediastinal lymph nodes found on chest CT scan to be greater than 1.0 cm in shortest transverse axis.

Mediastinoscopic evidence of metastases to N3 lymph nodes indicates inoperability (Stage IIIB). Mediastinoscopic evidence of metastases to N2 position nodes also represents inoperability in the majority of circumstances. However it is among this group of patients that the surgeon may identify selected ipsilateral nodal metastases that may be suitable for combined modality therapy possibly including resection (see section 6​).

Clinical Considerations

Ipsilateral vocal cord paralysis generally indicates dysfunction of the recurrent laryngeal nerve by pressure or involvement by tumour involving mediastinal nodes; this is a criterion of in-operability.

Similarly, Horner's Syndrome, phrenic nerve palsy and neurologic deficits associated with Pancoast's superior sulcus tumors usually indicate inoperable disease

Splaying of the tracheal carina may indicate subcarinal involvement and contralateral subcarinal node metastases are evidence of in-operability and should be confirmed by needle biopsy or mediastinoscopy.

Assessment of Pleural Effusions

If a pleural effusion is present, all efforts must be made to determine whether it is malignant or benign. Useful investigations include pleural fluid cytology, pleural biopsy, and thoracoscopy. A benign effusion has no independent significance in staging, whereas a malignant effusion indicates T4 status and in-operability (see footnotes to staging classification criteria).

1b. Screening for Extrathoracic Metastatic Disease 

The most common extrathoracic metastatic sites for lung cancer are supraclavicular lymph nodes, brain, bone, adrenals and liver. History and physical examination should focus on these sites. A search for metastatic disease in an asymptomatic patient with advanced NSCLC should be based on the evidence outlined below, with the understanding that the likelihood of finding metastasis increases with increasing T and N status, particularly in patients with non-squamous pathological subtypes.

Serum Chemistry 
Initial serum chemistry should routinely include serum calcium and serum albumin. Anorexia, nausea and vomiting and other gastrointestinal symptoms suggest hypercalcemia. Alkaline phosphatase, LDH and SGOT help to assess liver function and possible presence of liver metastases and bone metastases. CEA, if elevated, is a useful tumour marker for assessment of treatment for patients with index lesions that are difficult to evaluate (e.g. bone metastases).

Brain Metastases 
There is a very high incidence of detectable metastases in patients with specific neurologic complaints (focal seizures, focal weakness) and CT confirmation is advised in such patients. There is a twenty-five to thirty percent incidence of detectable metastases in patients with non-specific neurologic complaints (headache, personality change, dementia). Asymptomatic patients with bulky primary or extensive nodal involvement with non-squamous carcinomas have a 0% to 10% probability of brain metastases.

CT brain screening is not recommended for asymptomatic patients receiving treatment with palliative intent but such assessment should be considered in locally advanced cases where radical curative intent therapy is planned.

CT scanning with infusion of contrast material is the routine assessment in suspect cases. MRI is more sensitive than CT scanning, and should be considered in cases where suspicion persists after a normal or equivocal CT scan. MRI may also be useful to delineate if there is a solitary lesion or multiple lesions which may affect surgical and radiation planning.

Bone Metastases 
Bone scans are not recommended unless the patient has bone pain, chest pain or elevation of serum calcium and/or alkaline phosphatase. Clinical correlation with trauma and arthritis is necessary.

Adrenal Metastases

The adrenal glands are abnormal by CT scan in ten percent of patients with lung cancer. It is technically easy and cost effective to include the adrenal glands routinely in the chest CT scan and this procedure is recommended. The finding of an isolated adrenal mass on ultrasonographic or CT examination requires biopsy to rule out metastatic disease if the patient is otherwise considered to be potentially resectable. PET scanning may be useful in select circumstances.

Liver
It is not common for the liver to harbour detectable metastases in the absence of liver enzyme abnormalities. Nevertheless, as is the case for the adrenal glands, the extended chest CT scan and ultrasound can accurately assess the liver. Malignancy should be confirmed in an isolated hepatic mass if the patient is otherwise considered to be potentially resectable.  

1c. General Tests for Pre-treatment Evaluation

Pulmonary Function Evaluation 
The general fitness of the patient is important since a relatively fit young patient may have a good post-treatment exercise tolerance despite poor lung function. Patients with chronic obstructive lung disease and consequent reduced pulmonary function tests will have more postoperative complications with greater need for pulmonary ventilation. Pulmonary function can improve after poorly ventilated or perfused lung is removed.

The measurement of preoperative lung function is intended to predict the patient's post-treatment pulmonary status. Spirometric examination and arterial blood gases while the patient breathes room air are minimum investigations for proper planning.

Key References:

1. Silvestri, GA, Gould, MK, Margolis, ML, et al. Noninvasive Staging of Non-small Cell Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition). Chest 2007: 132:178S.

2. Vansteenkiste JF, Stroobants SS. PET scan in lung cancer: current recommendations and innovation. J Thorac Oncol. 2006;1(1):71.

3. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. Adopted on May 16, 1997 by the American Society of Clinical Oncology. JCO. 1997 Aug;15(8):2996-3018.

2 Small Cell Lung Cancer Staging Procedures

Because the intent (curative versus palliative) and structure of treatment for SCLC is determined by the extent of disease, accurate and expedient staging is crucial.

Clinical Assessment 
Small cell lung cancer is metastatic outside the chest in 60% of cases. Common sites of extrathoracic spread include the supraclavicular and cervical lymph nodes, liver, adrenals, bones, brain and subcutaneous sites. Careful history and physical examination are the most important staging procedures.

Assessment of Intrathoracic Disease 
Chest radiograph and computed tomography (CT) of the mediastinum with infusion of contrast material is recommended to stage locoregional disease. The CT scan should extend inferiorly to include the liver and the adrenal glands.

Pleural effusions in SCLC are presumed to be malignant if they are readily visible on the routine chest radiograph. Pleural effusions seen on the CT scan but not evident on the chest radiograph are of uncertain significance and for treatment purposes, the patient should be considered to have limited stage disease. Although a definite effusion is technically evidence of extensive stage disease, if pleural effusion or pericardial effusion is the only site of metastatic spread, patients should be considered for early integrated chemoradiation if the pleural effusion readily responds to systemic chemotherapy.

Blood Tests
Initial blood work should include CBC, electrolytes, calcium, alkaline phosphatase, SGOT, LDH, serum albumin, BUN, and creatinine. Serum LDH is an independent prognostic factor in both limited and extensive stage SCLC. Approximately 5% of SCLC patients will present with hyponatremia secondary to inappropriate secretion of antidiuretic hormone. Hypercalcemia is uncommon with pure SCLC and should prompt careful review of pathology to exclude a non-small cell component. Ectopic secretion of ACTH is present in only 1-2% of cases and is usually associated with hypertension, hypernatremia and hypokalemia. CEA is elevated in about half of extensive stage SCLC patients and it may be useful to assess chemotherapy response in cases that do not have easily measurable lesions.

CNS Metastases
CT assessment of the brain should be routine for all patients with suspicious neurological

symptoms. CT screening of the brain is recommended for asymptomatic patients that are intended to receive integrated chemoradiation with curative intent. Brain scanning is not mandatory for asymptomatic patients that already have documented extensive stage disease that precludes treatment with curative intent.

Bone Metastases 
Radionuclide bone scans are recommended for symptomatic patients and asymptomatic patients intended for combined modality therapy with curative intent. Clinical correlation with trauma and arthritis is necessary. An equivocal bone scan should not preclude combined modality therapy in a patient that otherwise has limited stage SCLC.

Bone marrow biopsy is no longer routinely performed as a staging procedure for small cell lung cancer. Bone marrow aspiration and biopsy is positive for tumour involvement in <5% of patients who have limited disease on all imaging procedures. Bone marrow biopsy may be considered for patients that have negative clinical assessment and staging procedures but extensive stage disease continues to be highly suspect because of poor performance status, weight loss, abnormal LDH or abnormalities of the CBC (anemia or leukoerythroblastic changes on the peripheral smear).

Liver and Adrenal 
The CT scan used for assessment of thoracic disease should include the liver and adrenal glands. The finding of an isolated mass on ultrasonographic or CT examination requires biopsy to rule out metastatic disease if the patient is otherwise considered a candidate for combined modality therapy with curative intent. Ultrasound of the abdomen is accepted as an alternative to CT scanning for staging of the upper abdomen.

Pulmonary Function Evaluation
Patients receiving integrated chemotherapy and thoracic irradiation for limited stage small cell lung cancer must have adequate pulmonary reserve. As a rough generalisation, pulmonary function loss associated with thoracic irradiation for SCLC is similar to the loss from surgical lobectomy.

The measurement of lung function is intended to predict the patient's post-treatment pulmonary status. Spirometric examination and arterial blood gases should be obtained in all patients where adequate pulmonary reserve is uncertain. A FEV 1 of 0.8 to 1.0 litre is the minimum acceptable function for most patients after thoracic irradiation.

Key References:

  1. Argiris A, Murren JR. Staging and clinical prognostic factors for small-cell lung cancer. Cancer J. 2001;7(5):437.

  2. van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lan​cet. 2011 Nov 12;378(9804):1741-55. Epub 2011 May 10.

  3. Richardson G, Venzon D, Phelps R, et al. Application of an algorithm for staging small cell lung cancer can save one third of the initial evaluation costs. Arch Intern Med 1993;153:329.

  4. Shepherd FA. Screening, diagnosis and staging of lung cancer. Curr Opin Oncol 1993;5:310.

6. Management


​The Lung Tumour Group of the BC Cancer Agency is a multi-disciplinary committee charged with the development of management policy for lung cancer, mesothelioma and thymoma. This policy results from the deliberations of the group that include literature review of published practice guidelines, experience with prior policy with outcome analysis where possible, and results of clinical trials performed at BCCA or in co-operation with communities oncology investigators and other cancer centres. It is recognized that management of the individual patient must take into consideration such additional factors as ability to withstand the proposed therapy.

The Lung Tumour Group is committed to the improvement of the results of cancer treatment by participation in a broad clinical research effort. Practitioners with a special interest in lung cancer are encouraged to become a member of the International Association for the Study of Lung Cancer (IASLC). Detailed protocols are available on the internet. Investigational trials are often complex and frequently change. It is recommended that the principal investigator be contacted directly regarding patients who may be eligible.

Careful documentation before, during, and after treatment is an integral component of clinical research. Problematic toxicity, cancer relapse and patient death (from any cause) are particularly important. The participation of the patient's referring and family physician in this process is essential and appreciated.

Levels of Evidence 

  1. Evidence obtained from meta-analysis of multiple, well-designed, controlled studies. Randomized trials with low false-positive and low false-negative errors (high power).  
  2. Evidence obtained from at least one well-designed experimental study. Randomized trials with high false-positive and/or negative errors (low power).  
  3. Evidence obtained from well-designed, quasi-experimental studies such as non-randomized, controlled single-group, pre-post, cohort, time, or matched case-control series.  
  4. Evidence from well-designed, non-experimental studies such as comparative and correlational descriptive and case studies.  
  5. Evidence from case reports and clinical examples.

Grades of Recommendations 

  1. There is evidence of type I or consistent findings from multiple studies of types II III, or IV.  
  2. There is evidence of types II, III, or IV and findings are generally consistent.  
  3. There is evidence of types II, III or IV but findings are inconsistent.  
  4. There is little or no systematic empirical evidence.

Key References:

  1. Sackett DL: Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 95:2S-4S, 1989 (suppl 2)  

  2. Cook DL, Guyatt GH, Laupacis A, et al: Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 102:S305-S311, 1992 (suppl 4)

6.1 Non-Small Cell Lung Cancer (NSCLC)

Updated July 17, 2014

Please see the content listing at the top of the Management section​: from 01 to 16.

1. Resectable NSCLC

Updated February 2008 

Approximately one third of NSCLC patients have clinically operable disease.

Guideline: For patients with clinically operable NSCLC, surgical resection is the treatment with the best potential for cure.

Level of Evidence: III

Grade of Recommendation: B

The development of consistent criteria for resectability has proven elusive, as the assessment is influenced by surgical judgement. Patients with stage I or II NSCLC are routinely resected. However, only selected patients with stage IIIA, disease are resectable, especially those with T3N0M0 disease; patients with bulky N2 disease are generally not resectable. Almost all patients with stages IIIB and IV disease are unresectable. Exceptions would include highly selected patients with T4 disease (e.g., those found with limited invasion of the vertebral body, carina, great vessels, esophagus, or atrium; a satellite lesion in the same lobe) but without N2-3 disease. Rarely, a carefully selected patient with a solitary brain metastasis and a stage I to II primary lung tumor will be considered for resection. Patients with malignant pleural effusions are unresectable and are not appropriate candidates for curative treatment.

2. Surgical Treatment of Stage I-IIIA

​Updated Feb. 2008

The majority of patients with a normal mediastinum at mediastinoscopy and negative metastatic work-up preoperatively prove to be resectable at the time of thoracotomy. Occasionally intraoperative findings deem the patient unresectable. These findings include unsuspected pleural metastases, invasion of the heart, great vessels, or esophagus.

At thoracotomy, all important node stations must be sampled and labeled in accordance with the IASLC/UICC staging diagram. Lymph nodes at the planned resection margin, including the bronchial resection margin, should be assessed by intraoperative frozen section if there is a question of obtaining a clear margin.

Stage I

Standard lobectomy is the treatment of choice for Stage I lung cancer. Occasionally, pneumonectomy may be required because of extension of tumour across the fissure. Sleeve lobectomy may be performed in selected patients who have limited lung function with superficial tumour extension to a main bronchus or lower trachea,, thus avoiding pneumonectomy. Sleeve resection should be avoided in patients with N1 nodal disease. Segmental or wedge resection may be performed for small peripheral T1N0 lesions in patients with limited lung function, however, lobectomy is the preferred treatment of choice for patients with satisfactory pulmonary reserve.

Key Reference:

  1. Ginsberg RJ, Rubenstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small-cell lung cancer. Ann Thorac Surg 1995;60;615-23

Stage II

Standard lobectomy is performed if technically feasible however, pneumonectomy may be necessary if the cancer is central, involving the hilum, or involving intralobar location 11 lymph nodes.

Stage IIIA

Extended pulmonary resection may be performed for potential cure in selected lesions. These include peripheral lesions invading chest wall, apical lung carcinomas, central lesions with limited mediastinal invasion, or focal pericardial or phrenic nerve invasion. Tumours within 2 cm of the carina, or carinal tumours occasionally may be amenable to resection with airway reconstruction. Extended resection is indicated for selected patients with positive N2 nodes. Stage IIIA cases where resectability is uncertain should be considered for combined modality therapy (see 6.1.6).

Key References:

  1. Feins RH: Surgery for early-stage non-small-cell lung cancer. Semin Oncol 1997; 24:419-422

  2. Warren WH, Faber LP. Extended resections for locally advanced pulmonary carcinomas. Lung Cancer: Principles and Practice. Pass H, Mitchell J, Johnson D, Turrisi A Eds. Lippincott-Raven, Philadelphia, 1996;567.

3. Adjuvant Radical Radiotherapy Following Surgical Resection

​Updated December 2013

Recommendation: Post-operative adjuvant radiotherapy should not be used after complete resection of Stage I or II NSCLC, due to an increased risk of non-cancer deaths. There is lower-level evidence that adjuvant post-operative radiotherapy may confer some survival benefit to patients with Stage III NSCLC after complete resection. Radiotherapy after complete resection decreases local recurrence in all stages.

Amongst patients with positive bronchial resection margins, postoperative adjuvant radiotherapy will decrease the chance of local recurrence. Those with macroscopically positive resection margins are less apt to benefit from adjuvant radiotherapy because of generally poorer results for these patients.

Discussion:

For patients with complete resection of Stage I or II lung cancers post-operative radiation is not recommended due to a suggestion of non-cancer deaths. Many studies show lower recurrence rates yet no effect or a detrimental effect of radiation on overall survival. More recent studies of smaller field radiation and modern radiation planning techniques have demonstrated small gains in overall survival yet these series are limited.

In the case of positive resection margins in early stage lung cancer, patients should be referred for a discussion regarding the merits of radiation. Factors to consider include the stage of the disease, the location of the margin, the patients overall health and respiratory status.

There is evidence from randomized controlled trials that post-operative radiotherapy (PORT) reduces local recurrence by 11% to 18% (or 1.6-19 fold) in patients with completely resected, pathologic stage II and IIIA NSCLC. Data from several RCT and the PORT meta-analysis show that non-cancer deaths are increased in those treated with PORT after complete resection of Stage I and II NSCLC. This increase in non-cancer deaths was not seen amongst Stage III NSCLC patients who had complete resection, and some studies showed a trend towards a survival advantage to PORT in those patients. There is a suggestion that older radiation therapy techniques may have impacted the benefits of PORT. A recent review of the SEER database and ANITA trial suggest that patients with N2 disease are most likely to benefit from PORT. Thus treatment may be considered in the following circumstances:

  1. Microscopic involvement of the resection margin, including bronchial resection margin.
  2. Limited involvement of completely resected N2 nodal stations, particularly in a young, fit patient with significant extra nodal extension.
  3. Infiltration of the chest wall in a patient who did not receive pre-operative radiotherapy.

Discussion with the Radiation Oncology service is recommended in patients with Stage III NSCLC, or incompletely resected Stage I or II NSCLC patients.

Key References:

  1. Logan DM, Lochrin CA, Darling G et al. Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group. Cancer Prevention & Control,1997;1(5):366-78.

  2. PORT metaanalysis. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998; 352; 257-63

  3. Cochrane Review. The Cochrane Library 2000, Issue 2

  4. Burdett S, Stewart L; PORT Meta-analysis Group. Postoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis.Lung Cancer 2005; 47, 81-83

  5. Dautzenberg B Arriagada RChammard AB et al, A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques. Cancer 1999 ; 86; 265-273

  6. Trodella L, Granone P, Valente S et al, Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial. Radiother Oncol 2002; 62:11-19

  7. Feng QF, Wang M, Wang LJ et al. A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):925-9.

  8. Lally BE, Zelterman D, Colasanto JM et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol. 2006;24(19):2998.

  9. Douillard JY, Rosell R, De Lena M et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys. 2008;72(3):695.

4. Post-operative Adjuvant Chemotherapy for Resected NSCLC

Updated November 2011


Guideline : There is evidence to recommend platinum-based chemotherapy regimens as post-operative adjuvant therapy in the management of patients with completely resected stage II and IIIA NSCLC. Cisplatin-based treatment is preferred, although a carboplatin-based regimen can be used as an alternative if there is a contraindication to cisplatin. There is uncertainty about a benefit to patients with resected stage IB NSCLC, although adjuvant chemotherapy may still be considered in selected individuals.

Level of Evidence: I

Grade of Recommendation: A

A meta-analysis published in 1995 indicated that post-operative chemotherapy did not significantly reduce the risk of death in surgically resected, pathologic stage IB, II and IIIA NSCLC.1 However, the trials included in this study used older chemotherapy combinations and an analysis looking specifically at regimens that included cisplatin showed a trend in favour of adjuvant chemotherapy. 

Subsequently, ECOG 3590 and ALPI failed to demonstrate any benefit from adjuvant chemotherapy.2,3 There was some concern however due to the use of post-operative radiotherapy in these trials and the negative impact this may have had on outcomes based on the Post-Operative RadioTherapy meta-analysis that suggested that radiotherapy may be detrimental in resected NSCLC. 4 IALT renewed interest in adjuvant therapy, as cisplatin-based combination chemotherapy was shown to improve relapse-free survival by 5.1%, and overall survival by 4.1% at five years.5

Data from NCIC CTG BR.10 and ANITA support a role for platinum-based combination chemotherapy as adjuvant therapy in resected NSCLC.6,7 These trials had stringent enrollment criteria and used a cisplatin and vinorelbine regimen only. NCIC CTG BR.10 enrolled patients with Stage IB and II disease whereas ANITA included Stages IB-IIIA. Both trials demonstrated an improvement in overall survival with the addition of cisplatin and vinorelbine adjuvant therapy: NCIC CTG BR.10 15% at 5 years, and ANITA 8.6% at 5 years.

A number of factors may account for the lack of benefit seen in previous trials as compared to IALT, NCIC CTG BR.10, and ANITA. These include the potentially detrimental effect of post-operative radiotherapy, the impact of newer chemotherapy agents, and the total dose of chemotherapy delivered.

IALT, NCIC CTG BR.10, and ANITA provide compelling evidence in favour of adjuvant cisplatin-based chemotherapy, although appropriate selection of patients for treatment is highlighted by the 0.8% risk in IALT of chemotherapy-related adverse events resulting in death. Both NCIC CTG BR.10 and ANITA also reported treatment-related deaths, accounting for 0.8% and 1.7% of those treated with chemotherapy, respectively.

While the majority of adjuvant trials have focused on the use of cisplatin, carboplatin has also been evaluated. The initial report of CALGB 9633 in 2004 indicated that adjuvant treatment with the combination of carboplatin and paclitaxel in resected stage IB NSCLC was associated with a 12% improvement in survival at 4 years.8 However, further follow up demonstrated only a non-significant trend in favour of treatment at 5 years. A subgroup analysis conducted of this study suggested that patients with tumors > 4 cm benefited from adjuvant therapy. It is unclear where this trial was negative because of the lower risk population (IB) or the selected chemotherapy (carboplatin-based).

The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis assessed the use of adjuvant cisplatin-based chemotherapy. This analysis confirmed the benefit of post-operative chemotherapy in Stage II and III NSCLC.

Various biomarkers have been evaluated retrospectively to identify a population for adjuvant treatment including ERCC1, MSH1, p27, p53, Bax, K-ras, EGFR, beta tubulin and gene signatures. None have been validated for clinical use and selection for adjuvant treatment using markers remains experimental.

The Lung Tumour Group recommends routine consideration of adjuvant platinum-based combination chemotherapy in patients with fully resected stage II and IIIA NSCLC, but there is uncertainty about its prescription in those with resected stage IB NSCLC. The magnitude of benefit of adjuvant therapy is likely proportional and dependent on the risk of relapse according to stage. There may be individuals with stage IB NSCLC with features associated with a risk of relapse similar to those with a higher stage of NSCLC. However, those high risk factors that might support selection for adjuvant chemotherapy have not been defined with certainty. Adjuvant chemotherapy may be offered to highly motivated individuals with resected stage IB NSCLC, but a discussion regarding the potential risks and harms of treatment is necessary.

Only chemotherapy regimens used in the most recent trials are evidence-based. The BC Cancer Agency currently views the combination of cisplatin and vinorelbine as standard, as these two agents were employed in IALT, NCIC CTG BR.10 and ANITA. Cisplatin-based treatment is preferred, but in individuals with a contraindication to cisplatin, the combination of carboplatin and paclitaxel is an acceptable alternative.

References:

  1. Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995

  2. Keller SM, Adak S, Wagner H, et al: A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group.[comment]. New England Journal of Medicine. 343:1217-22, 2000

  3. Scagliotti GV, Fossati R, Torri V, et al: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer.[comment]. Journal of the National Cancer Institute. 95:1453-61, 2003

  4. Postoperative radiotherapy for non-small cell lung cancer. PORT Meta-analysis Trialists Group. Cochrane Database Syst Rev.2000;(2):CD002142. Review. Update in: Cochrane Database Syst Rev. 2003;(1):CD002142

  5. The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non-Small-Cell Lung Cancer. N Engl J Med 350:351-360, 2004

  6. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-97, 2005

  7. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzáles-Larriba JL, Grodzki T, Pereira JR, Le Groumellec A, Lorusso V, Clary C, Torres AJ, Dahabreh J, Souquet PJ, Astudillo J, Fournel P, Artal-Cortes A, Jassem J, Koubkova L, His P, Riggi M, Hurteloup P. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006 Sep;7(9):719-27

  8. Strauss GM, Herndon JE 2nd, Maddaus MA, Johnstone DW, Johnson EA, Harpole DH, Gillenwater HH, Watson DM, Sugarbaker DJ, Schilsky RL, Vokes EE, Green MR. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008 Nov 1;26(31):5043-51

  9. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008 Jul 20;26(21):3552-9.

5. Radical Radiotherapy for Potentially Resectable but Inoperable T1, T2, N0, M0

Updated February 2008

Guideline: Where the tumour is operable, surgical resection is the treatment of choice. Radical radiation treatment, however, may be considered when the patient refuses surgery in otherwise operable situations, or when the patient is medically unfit for thoracotomy.

Level of Evidence: III

Grade of Recommendation: B

The terms "unresectable" and "inoperable" are not synonymous. The former applies to the tumour; the latter applies to patient factors that preclude resection. Although surgery is standard treatment for potentially curable non-small cell lung cancer, radical radiotherapy may provide a reasonable alternative in the following circumstances:

  1. High risk of general anaesthesia.
  2. Inoperability because of limited pulmonary reserve.
  3. Patient's refusal of surgery.

Patients may not tolerate radical radiotherapy due to poor pulmonary function, and possibly those with significant collagen vascular disease. Some of these patients may still benefit from palliative treatment (see sections below).

Key References:

  1. Armstrong JG, Minsky BD. Radiation therapy for medically inoperable stage I and II non-small cell lung cancer. Cancer Treat Rev 1989;16:247. 

  2. Coy P, Kennelly GM. The role of curative radiotherapy in the treatment of lung cancer. Cancer 1980;45:158. 

  3. Graham P, Gebski V, Langlands A. radical radiotherapy for early Non small cell Lung Cancer. Int J Radiation Oncology, Biol, Phys 1995 Jan 15;31(2):261-6

6. Combined Modality Therapy for Unresectable Stage III

​Updated February 2008 

Guideline: Stage III patients with good performance status (ECOG 0 to 1), minimal weight loss (less than 5% in the preceding 3 months) and suitable distribution of intrathoracic disease have been shown to have a survival benefit from treatment with cisplatin-based chemotherapy combined with definitive local therapy (thoracic irradiation and/or surgical resection).1 Such patients should be considered for a combined modality treatment approach. A full discussion should occur between the patient and physician concerning the benefits, limitations and toxicities of therapy. Patients not fitting the above criteria are not candidates for combined modality treatment and should be evaluated for palliative radiotherapy or chemotherapy.

Level of Evidence: I


Grade of Recommendation: A

Until recently, the generally accepted standard therapy for patients with locally advanced, unresectable NSCLC was radiation therapy. Radiotherapy commonly relieves symptoms resultant from locally advanced NSCLC and there is a small percentage (approximately 5%) of long-term survivors following radical radiotherapy. The use of systemic treatment in combination with radiation (and/or surgery) was investigated because of evidence of tumour regression and a small survival benefit in metastatic NSCLC with chemotherapy. Several studies, but not all, have demonstrated a survival benefit for patients treated with combined modality therapy. However, much of the evidence supporting the use of aggressive regimens is based on patients selected by virtue of better performance status, minimal or no weight loss, favourable distribution of disease and/or other factors, and thus may not be representative of many patients seen in a typical clinical practice. The recommendations provided must be interpreted in this context.

The strongest evidence r​​​egarding combined modality therapy is derived from a meta-analysis of 52 randomized trials conducted by the Non-small Cell Lung Cancer Collaborative Group.1 Twenty-two trials were identified that compared radical radiation to radical radiation plus chemotherapy, of which eleven employed chemotherapy regimens including cisplatin. The addition of cisplatin-based chemotherapy to thoracic irradiation led to a 13% reduction in the risk of death, although the absolute survival advantage at 2 years was a modest 4%.

In an influential randomized trial performed in the early 1980's by the Cancer and Leukemia Group B, thoracic irradiation alone (60 Gy) was compared to two cycles of neoadjuvant chemotherapy with cisplatin plus vinblastine followed by the same thoracic irradiation.2   Median survival for stage III patients increased from 9 mos to 14 mos. More importantly, three times as many patients were alive at 5 years on the sequential chemoradiation arm (17% versus 6%). However, because the study was closed early before full planned accrual, the actual number of long-term survivors was small. Furuse et al conducted a randomized phase III study of concurrent versus sequential radiotherapy in combination with mitomycin, vindesine and cisplatin that also demonstrated an improvement in median survival, 16.5 versus 13.3 months.3  A larger study by the Radiation Therapy Oncology Group was designed to confirm the CALGB results.  RTOG trial 94-10 compared sequential treatment using cisplatin and vinblastine to concurrent treatment and the same chemotherapy program.4  A significantly improved overall survival was demonstrated with a median survival difference of 2.4 months and 5-year survival difference was 9%.

Concurrent chemoradiotherapy has become the standard for fit patients with unresectable stage III NSCLC. Trials have been conducted to evaluate the role of consolidation chemotherapy in this setting.  Gandara et al conducted the influential SWOG 9504 phase II trial of concurrent chemoradiotherapy with cisplatin and etoposide followed by consolidation docetaxel.5  The median survival from this trial was 26 months, an impressive improvement and this strategy was widely adopted in the USA, in spite of this being a phase II data only. This approach was recently evaluated by the Hoosier Oncology Group and US Oncology. This phase III trial, HOG LUN 01-24, assessed outcomes after two cycles of cisplatin and etoposide with concurrent radiotherapy with or without consolidation docetaxel.  The median survival was not different in the two groups, observation 24.1 months, docetaxel 21.5 months (p=0.94).6 As a result, the use of consolidation docetaxel has fallen out of favor and this trial raises the questions whether two cycles of platinum base chemotherapy is sufficient in this setting.

References: 

  1. Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995

  2. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial.[see comment]. Journal of the National Cancer Institute. 88:1210-5, 1996

  3. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. Journal of Clinical Oncology. 17:2692-9, 1999

  4. Curran W, Jr.; Scott, C. B.; Langer, C.; Komaki, R.; Lee, J.; Hauser, B.; Movsas, T.; Sause, W.; Cox, J.D.: Long-term benefit is observed in a phase III comparison of sequential vs concurrent chemo-radiation for patients with recurrent unresected stage III NSCLC: RTOG 9410, ASCO. Chicago, 2003

  5. Gandara DR, Chansky K, Albain KS, et al: Consolidation Docetaxel After Concurrent Chemoradiotherapy in Stage IIIB Non-Small-Cell Lung Cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 21:2004-2010, 2003

  6. Hanna NH, Neubauer M, Ansari R, et al: Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023. ASCO Meeting Abstracts 25:7512-, 2007

7. Combined Modality Therapy for Potentially Resectable Stage III

Updated February 2008

Assessment by thoracic surgery with appropriate diagnostic imaging is required prior to any therapy and after induction therapy. The Lung Tumour Group recommends that such cases be referred to surgeons with experience in combined modality therapy of lung cancer to minimize risks of treatment-related morbidity and mortality.

The optimal sequencing of chemotherapy, radiotherapy and/or surgery for potentially resectable stage III lung cancer is still controversial.

The role of pre-operative chemotherapy has been evaluated in a meta-analysis conducted by Burdett et al.1 This systematic review encompasses all randomized controlled trials enrolling patients with stage I-III NSCLC who had pre-operative platinum-based chemotherapy. The trials were heterogeneous and several included post-operative chemotherapy and/or radiotherapy. The 5 year absolute benefit in survival for stage IIIA disease was 6-7% and stage IIIB 3-5%. This data demonstrates the benefit of chemotherapy when added to definitive surgical management however, the timing, neoadjuvant versus adjuvant, remains controversial.

Tri-modality therapy with induction chemoradiation followed by surgical resection has been reported to generate 20% 6-year survival rates in selected IIIA and IIIB NSCLC. The evaluation of surgery in the trimodality approach was the subject of an intergroup trial, INT 0139.2 Patients with stage III, N2 positive disease were treated with concurrent cisplatin/etoposide and radiotherapy to 45 Gy. If there was no evidence of progression at re-evaluation, they were randomized to continued radiotherapy to 60 Gy or surgical resection followed by consolidation with 2 further cycles of cisplatin/etoposide. The median overall survival was not statistically significantly different, 22.2 months and 23.6 months respectively. However, subgroup analysis of patients who underwent trimodality with a lobectomy versus matched patients who underwent chemoradiotherapy alone indicated a survival benefit with the former approach. This benefit in overall survival was not observed in patients who required pneumonectomy. The trimodality approach may be discussed with carefully selected stage III patients and requires evaluation by a multidisciplinary team before it is adopted.​

References
1. Burdett S, Stewart LA, Rydzewska L: A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol 1:611-21, 2006

2. Albain KS, Swann RS, Rusch VR, et al: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol (Meeting Abstracts) 23:7014-, 2005

8. Patient Selection for Combined Modality Therapy

Updated February 2008

Unresectable stage III NSCLC patients appropriate for combined modality therapy must have a good performance status (ECOG 0 to 1) and minimal weight loss (less than 5% in the preceding three months). Favourable distribution of thoracic disease for definitive local therapy (surgery or radical radiotherapy) is a major factor. It is crucial that all treating oncologists (thoracic surgeon, radiation oncologist and medical oncologist) mutually agree on the proposed treatment plan and the suitability of the individual patient for such therapy before any component of therapy has commenced. Such cases should be considered for a Multi-disciplinary Lung Conference.

Active patient participation in decision making respects the fundamental ethical and legal doctrine of autonomy, while exploring the concerns of these individuals, including functional limitations, symptom distress, and significant side effects of therapy. Patient preferences for therapy vary widely, with some patients choosing to avoid side effects and others willing to accept side effects for a chance of improved survival.

9. Chemotherapy in Combined Modality Regimens

Updated February 2008 


Chemotherapy should be a platinum-based regimen.

Sequential Chemoradiation

Sequential therapy is a consideration in individuals otherwise fit enough to receive combined modality therapy, but decline concurrent chemoradiation for personal reasons. As this method is not favored, there is limited data on chemotherapy combinations, published regimens include cisplatin-vindesine-cyclophosphamide-lomustine, cisplatin-vinblastine and cisplatin-vinblastine followed by thoracic irradiation.1-3 At the BCCA, cisplatin-based therapy is the chemotherapy option of choice.

Concurrent Chemoradiation

Concurrent cisplatin-etoposide chemotherapy plus thoracic irradiation has been widely used in NSCLC. Carboplatin may be substituted in situations where patients are unable to tolerate cisplatin due to co-morbid disease or toxicity. The platinum-etoposide combination can be delivered at full systemic doses with radiotherapy, rendering it the preferred drug regimen.

Third generation cytotoxics have been explored in combination with radiotherapy. Many are associated with increased normal tissue toxicity and as a result the doses with radiotherapy need to be attenuated eg. gemcitabine, docetaxel, vinorelbine and paclitaxel.4,5 This therapeutic strategy focuses on the radiosensitizing effect of the drugs, however, may undermine the efficacy of therapy from a systemic perspective.

Consolidation Chemotherapy

Consolidation chemotherapy has been explored in an effort to improve systemic control of disease by adding a non-cross reactive agent post-chemoradiotherapy with a platinum based regimen. The most commonly evaluated drug has been docetaxel.6,7 In two phase II studies there appeared to be a benefit to the addition of consolidation docetaxel. However, a larger phase III trial conducted by the Hoosier Oncology Group (HOG) failed to confirm this result.8 Current recommendation at the BCCA is for two cycles of platinum-etoposide chemotherapy concurrent with radiotherapy followed by two cycles of consolidation platinum-etoposide alone. The need for 4 cycles of treatment has been brought into question by the HOG study. However, until further data becomes available, adequate delivery of platinum in the upfront setting is felt to be most important.

References:​

1. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial.[see comment]. Journal of the National Cancer Institute. 88:1210-5, 1996

2. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in unresectable non-small cell lung carcinoma. Lung Cancer 10 Suppl 1:S239-44, 1994

3. Sause W, Kolesar P, Taylor SI, et al: Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest. 117:358-64, 2000

4. Maas KW, El Sharouni SY, Smit EF, et al: Sequencing chemotherapy, radiotherapy and surgery in combined modality treatment of stage III nonsmall cell lung cancer. Curr Opin Pulm Med 13:297-304, 2007

5. Rigas JR, Kelly K: Current treatment paradigms for locally advanced non-small cell lung cancer. J Thorac Oncol 2 Suppl 2:S77-85, 2007

6. Gandara DR, Chansky K, Albain KS, et al: Consolidation Docetaxel After Concurrent Chemoradiotherapy in Stage IIIB Non-Small-Cell Lung Cancer: Phase II Southwest Oncology Group Study S9504. J Clin Oncol 21:2004-2010, 2003

7. Sekine I, Nokihara H, Sumi M, et al: Docetaxel consolidation therapy following cisplatin, vinorelbine, and concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer. J Thorac Oncol 1:810-5, 2006

8. Hanna NH, Neubauer M, Ansari R, et al: Phase III trial of cisplatin (P) plus etoposide (E) plus concurrent chest radiation (XRT) with or without consolidation docetaxel (D) in patients (pts) with inoperable stage III non-small cell lung cancer (NSCLC): HOG LUN 01-24/USO-023. ASCO Meeting Abstracts 25:7512-, 2007

10. Thoracic Radiotherapy In Combined Modality Therapy

Updated February 2008 


Curative radiotherapy to the primary tumour and involved mediastinal lymph nodes should be integrated with the appropriate chemotherapy regimen for appropriate patients for an additional survival benefit when compared to radical radiotherapy alone in patients with non-small cell lung cancer or chemotherapy alone in patients with small cell lung cancer.

Concurrent chemoradiation has been shown to be superior to sequential chemoradiation in 2 randomised studies. For patients with non-small cell lung cancer, thoracic irradiation and chemotherapy (cisplatin plus etoposide) should begin together starting on day 1. For patients receiving preoperative chemoradiation, the thoracic irradiation dose is 45 Gy in five weeks. For definitive chemoradiation (without surgical resection), the thoracic irradiation dose should be at least 60 Gy. For patients receiving chemoradiotherapy for limited stage small cell lung cancer, radiotherapy may start with day 1 of either cycle 1 or 2. The total dose is 40 Gy/15 fractions in 3 weeks for patients with small cell lung cancer.

For patients who are not eligible for concurrent chemoradiotherapy, but are thought to be eligible for sequential chemoradiotherapy, e.g. either due to decrease patient performance status or very large lung cancers that are not easily treated with radiotherapy initially, thoracic radiotherapy can be given after completion of chemotherapy in a sequential fashion. The dose is similar to that given with concurrent chemoradiotherapy.

For all patients, these doses may need to be modified due to poor underlying pulmonary function, and total volume of lung that needs to be irradiated.

References:

  1. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. JCO 17:2692-9, 1999

  2. Le Chevalier T, Arriagada R, Quoix E, et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: first analysis of a randomized trial in 353 patients. J Natl Cancer Inst. 1991 Mar 20;83(6):417-23.

  3. Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 88:1210-5, 1996

  4. K. S. Albain, R. S. Swann, V. R. Rusch et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). ASCO 2005: 7014

  5. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. JCO 22:330-53, 2004

11. Thoracic Radiotherapy Alone in Stage III

Update: December 2013

Recommendation: The value of radical radiotherapy alone in unresectable Stage III NSCLC is questionable. Local therapy alone rarely results in a 5 year survival greater than 5% and thus in most instances is palliative in intent. There may be an increased likelihood of local control with the use of higher radiation doses.

Discussion:

Patients with good performance status and minimal weight loss who decline or are unsuitable for combined modality/altered fractionation schemes and whose disease can be readily encompassed in a reasonable radiotherapy volume may be candidates for radical radiotherapy.

The use of radical radiotherapy alone in unresectable Stage III disease is controversial. Radical radiotherapy alone using conventional fractionation (2 Gy or equivalent to a total dose of 60 Gy) has been associated with a median survival of 9 – 12 months and 5-year survival of 5 percent. This is not markedly different from that observed with the use of palliative radiotherapy alone in the BCCA experience. Radiation may help with symptoms related to local tumor and control of local tumor growth.

References:

1. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial J Natl Cancer Inst. 1996;88(17):1210.

2. Sause WT, Scott C, Taylor S, Johnson et. al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst. 1995;87(3):198

3. Johnson DH, Einhorn LH, Bartolucci A, Birch R, Omura G, Perez CA, Greco FA. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med. 1990;113(1):33.

12. Advanced NSCLC Treated with Palliative Intent

Updated November 2013

About 30% of NSCLC patients have stage IV disease and a large proportion of patients with stage III NSCLC are not treatable with curative intent. Patients with a malignant pleural effusion are not curable and are most appropriately treated similarly to those with stage IV disease. (see management of pleural effusions section). Important prognostic factors include: stage, performance status and weight loss.

Treatment goals in these patients should always include palliation of symptoms and improvement in quality-of-life, but may include an attempt to prolong survival in patient groups suitable for chemotherapy. Treatment options include supportive care, palliative radiotherapy or chemotherapy. Toxicity of concurrent chemoradiation as applied in the curative setting is not justified in the palliative setting.

The prognosis for patients with stage IV NSCLC is poor with 6-10 month median survival times being typical even with the best available therapies. Most patients die within 1 or 2 years.

13. Palliative Radiotherapy for Locally Advanced and Metastatic NSCLC

Updated November 2013

Recommendation: Palliative radiotherapy should be considered for all patients where symptomatic disease can be encompassed within a reasonable radiotherapy volume.

For patients with locally advanced lung cancer who are not eligible for radical treatment or for patients with metastatic disease with respiratory symptoms, palliative radiotherapy to the lung can improve symptoms and improve the quality of life.

Palliative radiotherapy may be given for metastatic osseous, cerebral, subcutaneous, nodal, or pulmonary metastases to improve quality of life and minimize symptoms.

Symptomatic patients

Radiation therapy can help with symptoms from local disease and metastases. In the case of spinal cord compression and brain metastases an urgent referral to radiation oncology should occour.

Examples where radiation may be useful for the treatment of symptoms due to direct extension of local disease or involvement of lymph nodes may include:

a) Atelectasis
b) Obstruction of a main stem bronchus
c) Superior vena cava obstruction
d) Hemoptysis
e) Severe Dysphagia
f) Pain

Examples where radiation may be useful for the treatment of symptoms due to metastases include:

a) Bone metastases
b) Spinal Cord Compression
c) Brain Metastases
d) Fungating Cutaneous Mass

Asymptomatic patients

Some patients with advanced lung cancer are asymptomatic or have only mild symptoms. However, palliative radiotherapy should be considered in cases if:

a) A lesion occludes a significant proportion of a large bronchial lumen
b) A lesion on CT scan shows compression of the superior vena cava without clinical superior venal caval obstruction
c) A lesion near the spinal column with potential risk of spinal cord compression
d) Paraspinal mass
e) Large lytic lesion in a weight-bearing bone. Surgical consultation regarding prophylactic stabilization may be necessary as well
f) Asymptomatic multiple brain metastasis

 

Duration of Palliative Radiotherapy

In general, a short course of treatment will be given, in most situations one to ten sessions of radiation given over a period of one-two weeks. Randomized trials have shown that prolonged palliative fractionation schedules for thoracic radiotherapy can improve disease-free survival for patients with locally advanced lung cancer, when compared to shorter fractionation schemes.

Re-treatment

While palliative radiation may be repeated to an area several factors are taken into account including:

a) The location of the radiation (anatomical region and field size)
b) The dose and fractionation of radiation received
c) The time since the last radiation was given
d) The response to the prior radiation
e) The patients symptoms

Usually this is best discussed on a case by case basis.

References:

1. Macbeth FR, Bolger JJ, Hopwood P, et al. Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party. Clin Oncol (R Coll Radiol). 1996;8(3):167-75.

2. MRC. Inoperable non-small-cell lung cancer (NSCLC): a Medical Research Council randomised trial of palliative radiotherapy with two fractions or ten fractions. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer. 1991 Feb;63(2):265-70

3. MRC. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working Party. Br J Cancer 1992;65:934-41

4. Rees GJ, Devrell CE, Barley VL, et al. Palliative radiotherapy for lung cancer: two versus five fractions. Clin Oncol (R Coll Radiol). 1997;9(2):90-5.

6. Sundstrøm S, Bremnes R, Aasebø U, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol. 2004 Mar 1;22(5):801-10.

7. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al. A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC) Br J Cancer. 2005 Mar 28;92(6):1038-45

8. Bezjak A, Dixon P, Brundage M, et al. Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):719-28

9. Fairchild A, Harris K, Barnes E, et. al. Palliative thoracic radiotherapy for lung cancer: a systematic review. J Clin Oncol. 2008;26(24):4001.

14. Palliative Chemotherapy of Advanced NSCLC

Updated May 2014

Palliative systemic therapy for advanced non-small-cell lung cancer (NSCLC) including chemotherapy and targeted therapy may improve symptoms related to cancer and quality of life. Systemic therapy may also improve progression free survival and/or overall survival. Systemic therapy is an option for palliation of patients with NSCLC provided there is a full discussion of the benefits, limitations and toxicities of treatment. Active patient participation in decision-making is crucial. Outcome measurements should reflect more than just the selected disease measures (e.g. survival), but other concerns as well, including symptom control and quality-of-life, patients’ values or meaning of life, their feelings about themselves, and their perceptions and attitudes about a specific treatment.

After an assessment of the patient’s stage and general medical condition the choice of systemic therapy is guided by histologic subtype. The two broad categories of NSCLC histopathology are squamous and non-squamous. Adequate sample sizes are required to perform immunohistochemical tests in order to determine the histologic subtype. These are best obtained through core or excisional biopsies. Cytology from fine needle aspiration biopsies, sputa or pleural fluid (unless a cell block can be performed) often does not yield adequate tissue for subtyping. In addition, further genotyping can only performed on adequate samples to determine patient eligibility for therapies targeting EGFR mutations and EMLA4-ALK rearrangements. These will be discussed in further detail. Other actionable molecular targets will be likely be available in the not-too-distant future. The recent collaboration between the Europe based Clinical Cancer Genome Project and Network Genomic Medicine found that in 1255 lung cancer specimens suitable for genetic analysis there was at least one cancer-causing mutation or alteration “potentially amenable to specific therapeutic intervention” in 55% of them.1 In a prospective set of 5145 lung cancer patients, the 75% who could have genotyping of their tumors done (whether or not they had an actionable mutation) had a median OS of 31.6 months compared to just 15.1 months for those not able to be genotyped.1 Ideally, testing for EFGR and ALK (recommended in advanced NSCLC only) would be initiated at the time of diagnosis so that the results would be available at the time of oncology consultation. 

Targeted Therapy Plus Chemotherapy

Over the years several biological targeting drugs have been added to first line platin-doublet chemotherapy to improve the modest results. The most studied have been those targeting the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EFGR).

The ligand of the VEGFR is expressed in NSCLC. Over-expression is associated with poor prognosis. Bevacizumab is a humanized monoclonal antibody that binds the VEGF and therefore prevents binding with its receptor. This results in inhibited tumor revascularization and/or neovascularization which are critical for tumor growth. Several trials have looked at the addition of bevacizumab to first line platin-based doublet chemotherapy. A phase II trial found unacceptable rates of fatal hemoptysis in patients with predominantly squamous cell carcinoma.29 As a result, the first phase III trial, Eastern Cooperative Oncology Group E4599, randomized 878 patients with nonsquamous NSCLC and absence of significant bleeding to 6 cycles of carboplatin and paclitaxel alone or the same chemotherapy with bevacizumab at a dose of 15mg/kg every 3 weeks. The bevacizumab continued until disease progression or unacceptable toxicity. The chemotherapy plus bevacizumab arm was superior to the chemotherapy alone arm with respect to RR (35% versus 15%; p<0.001), mPFS (6.2 months versus 4.5 months; HR 0.66 p<0.001) as well as mOS (12.3 months versus 10.3 months; HR 0.79 p=0.003). There were still significantly more fatal bleeding events in the bevacizumab arm than in the chemotherapy alone arm.30 The subsequent AVAiL study looked at the addition of bevacizumab to the European standard of cisplatin and gemcitabine as well as 2 different doses of bevacizumab in a similar group of patients. 1043 patients were randomized to 3 arms: cisplatin and gemcitabine plus placebo versus cisplatin and gemcitabine plus bevacizumab 7.5mg/kg versus cisplatin and gemcitabine plus bevacizumab 15mg/kg. In all 3 arms patients received up to 6 cycles of chemotherapy and then continued on “maintenance” bevacizumab until PD or unacceptable toxicity. The primary endpoint of mPFS was significantly better with both bevacizumab groups than placebo (6.7 months for low-dose and 6.5 months for high dose bevacizumab versus 6.1 months for placebo; HR 0.75 [95% CI 0.64-0.87 p=0.0003] and 0.85 [95% CI 0.73-1.00 p=.0.456] respectively). The mOS was just over 13 months for all groups despite the fact that post study therapies were similar in all arms and <1% of those on the placebo arm received subsequent bevacizumab. As with ECOG 4599, the number of fatal pulmonary events was significantly higher in both bevacizumab groups.31-32 A meta-analysis based on the data from these and other trials showed that bevacizumab only modestly improved PFS and OS compared to chemotherapy alone (a smaller absolute benefit than other interventions adopted as standard of care) but it also showed that grade 3 toxicities were significantly greater when bevacizumab was added to chemotherapy.33 In another meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone , was associated with increased-related mortality34.Lastly, the cost-effectiveness of bevacizumab is likely unfavourable in a typical NSCLC population.35 Because of these factors current practice at the BCCA does not incorporate bevacizumab in standard systemic therapy. In fact no provincial funding agency in Canada has approved bevacizumab in combination with chemotherapy as standard of care.

Cetuximab is a monoclonal antibody that binds to the extracellular domain of the EGFR to interfere with downstream signaling of this pathway. Two studies combined cetuximab with platin-based chemotherapy. The FLEX trial randomized 1125 patients to cisplatin plus vinorelbine or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered while the cetuximab was maintained until PD or unacceptable toxicity. The mPFS was 4.8 months in both groups but the RR (36% versus 29%) and mOS (11.3 months versus 10.1 months HR 0.87 95% CI 0.762-0.996, p=0.996) favoured the cetuximab group. Toxicities including rash, diarrhea and febrile neutropenia were worse in the cetuximab arm however.36 The BMS-099 study randomized 676 patients to carboplatin plus either docetaxel or paclitaxel or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered and, again, the cetuximab was continued as maintenance. When assessed by independent radiologic review the mPFS was similar in both groups (4.2 months versus 4.4 months for the cetuximab arm). The mOS was 9.7 months in the cetuximab group and 8.4 months in the chemotherapy alone group but this was not statistically significant (HR 0.89, 95% CI 0.75-1.05, p=0.169).37 Because of the inconsistent OS benefit in clinical trials and unfavourable cost-effectiveness current practice at the BCCA does not incorporate cetuximab into standard therapy.

Several large randomized studies in patients unselected for EGFR mutations showed no benefit to the addition of a first-generation EFGR TKI to platin-doublet chemotherapy.

Duration of First-Line Therapy

There is no evidence that continuing doublet chemotherapy beyond 4 to 6 cycles in responding patients prolongs survival and cumulative treatment toxicity is a concern and should be minimized. Maintenance therapy with single agent chemotherapy or EGFR tyrosine kinase inhibitors may improve outcomes in patients with stable or responding disease after initial doublet chemotherapy and this topic will be discussed separately below.

Second-Line Systemic Therapy and Beyond

Many patients who receive first-line doublet chemotherapy will be willing and able to receive further systemic therapies. The choice of therapies depends on the histologic subtype, prior systemic therapy, genotype, extent of disease and multiple patient factors including age, ECOG PS, comorbidities and patient preference.

For patients with advanced NSCLC without a driver mutation who received initial first line platin-based combination chemotherapy single agent chemotherapy with a non-cross-resistant agent is usually the preferred approach in the second line setting. Pemetrexed and docetaxel are the most commonly prescribed second-line chemotherapy drugs.

Docetaxel was studied in a phase III trial of 104 previously treated patients who were randomized to either 100mg/m2 every 3 weeks or 75mg/m2 every 3 weeks or BSC. The high dose arm proved too toxic but the docetaxel 75mg/m2 arm was superior to BSC in terms of mOS (7.5 versus 4.6 months), pain control and deterioration in QOL.38 Another study demonstrated similar efficacy but better tolerability of weekly docetaxel at a dose of 33.3 mg/m2 for 6 weeks out of 8 weeks.39Second-line docetaxel is approved in BC after progression following first-line platin-doublet chemotherapy that did not contain docetaxel. 

Pemetrexed was compared to docetaxel in the second-line setting. 571 patients were randomized to either pemetrexed 500 mg/m2 or docetaxel 75mg/m2 both given every 3 weeks until PD or unacceptable toxicity. The usual folic acid, vitamin B12 and dexamethasone premedications were given with the pemetrexed. In the overall analysis, both drugs were equivalent in terms of RR (9% for both) and mOS (8 months for both). The hematolologic toxicity was better with pemetrexed.40 In a subsequent analysis of this and another trial based on histology that mirrors combination studies in the first-line setting, mOS was better with pemetrexed than docetaxel in patients with nonsquamous NSCLC (9.3 months versus 8.0 months, HR 0.78, 95% CI 0.61-1.00) while the reverse was true in squamous cell carcinoma where pemetrexed had a lesser impact on mOS than docetaxel (6.2 months versus 7.4 months, HR 1.56, 95% CI 1.08-2.26).41 It is reasonable to consider second-line docetaxel for those with squamous cell carcinoma who did not receive docetaxel in the first line setting and second-line pemetrexed for those with non-squamous histology who did not receive pemetrexed in the first line setting.

First-generation EGFR TKI erlotinib can also be considered second or third line therapy in EGFRwt NSCLC. The NCIC BR.21 trial randomized patients to erlotinib and BSC or placebo and BSC after first line platin-doublet chemotherapy. Almost half of the patients also received second-line docetaxel before being randomized. In these patients unselected for EGFR mutations the erlotinib significantly improved mOS compared to BSC (6.7 months versus 4.7 months, HR 0.70, 95% CI 0.58-0.85).42 Despite these results single agent chemotherapy is still preferred over EGFR TKIs in EGFRwt NSCLC after first-line platin-doublet chemotherapy, especially for patients who had clinical benefit (PR+SD) from first-line chemotherapy. The TAILOR trial is one of several studies that randomized patients with EGFRwt NSCLC to either chemotherapy or an EGFR TKI. In this trial 222 patients were randomized to erlotinib or docetaxel 75mg/m2 every 3 weeks. Median PFS was superior in the docetaxel arm (2.9 months versus 2.4 months, HR 0.71, 95% CI 0.53-0.95) as was mOS (8.2 months versus 5.4 months, HR 0.73, 95% CI 0.53-1.00). In a planned subgroup analysis those patients with ECOG PS 2 and those who progressed while receiving first-line platin doublet chemotherapy did not have greater benefit from docetaxel with respect to PFS or OS.43 These observations reinforce the concept that patient as well as tumor factors must be considered when deciding on the most appropriate second and third line therapies.

Maintenance Therapy

While continuing platin doublet therapy beyond 4 to 6 cycles in those with a response or stable disease can improve PFS, cumulative toxicities can have a negative impact on QOL and survival is not likely impacted. In contrast, single agent maintenance therapy can improve PFS while having a smaller impact on QOL and may also improve OS. The choice of post-doublet systemic therapy depends both on the regimen used in the first line setting as well as patient factors. These include PS, toxicities of the original therapy and philosophy of care i.e. balancing QOL with treatment benefits and toxicities. Close observation with institution of second-line systemic therapy at the time of disease progression is an acceptable alternative for the well-informed patient.

Pemetrexed, docetaxel and gemcitabine have all been shown to improve PFS versus no maintenance therapy. A large RCT of maintenance pemetrexed after a response or stable disease from 4 cycles of one of three platin-containing doublets not including pemetrexed showed significantly improved mPFS (4.3 versus 2.6 months) and mOS (13.4 versus 10.6 months). This trial has been criticized because only 19% of the placebo group received pemetrexed in the second-line setting. The benefit of maintenance pemetrexed was limited to those with non-squamous NSCLC and supports the preference of this drug in this population.44 The more recent PARAMOUNT study in an all non-squamous NSCLC population showed that maintenance pemetrexed after a response or SD from 4 cycles of cisplatin/pemetrexed also significantly improved mPFS (4.1 versus 2.8 months) and mOS (13.9 versus 11.0 months) compared to placebo.45 The PointBreak study, however, is not supportive of maintenance pemetrexed or the concept that nonsquamous NSCLC are better treated with pemetrexed versus other platin-companion drugs. In this study exclusively nonsquamous NSCLC patients were randomized to either carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab or carboplatin/paclitaxel/bevacizumab followed by bevacizumab. The pemetrexed arm was superior in terms of mPFS (6.0 versus 5.6 months) but not mOS (12.6 versus 13.4 months).46 Cost-effectiveness of maintenance pemetrexed has also not been well established. Overall, however, the data are supportive of maintenance pemetrexed as an option for suitable patients with non-squamous NSCLC who have had SD or a response from 4 to 6 cycles of platin-based doublet chemotherapy and is approved at the BC Cancer Agency for patients who did not receive pemetrexed as part of their induction regimen.

Maintenance docetaxel was studied in a population of patients who had not progressed after 4 cycles of carboplatin/gemcitabine. Those randomized to receive up to 6 cycles of immediate docetaxel had significantly improved mPFS compared to those who were randomized to observation and second-line docetaxel at disease progression (5.7 versus 2.7 months) but there was only a trend to improved mOS (12.3 versus 9.7 months, p=0.09) in the maintenance group. Like other maintenance studies this one was criticized because only 63% of the delayed group received second-line docetaxel. Those who did had similar outcomes compared to those who received immediate docetaxel.47 Maintenance gemcitabine has also been shown in a large RCT to improve mPFS after first line platin-doublet chemotherapy without a significant improvement in mOS compared to placebo.48 Maintenance docetaxel and gemcitabine are not as well supported as maintenance pemetrexed and are not approved at the BC Cancer Agency.

Several trials have explored the value of maintenance EGFR TK inhibitors in unselected patients with NSCLC with a response or SD after first line doublet chemotherapy. The two most robust trials demonstrated significantly improved mPFS with maintenance erlotinib versus placebo but no improvement in mOS. The SATURN trial demonstrated significantly improved mPFS (12.3 versus 11.1 weeks) but not mOS (12.0 versus 11.0 months).49 The PFS advantage was preserved in the 89% with EGFR wildtype cancers when tissue samples were subsequently reanalyzed.50 The ATLAS study showed similar results in a population of patients who received bevacizumab in combination with platin-doublet chemotherapy. Those randomized to maintenance bevacizumab/erlotinib had significantly improved mPFS (4.8 versus 3.7 months) but not mOS (14.4 versus 13.2 months) compared to those who received bevacizumab and placebo.51 EGFR status was determined in 45% and both mPFS and mOS were significantly improved in those with an EGFR mutation. The significance of these results and the value of maintenance EGFR TKIs in patients with known EGFR mutations are unclear with the availability of first line EGFR TKIs in EGFRm+ NSCLC. The comparative value of maintenance pemetrexed versus maintenance erlotinib in EGFRwt NSCLC is also unclear. 

References

1. The Clinical Lung Cancer Genome Project (CLCGP) and Network Genomic Medicine (NGM): A Genomics-Based Classification of Human Lung Tumors. Sci Transl Med 5: 209ra153, 2013

2. Lynch TJ, Bell DW, Sordella R, et al: Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. NEJM 350: 2129-39, 2004

3. Paez JG, Janne PA, Lee JC, et al: EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Science 304: 1497-1500, 2004

4. Mok TS, Wu Y-L, Thongprasert S, et al: Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. NEJM 361: 947-957, 2009

5. Fukuoka M, Wu Y-L, Thongprasert S, et al: Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non-Small-Cell Lung Cancer in Asia (IPASS). JCO 29: 2866-2874, 2011

6. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial. Lancet Oncology 13: 239-246, 2012

7. Solca F, Dahl G, Zoephel A, et al: Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an IrreversibleErbB Family Blocker. J Pharmacol Exp Ther 343: 342-350, 2012

8. Sequist LV, Yang JC-H, Yamamoto N, et al: Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. JCO 31: 3327-3334, 2013

9. Yang JC-H, Hirsch V, Schuler M, et al: Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With EGFR Mutations. JCO 31: 3342-3350, 2013

10. Wu Y-L, Zhou C, Hu C-P, et al: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomized phase 3 trial. Lancet Oncology 15: 213-222, 2014

11. Lee CK, Brown C, Gralla R, et al: Impact of EGFR Inhibitor in Non-Small-Cell Lung Cancer on Progression-Free and Overall Survival: A Meta-Analysis. J Natl Cancer Inst 105: 595-605, 2013

12. Miller VA, Hirsch V, Cadranel J, et al: Afetinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomized trial. The Lancet Oncology 13: e186 2012

13. Soda M, Choi YL, Enomoto M, et al: Identification of the transforming EMLA4-ALK fusion gene in non-small-cell lung cancer. Nature 448: 561-567, 2007

14. Camidge DR, Bang Y-J, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncology 13: 1011-1019, 2012

15. Kim D-W, Ahn M-J, Shi Y, et al: Results of a global phase II study with crizotinib in advanced ALK-positive non-small-cell lung cancer (NSCLC). JCO 30 (suppl; abstr 7533), 2012

16. Shaw A, Kim D-W, Nakagawa K, et al: Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. NEJM 368: 2385-2394, 2013

17. Shaw A, Yeap BY, Mino-Kenudson M, et al: Clinical Features and Outcomes of Patients With Non-Small-Cell Lung Cancer Who Harbor EML4-ALK. J Clin Oncol 26: 4247-4253, 2009

18. Non-small Cell Lung Cancer Collaborative Group: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ 311: 899-909

19. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. NEJM 346: 92-98, 2002

20. Fossella F, Pereira JR, von Pawel J, et al: Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non-Small-Cell Lung Cancer: The TAX 326 Study Group. J Clin Oncol 21: 3016-3024, 2003

21. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 20: 4285-4291, 2002

22. Kelly K, Crowley J, Bunn PA, et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatments of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19: 3210-3218, 2001

23. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III Study Comparing Cisplatin plus Gemcitabine with Cisplatin plus Pemetrexed in Chemotherapy-Naïve Patients With Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 26: 3543-3551, 2008

24. Syrigos KN, Vansteenkiste J, Parikh P, et al: Prognostic and predictive factors in a randomized phase III trial comparing cisplatin-pemetrexed versus cisplatin-gemcitabine in advanced non-small-cell lung cancer. Ann of Oncol 21: 556-561, 2009

25. Hotta K, Matsuo K, Ueoka K, et al: Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22: 3852-3859, 2004

26. Ardizzoni A, Tiseo M, Boni L, et al: CISCA (cisplatin versus carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer (NSCLC). J Natl Cancer Inst 99: 847-857, 2007

27. D’Addario G, Pintilie M, Leighl NB, et al: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol23: 2926-2936, 2005

28. Rajeswaran A, Trojan A, Burnand B, et al: Efficacy and side effects of cisplatin and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: A systematic review of randomized controlled trials. Lung Cancer 59: 1-11, 2008

29. Johnson DH, Fehrenbacher L, Novotny WS, et al: Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer. J Clin Oncol 22: 2184-91, 2004.

30. Sandler A, Gray R, Perry, MC, et al: Paclitaxel-Carboplatin Alone or With Bevacizumab for Non-Small-Cell Lung Cancer. NEJM 355: 2542-50, 2006.

31. Reck M, von Pawel J, Zatloukal P, et al: Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer: AVAiL. J Clin Oncol 27: 1227-1234, 2009.

32. Reck M, von Pawel J, Zatloukal P, et al: Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomized phase III trial (AVAiL). Annals of Oncology 21: 1804-1809, 2010.

33. Soria J-C, Mauguen A, Reck M, et al: Systematic review and meta-analysis of randomized, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 24: 20-30, 2013.

34. Ranpura V, Hanapi S and Wu s: Treatment-Related Mortality With Bevacizumab in Cancer Patients. A Meta-analysis. JAMA 305: 487-494, 2011.

35. Dasanu CA: Bevacizumab in lung cancer: Lackluster performance and unjustified expense? J Oncol Pharm Practice 18: 1-2, 2012.

36. Pirker R, Peirera JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet 373: 1525-1531, 2009.

37. Lynch TJ, Patel T, Dreisbach L, el al: Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non-Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099. J Clin Oncol 28: 911-917, 2010.

38. Shepherd FA, Dancey J, Ramlau R, et al: Prospective Randomized Trial of Docetaxel Versus Best Supportive Care in Patients With Non-Small-Cell Lung Cancer Previously Treated With Platinum-Based Chemotherapy. J Clin Oncol 18: 2095-2103, 2000.

39. Gridelli C, Gallo C, Di Maio M, et al: A randomized clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study. Br J Cancer 91:1996-2004, 2004.

40. Hanna N, Shepherd FA, Fossella FV, et al: Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy. J Clin Oncol 22: 1589-1597, 2004.

41. Scagliotti G, Hanna N, Fossella F, et al: The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies. The Oncologist 14: 253-263, 2009.

42. Shepherd FA, Pereira JR, Ciuleanu T, et al: Erlotinib in Previously Treated Non-Small-Cell Lung Cancer. NEJM 353: 123-132, 2005.

43. Garassino MC, Martelli O, Broggini M, et al: Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomized controlled trial. Lancet Oncology 14: 981-988, 2013.

44. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, phase 3 study. The Lancet 374: 1432-1440, 2009.

45. Paz-Ares LG, de Marinis F, Dediu M, et al: PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 31:2895-2902, 2013.

46. Patel JD, Socinski MA, Garon EB, et al: PointBreak: A Randomized Phase III study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 31:4349-4357 2013.

47. Fidias PM, Dakhil SR, Lyss AP, et al: Phase III Study of Immediate Compared With Delayed Docetaxel After Front-Line Therapy With Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 27:591-598, 2008.

48. Perol M, Chouaid C, Perol D, et al: Randomized, Phase III Study of Gemcitabine or Erlotinib Maintenance Therapy Versus Observation, With Predefined Second-Line Treatment, After Cisplatin-Gemcitabine Induction Chemotherapy in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 30:3516-3524, 2012.

49. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomized, placebo-controlled phase 3. Lancet Oncology 11:521-529, 2010.

50. Brugger W, Triller N, Blasinska-Morawiec M, Curescu S, et al: Prospective Molecular Marker Analysis of EGFR and KRASFrom a Randomized, Placebo-Controlled Study of Erlotinib Maintenance Therapy in Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 29:4113-4120, 2011.

51. Johnson BE, Kabbinavar F, Fehrenbacher L, et al: ATLAS: Randomized, Double-Blind, Placebo-Controlled, Phase IIIB Trial Comparing Bevacizumab Therapy With or Without Erlotinib, After Completion of Chemotherapy, With Bevacizumab for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 31:3926-3934, 2013.

52. Lilenbaum R, Axelrod R, Thomas S, et al: Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2. J Clin Oncol 26: 863-869, 2008.

53. The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients With Advanced Non-Small-Cell Lung Cancer. J Natl Cancer Inst 91:66-72, 1999.

54. Kudoh S, Takeda K, Nakagawa K, et al: Phase III Study of Docetaxel Compared With Vinorelbine in Elderly Patients With Advanced Non-Small-Cell Lung Cancer: Results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904). J Clin Oncol 24: 3657-3663, 2006.

55. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for Elderly Patients With Advanced Non-Small-Lung Cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) Phase III Randomized Trial. J Natl Cancer Inst 95:362-372, 2003.

56. Quoix E, Zalcman G, Oster J-P, et al: Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomized phase 3 trial. Lancet 378: 1079-1088, 2011.

57. Zukin M, Barrios CH, Pereira JR, et al: Randomized Phase III Trial of Single-Agent Pemetrexed Versus Carboplatin and Pemetrexed in Patients With Advanced Non-Small-Cell Lung Cancer and Eastern Cooperative Oncology Group Performance Status of 2. J Clin Oncol 31: 2849-2853, 2013.

14a. Systemic Therapy for EGFR MMutation Positive Nonsquamous NSCLC

​Guideline: Patients with advanced NSCLC harboring an activating EGFR mutation should receive an EGFR TKI in the first line setting. 

Level of Evidence: I

Ten to 15% of all NSCLC have a somatic mutation within the EGFR gene at exons 18-21. 90% of those mutations are either a deletion in exon 19 or a point mutation in exon 21. Most pathology labs including the BCCA lab test for these 2 common activating mutations. When these mutations are present, the EGFR, also known as EbrB1/HER1 in the 4 member ErbB family, is abnormally activated. This abnormal activation results in an enzymatic cell-signaling cascade kicked off by the phosphorylation of the intracellular component of the transmembrane EGFR by the EGFR tyrosine kinase. EGFR tyrosine kinase inhibitors (EGFR TKIs) interfere with the activation and down-stream signaling of EGFR and have antitumor activity in EGFR mutated (EGFRm+) NSCLC.2Adenocarcinoma histology, Asian background, female gender and non-smoker status increase the likelihood of a patient with NSCLC harboring an EGFR mutation but clinical profiling is not considered an appropriate replacement for mutation testing.2-3

Gefitinib and erlotinib are known as first-generation, reversible, EGFR TKIs. They have both shown activity in advanced NSCLC harboring activating EGFR mutations. Among the two summarized below, several phase III clinical trials have demonstrated that these EGFR TKIs are superior to chemotherapy in the first-line treatment of EGFRm+ NSCLC.

The Iressa Pan Asian Study (IPASS) randomized Asian non-smokers or former light smokers with adenocarcinoma to either gefitinib or carboplatin and paclitaxel. Of the 1200 patients involved in this study 437 had tumor specimens suitable for EGFR mutation testing and 59.7% of these were EGFR mutation positive. In those patients the RR for gefitinib was 71.2% versus 47.2% for the chemotherapy. Median PFS (mPFS) also favoured the gefitinib (9.5 versus 6.3 months, HR 0.48). Median OS (mOS) was not significantly different between the 2 arms (22 months for both). This was likely because of significant crossover (almost 40% in each arm). Quality of life (QOL) data significantly favored the gefitinib arm. 4-5

The European Tarceva versus Chemotherapy (EURTAC) trial randomized 174 non-Asian EGFRm+ patients with advanced NSCLC to either first line erlotinib or chemotherapy (either cisplatin/gemcitabine or cisplatin/docetaxel). This study was halted at the first interim analysis. Like IPASS the RR was better in the erlotinib arm than the chemotherapy arm (58% versus 15%) as was the mPFS (9.7 versus 5.2 months, HR 0.37, 95% CI 0.25-0.54). Also like IPASS there was no significant difference in mOS (19.3 months for erlotinib and 19.5 months for chemotherapy). Unfortunately there was poor compliance with symptom questionnaires and QOL data was not captured.6

Not all patients with EGFRm+ cancers respond to first generation EGFR TKIs (primary resistance) and the majority of those who do will ultimately develop secondary resistance. Primary resistance can occur through a mutation of the T790 domain of exon 20 which encodes the tyrosine kinase part of the EGFR. Other gene mutations likely account for the other mechanisms of resistance to first-generation EGFR TKIs.

Afatinib is a second-generation, irreversible, inhibiter of EGFR (ErbB1) as well as other members of the ErbB family. Preclinical data and non-randomized clinical studies suggest that afatinib may be able to overcome and even prevent the resistance of EGFRm+ NSCLC to the first-generation EGFR TKIs. For example Afatinib has been shown to block mutations inT790 of exon 20.7 Afatinib has also been compared favorably to first-line chemotherapy in randomized trials.

The LUX-Lung 3 trial randomized 345 EGFRm+ patients in a 2:1 fashion to afatinib or the chemotherapy regimen many would consider optimal in these adenocarcinoma patients: cisplatin and pemetrexed. RR was higher in the afatinib group (56.1% versus 22.6%) as was mPFS (11.1 months versus 6.9 months; HR 0.58). With a predefined analysis in those with the common exon 19 and 21 mutations the mPFS advantage of afatinib over chemotherapy was even more pronounced (13.6 months versus 6.9 months; HR 0.47; p<0.0001). HRQol as well as improvements in dyspnea and fatigue were greater with afatinib.8-9 The LUX-Lung 6 trial reinforced the findings of LUX-Lung 3 in a randomized comparison of afatinib with cisplatin and gemcitabine.10

These and other randomized studies as well as a meta-analysis of data from 13 phase III clinical trials confirm the relative value of EGFR TKIs over chemotherapy in the setting of first-line systemic therapy for EGFRm+ NSCLC with respect to RR and PFS.11 While there are no completed randomized trials that compare the different EGFR TKIs with each other there is an ongoing randomized study of the comparative efficacy and toxicity of afatinib and gefitinib. Gefitinib, erlotinib and Afatinib are all Health Canada approved for EGFRm+ patients.

EGFR TKIs are generally better tolerated than chemotherapy. Typical side-effects of EGFR TKIs are dry skin, acneiform rash, stomatitis, diarrhea and paronychia. Rare but clinically important pulmonary and hepatic toxicity may also occur. It is felt that afatinib, because of it’s affinity for multiple targets within the ErbB family, has higher toxicity compared to the first-generation EGFR TKIs but without direct randomized comparisons this is unconfirmed.

Treatment with first-line EGFR TKI usually continues until there is disease progression or intolerable toxicity. Second-line therapy in this circumstance involves the same platin-doublet chemotherapy regimens used in the first-line setting for those with EFGR wild type (EGFRwt) NSCLC. Refer to the section Systemic Therapy for Advanced NSCLC Without Actionable Driver Mutations. It is usually advised that chemotherapy begin, if possible, soon after withdrawal of EGFR TKIs, particularly in those with prolonged benefit, as rapid disease progression has been observed in this setting.

A phase II study (LUX-Lung 1) of afatinib in a small group of patients with acquired resistance to gefitinib or erlotinib showed an encouraging rate of disease control but further, larger, trials will be needed to support the use of this second-generation EGFR TKI in this particular setting.12

Lastly, several large randomized studies in patients not tested for EGFR mutations showed no benefit to the addition of a first-generation EFGR TKIs to platin-doublet chemotherapy. Whether patients with EGFRm+ NSCLC benefit from the addition of EGFR TKIs to chemotherapy remains an area of research interest. 

14b. Systemic Therapy for ALK Rearranged Nonsquamous NSCLC

Guideline: Patients with advanced NSCLC harboring an ALK rearrangement should receive an ALK TKI at some point in their systemic therapy.

Level of Evidence: I

A small proportion of NSCLC have a novel fusion oncogene called EML4-ALK. The EML4 portion mediates ligand-independent dimerization and/or oligomerization of the tyrosine kinase containing ALK portion of this chimeric protein resulting in constitutive TK activity-a potent oncogenic driver of these cancers. Small molecule inhibitors of the ALK tyrosine kinase have been found to inhibit the growth of these cancers in cell lines and animal models. The EML4-ALK fusion protein, which almost always occurs independent of EGFR and KRAS mutations, can be detected by IHC, FISH and RT-PCR.

EML4-ALK rearrangements (ALKr+) occur in about 4% of unselected cases.13 Clinicopathologic features that increase the likelihood of finding an ALK-fusion oncogene include: younger age, light/never smoking status, adenocarcinoma histology.17

Crizotinib is a small molecule TKI originally developed to inhibit c-MET but was also found to be a potent inhibitor of the ALK tyrosine kinase. This drug has been shown to induce significant tumour responses in patients whose cancers are ALKr+ in nonrandomized studies.14-15

A phase III clinical trial demonstrated the value of crizotinib over appropriate single agent chemotherapy in 347 patients with ALKr+ NSCLC who had received prior platin-doublet chemotherapy. The primary endpoint of median PFS was statistically superior for the crizotinib (7.7 months versus 3.0 months with pemetrexed or docetaxel). 112 patients (64%) who received initial chemotherapy crossed over to crizotinib and subsequently the median OS was similar between the 2 groups (20.3 months for the crizotinib and 22 months for the chemotherapy arms). Symptom and quality of life improvements were greater on the crizotinib arm.16 This study would support the use of crizotinib in the second or third line setting in ALKr+ patients previously receiving platin-based doublet chemotherapy with or without second line chemotherapy.

There are two phase III trials exploring the value of crizotinib over first line platin doublet chemotherapy in ALKr+ NSCLC. At least one of these studies may have results available by ASCO 2014. Until then, the current evidence best supports crizotinib in the second or third line setting.

Patients with a known ALK rearrangement and no EGFR mutation do not likely respond to EGFR TKIs and thus erlotinib should not be used in this setting.17

14c. Systemic Therapy for Advanced NSCLC Without Actionable Driver Mutations

Guideline: Appropriate patients with advanced NSCLC that do not harbor an activating EGFR mutation or ALK rearrangement or who are not appropriate candidates for therapies targeting these mutations or who have progressed on or after targeted therapies should receive 4 to 6 cycles of platin-based combination chemotherapy.

Level of Evidence: I

There are currently no established actionable molecular targets for the palliative systemic therapy of squamous cell carcinoma or nonsquamous NSCLC without an EFGR mutation or ALK rearrangement. Chemotherapy, therefore, remains the mainstay of treatment. Chemotherapy modestly improves median and one year survival in patients with distant metastatic NSCLC compared with best supportive care, but is not curative. The results of three published meta-analyses indicate that cisplatin-based chemotherapy yields an improvement in median survival of approximately 6 to 8 weeks in stage IV disease. One year survival improves from 10-15% to 25-35%.18 Newer generation trials, as discussed below, have shown median OS beyond 12 months.

Palliative chemotherapy patients should ideally have a performance status of ECOG 0, 1, or 2. The implications of decreased performance status will be reviewed separately. Extensive previous radiotherapy is associated with increased chemotherapy toxicity and symptomatic disease within a previous radiotherapy volume may be less chemosensitive. Renal, hematologic and hepatic function must be adequate. Nutritional status must be adequate.

First-Line Combination Chemotherapy

Of the chemotherapeutic agents with activity against NSCLC, the platins cisplatin and carboplatin, historically have been considered the most effective and remain the "backbone" of current chemotherapy. It is recognized that doublet therapy, with a second agent added to a platin, provides the best balance of benefit and toxicity in comparison to single agent or triplet chemotherapy. Multiple trials have established that platin combinations with vinorelbine, gemcitabine, docetaxel, paclitaxel are essentially equivalent with respect to response rate and survival benefit.19-22Histology may have a role to play in selecting chemotherapy combinations as some data suggests pemetrexed containing regimens may be more effective than gemcitabine containing regimens for adenocarcinoma while the reverse may be true for squamous cell carcinoma. Other data fail to show any trends for superior outcomes for pemetrexed containing regimens.23-24 Appropriate patients with advanced NSCLC without actionable driver mutations should therefore be offered first line platin-based doublet chemotherapy containing a second agent consisting of vinorelbine, gemcitabine, paclitaxel, pemetrexed or docetaxel. Trials have failed to consistently identify a regimen with superior efficacy.

Comparisons of the two commonly used platin agents in NSCLC, cisplatin and carboplatin, have been undertaken. A meta-analysis found that cisplatin plus a newer second agent yielded 11% longer survival than the same carboplatin doublet.25 When older chemotherapeutic regimens were included, the survival benefit was not statistically significant. Toxicity was noted to be lower with carboplatin-based chemotherapy. Subsequently, the CISCA meta-analysis looked at individual patient data and found an improvement in response rate with cisplatin over carboplatin. However, the survival benefit was not statistically significant (HR for death, carboplatin vs cisplatin 1.07 p=0.101).26 Again, carboplatin was better tolerated. For patients with good performance status and limited co-morbidities, cisplatin is the preferred agent for palliative chemotherapy but carboplatin remains an appropriate agent for patients with metastatic NSCLC in whom cisplatin is likely be poorly tolerated.

Non-platin third-generation regimens including various combinations of gemcitabine, docetaxel, paclitaxel, vinorelbine, pemetrexed have been compared to platin doublets in the phase II and III setting. Meta-analyses suggest that outcomes are similar for both groups with cisplatin-doublets faring a little better and carboplatin-doublets faring a little worse that non-platin doublets, but the toxicity profiles differ depending on the combination.27-28 Platin doublets remain the mainstay of first-line systemic therapy for advanced NSCLC in appropriate patients.

Targeted Therapy Plus Chemotherapy

Over the years several biological targeting drugs have been added to first line platin-doublet chemotherapy to improve the modest results. The most studied have been those targeting the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EFGR).

The ligand of the VEGFR is expressed in NSCLC. Over-expression is associated with poor prognosis. Bevacizumab is a humanized monoclonal antibody that binds the VEGF and therefore prevents binding with its receptor. This results in inhibited tumor revascularization and/or neovascularization which are critical for tumor growth. Several trials have looked at the addition of bevacizumab to first line platin-based doublet chemotherapy. A phase II trial found unacceptable rates of fatal hemoptysis in patients with predominantly squamous cell carcinoma.29 As a result, the first phase III trial, Eastern Cooperative Oncology Group E4599, randomized 878 patients with nonsquamous NSCLC and absence of significant bleeding to 6 cycles of carboplatin and paclitaxel alone or the same chemotherapy with bevacizumab at a dose of 15mg/kg every 3 weeks. The bevacizumab continued until disease progression or unacceptable toxicity. The chemotherapy plus bevacizumab arm was superior to the chemotherapy alone arm with respect to RR (35% versus 15%; p<0.001), mPFS (6.2 months versus 4.5 months; HR 0.66 p<0.001) as well as mOS (12.3 months versus 10.3 months; HR 0.79 p=0.003). There were still significantly more fatal bleeding events in the bevacizumab arm than in the chemotherapy alone arm.30 The subsequent AVAiL study looked at the addition of bevacizumab to the European standard of cisplatin and gemcitabine as well as 2 different doses of bevacizumab in a similar group of patients. 1043 patients were randomized to 3 arms: cisplatin and gemcitabine plus placebo versus cisplatin and gemcitabine plus bevacizumab 7.5mg/kg versus cisplatin and gemcitabine plus bevacizumab 15mg/kg. In all 3 arms patients received up to 6 cycles of chemotherapy and then continued on “maintenance” bevacizumab until PD or unacceptable toxicity. The primary endpoint of mPFS was significantly better with both bevacizumab groups than placebo (6.7 months for low-dose and 6.5 months for high dose bevacizumab versus 6.1 months for placebo; HR 0.75 [95% CI 0.64-0.87 p=0.0003] and 0.85 [95% CI 0.73-1.00 p=.0.456] respectively). The mOS was just over 13 months for all groups despite the fact that post study therapies were similar in all arms and <1% of those on the placebo arm received subsequent bevacizumab. As with ECOG 4599, the number of fatal pulmonary events was significantly higher in both bevacizumab groups.31-32 A meta-analysis based on the data from these and other trials showed that bevacizumab only modestly improved PFS and OS compared to chemotherapy alone (a smaller absolute benefit than other interventions adopted as standard of care) but it also showed that grade 3 toxicities were significantly greater when bevacizumab was added to chemotherapy.33 In another meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone , was associated with increased-related mortality34.Lastly, the cost-effectiveness of bevacizumab is likely unfavourable in a typical NSCLC population.35 Because of these factors current practice at the BCCA does not incorporate bevacizumab in standard systemic therapy. In fact no provincial funding agency in Canada has approved bevacizumab in combination with chemotherapy as standard of care.

Cetuximab is a monoclonal antibody that binds to the extracellular domain of the EGFR to interfere with downstream signaling of this pathway. Two studies combined cetuximab with platin-based chemotherapy. The FLEX trial randomized 1125 patients to cisplatin plus vinorelbine or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered while the cetuximab was maintained until PD or unacceptable toxicity. The mPFS was 4.8 months in both groups but the RR (36% versus 29%) and mOS (11.3 months versus 10.1 months HR 0.87 95% CI 0.762-0.996, p=0.996) favoured the cetuximab group. Toxicities including rash, diarrhea and febrile neutropenia were worse in the cetuximab arm however.36 The BMS-099 study randomized 676 patients to carboplatin plus either docetaxel or paclitaxel or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered and, again, the cetuximab was continued as maintenance. When assessed by independent radiologic review the mPFS was similar in both groups (4.2 months versus 4.4 months for the cetuximab arm). The mOS was 9.7 months in the cetuximab group and 8.4 months in the chemotherapy alone group but this was not statistically significant (HR 0.89, 95% CI 0.75-1.05, p=0.169).37 Because of the inconsistent OS benefit in clinical trials and unfavourable cost-effectiveness current practice at the BCCA does not incorporate cetuximab into standard therapy.

Several large randomized studies in patients unselected for EGFR mutations showed no benefit to the addition of a first-generation EFGR TKI to platin-doublet chemotherapy.

​Duration of First-Line Therapy

There is no evidence that continuing doublet chemotherapy beyond 4 to 6 cycles in responding patients prolongs survival and cumulative treatment toxicity is a concern and should be minimized. Maintenance therapy with single agent chemotherapy or EGFR tyrosine kinase inhibitors may improve outcomes in patients with stable or responding disease after initial doublet chemotherapy and this topic will be discussed separately below.

Second-Line Systemic Therapy and Beyond

Many patients who receive first-line doublet chemotherapy will be willing and able to receive further systemic therapies. The choice of therapies depends on the histologic subtype, prior systemic therapy, genotype, extent of disease and multiple patient factors including age, ECOG PS, comorbidities and patient preference.

For patients with advanced NSCLC without a driver mutation who received initial first line platin-based combination chemotherapy single agent chemotherapy with a non-cross-resistant agent is usually the preferred approach in the second line setting. Pemetrexed and docetaxel are the most commonly prescribed second-line chemotherapy drugs. 

Docetaxel was studied in a phase III trial of 104 previously treated patients who were randomized to either 100mg/m2 every 3 weeks or 75mg/m2 every 3 weeks or BSC. The high dose arm proved too toxic but the docetaxel 75mg/m2 arm was superior to BSC in terms of mOS (7.5 versus 4.6 months), pain control and deterioration in QOL.38 Another study demonstrated similar efficacy but better tolerability of weekly docetaxel at a dose of 33.3 mg/m2 for 6 weeks out of 8 weeks.39Second-line docetaxel is approved in BC after progression following first-line platin-doublet chemotherapy that did not contain docetaxel.

Pemetrexed was compared to docetaxel in the second-line setting. 571 patients were randomized to either pemetrexed 500 mg/m2 or docetaxel 75mg/m2 both given every 3 weeks until PD or unacceptable toxicity. The usual folic acid, vitamin B12 and dexamethasone premedications were given with the pemetrexed. In the overall analysis, both drugs were equivalent in terms of RR (9% for both) and mOS (8 months for both). The hematolologic toxicity was better with pemetrexed.40 In a subsequent analysis of this and another trial based on histology that mirrors combination studies in the first-line setting, mOS was better with pemetrexed than docetaxel in patients with nonsquamous NSCLC (9.3 months versus 8.0 months, HR 0.78, 95% CI 0.61-1.00) while the reverse was true in squamous cell carcinoma where pemetrexed had a lesser impact on mOS than docetaxel (6.2 months versus 7.4 months, HR 1.56, 95% CI 1.08-2.26).41 It is reasonable to consider second-line docetaxel for those with squamous cell carcinoma who did not receive docetaxel in the first line setting and second-line pemetrexed for those with non-squamous histology who did not receive pemetrexed in the first line setting.

First-generation EGFR TKI erlotinib can also be considered second or third line therapy in EGFRwt NSCLC. The NCIC BR.21 trial randomized patients to erlotinib and BSC or placebo and BSC after first line platin-doublet chemotherapy. Almost half of the patients also received second-line docetaxel before being randomized. In these patients unselected for EGFR mutations the erlotinib significantly improved mOS compared to BSC (6.7 months versus 4.7 months, HR 0.70, 95% CI 0.58-0.85).42 Despite these results single agent chemotherapy is still preferred over EGFR TKIs in EGFRwt NSCLC after first-line platin-doublet chemotherapy, especially for patients who had clinical benefit (PR+SD) from first-line chemotherapy. The TAILOR trial is one of several studies that randomized patients with EGFRwt NSCLC to either chemotherapy or an EGFR TKI. In this trial 222 patients were randomized to erlotinib or docetaxel 75mg/m2 every 3 weeks. Median PFS was superior in the docetaxel arm (2.9 months versus 2.4 months, HR 0.71, 95% CI 0.53-0.95) as was mOS (8.2 months versus 5.4 months, HR 0.73, 95% CI 0.53-1.00). In a planned subgroup analysis those patients with ECOG PS 2 and those who progressed while receiving first-line platin doublet chemotherapy did not have greater benefit from docetaxel with respect to PFS or OS.43 These observations reinforce the concept that patient as well as tumor factors must be considered when deciding on the most appropriate second and third line therapies.

Maintenance Therapy

 While continuing platin doublet therapy beyond 4 to 6 cycles in those with a response or stable disease can improve PFS, cumulative toxicities can have a negative impact on QOL and survival is not likely impacted. In contrast, single agent maintenance therapy can improve PFS while having a smaller impact on QOL and may also improve OS. The choice of post-doublet systemic therapy depends both on the regimen used in the first line setting as well as patient factors. These include PS, toxicities of the original therapy and philosophy of care i.e. balancing QOL with treatment benefits and toxicities. Close observation with institution of second-line systemic therapy at the time of disease progression is an acceptable alternative for the well-informed patient.

Pemetrexed, docetaxel and gemcitabine have all been shown to improve PFS versus no maintenance therapy. A large RCT of maintenance pemetrexed after a response or stable disease from 4 cycles of one of three platin-containing doublets not including pemetrexed showed significantly improved mPFS (4.3 versus 2.6 months) and mOS (13.4 versus 10.6 months). This trial has been criticized because only 19% of the placebo group received pemetrexed in the second-line setting. The benefit of maintenance pemetrexed was limited to those with non-squamous NSCLC and supports the preference of this drug in this population.44 The more recent PARAMOUNT study in an all non-squamous NSCLC population showed that maintenance pemetrexed after a response or SD from 4 cycles of cisplatin/pemetrexed also significantly improved mPFS (4.1 versus 2.8 months) and mOS (13.9 versus 11.0 months) compared to placebo.45 The PointBreak study, however, is not supportive of maintenance pemetrexed or the concept that nonsquamous NSCLC are better treated with pemetrexed versus other platin-companion drugs. In this study exclusively nonsquamous NSCLC patients were randomized to either carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab or carboplatin/paclitaxel/bevacizumab followed by bevacizumab. The pemetrexed arm was superior in terms of mPFS (6.0 versus 5.6 months) but not mOS (12.6 versus 13.4 months).46 Cost-effectiveness of maintenance pemetrexed has also not been well established. Overall, however, the data are supportive of maintenance pemetrexed as an option for suitable patients with non-squamous NSCLC who have had SD or a response from 4 to 6 cycles of platin-based doublet chemotherapy and is approved at the BC Cancer Agency for patients who did not receive pemetrexed as part of their induction regimen.

Maintenance docetaxel was studied in a population of patients who had not progressed after 4 cycles of carboplatin/gemcitabine. Those randomized to receive up to 6 cycles of immediate docetaxel had significantly improved mPFS compared to those who were randomized to observation and second-line docetaxel at disease progression (5.7 versus 2.7 months) but there was only a trend to improved mOS (12.3 versus 9.7 months, p=0.09) in the maintenance group. Like other maintenance studies this one was criticized because only 63% of the delayed group received second-line docetaxel. Those who did had similar outcomes compared to those who received immediate docetaxel.47 Maintenance gemcitabine has also been shown in a large RCT to improve mPFS after first line platin-doublet chemotherapy without a significant improvement in mOS compared to placebo.48 Maintenance docetaxel and gemcitabine are not as well supported as maintenance pemetrexed and are not approved at the BC Cancer Agency.

Several trials have explored the value of maintenance EGFR TK inhibitors in unselected patients with NSCLC with a response or SD after first line doublet chemotherapy. The two most robust trials demonstrated significantly improved mPFS with maintenance erlotinib versus placebo but no improvement in mOS. The SATURN trial demonstrated significantly improved mPFS (12.3 versus 11.1 weeks) but not mOS (12.0 versus 11.0 months).49 The PFS advantage was preserved in the 89% with EGFR wildtype cancers when tissue samples were subsequently reanalyzed.50 The ATLAS study showed similar results in a population of patients who received bevacizumab in combination with platin-doublet chemotherapy. Those randomized to maintenance bevacizumab/erlotinib had significantly improved mPFS (4.8 versus 3.7 months) but not mOS (14.4 versus 13.2 months) compared to those who received bevacizumab and placebo.51 EGFR status was determined in 45% and both mPFS and mOS were significantly improved in those with an EGFR mutation. The significance of these results and the value of maintenance EGFR TKIs in patients with known EGFR mutations are unclear with the availability of first line EGFR TKIs in EGFRm+ NSCLC. The comparative value of maintenance pemetrexed versus maintenance erlotinib in EGFRwt NSCLC is also unclear.

14d. Elderly Patients and Patients with Poor Performance Status

Most clinical trials of NSCLC therapies have excluded elderly patients (typically described as those ≥70 years of age) and patients with borderline or poor performance status (ECOG ≥2) even though these patients comprise a significant proportion of typical lung cancer populations.

Elderly patients or those with decreased performance status with a sensitizing EGFR mutation are usually considered for EGFR TKI therapy even though studies done in similar patients whose cancers were unselected for EGFR mutation status did not show an advantage for these agents over chemotherapy or placebo.52 These patients are also underrepresented in the large phase III studies of EGFR TKIs versus chemotherapy in EGFRm+ patients. For example, 10% of the patients in the IPASS study were ECOG 2 and the median age was 57 in both treatment arms.4These agents, however, are generally thought to be well-tolerated in this group of patients although toxicities must be followed closely. Similarly, large trials of ALK TKIs versus chemotherapy in patients with ALK rearrangements did not include many elderly patients or patients with decreased PS but these agents also appear to be well tolerated and would be favored over chemotherapy in such patients.

For patients with advanced NSCLC without EGFR mutations or ALK rearrangements or those with such mutations who have progressed on targeted therapies, the decision to proceed with cytotoxic chemotherapy is a challenging one. Retrospective reviews of first-line combination studies have been undertaken. Studies of single agent chemotherapy regimens have been done. More recent studies have looked at combination chemotherapy regimens versus single agent regimens in these patients. It is important to note that elderly patients with good performance status cannot be considered analogous to younger patients with poor performance status.

In the Italian ELVIS trial 161 patients with advanced NSCLC ≥70 years old were randomized to vinorelbine plus BSC versus BSC alone. After adjusting for stage and ECOG PS the vinorelbine arm had improved mOS (28 versus 21 weeks, HR 0.65, 95% CI 0.45-0.93) as well as QOL compared to BSC. 24% of patients in both arms were ECOG 2 but there was no analysis of benefit specifically in these patients.53 In the West Japan Thoracic Oncology Trial 9904 182 patients with advanced NSCLC ≥70 years old were randomized to either docetaxel or vinorelbine. The docetaxel appeared to be at least as effective as the vinorelbine although the toxicity profiles were different. Well over 90% of the patients in both arms were ECOG 0 or 1 so this trial also did not address the value of single agent chemotherapy in elderly patients with decreased performance status.54Vinorelbine remains the BCCA standard for single agent chemotherapy in elderly patients with advanced NSCLC who cannot tolerate or do not want platin-based combination chemotherapy.

Several trials have compared combination chemotherapy regimens to single agents in older patients. The largest, the Italian MILES study, randomized 698 patients ≥70 years of age to single agent gemcitabine or vinorelbine versus the non-platin doublet of gemcitabine plus vinorelbine at combination doses tested in a previous multi-arm phase I/II study. The primary endpoint of mOS and additional endpoints of QOL and toxicity did not favor the combination in this population.55 A French intergroup trial randomized 451 patients aged 70-89 to vinorelbine or gemcitabine monotherapy versus the combination of carboplatin plus paclitaxel. The study was stopped at the first interim analysis. The primary endpoint of mOS was 10.3 months in the combination group and 6.2 months in the monotherapy group (HR 0.64, 95% CI 0.52-0.78; p<0.0001). Hematologic toxicities were higher in the combination arm but QOL was similar in the 2 groups.56

The management of patients with advanced NSCLC with ECOG PS 2 is less clear than the management of well elderly patients with this disease. Little prospective data has been gathered. In a multicenter phase III trial 205 patients with advanced NSCLC patients with PS ECOG 2 were randomized to either single agent pemetrexed or the combination of carboplatin and pemetrexed. Initially patients with all histologies were invited to participate but later the protocol was amended to include only those with nonsquamous histologies. Over 80% of the patients in each arm had adenocarcinoma. Analyses were done ITT as well as in the nonsquamous patients only and were similar. The mPFS was 2.8 months for the single agent regimen and 5.8 months for the combination (HR 0.46; 95% CI 0.35 to 0.63; p<0.001). The primary endpoint of mOS was 5.3 months for the pemetrexed and 9.3 months for the carboplatin plus pemetrexed (HR 0.62; 95% CI 0.46-0.83; p=0.001). Hematologic toxicities were greater in the combination arm and there were 4 treatment related deaths compared to none in the single agent arm. QOL data was not collected.57

Chemotherapy, either platin-doublet or single agent, may be considered for appropriate elderly patients and/or patients with PS ECOG 2 as long as they have acceptable organ function and bone marrow reserve and are aware of the potential for greater toxicities and uncertain overall benefit. The roles of bevacizumab, which is not included in standard BCCA chemotherapy regimens, as well as maintenance therapy in these patients are even far less certain and are not routinely recommended.

15. Endobronchial Therapy

Several local modalities of therapy can be used for palliation of lung cancers involving the bronchial wall.

Guideline: Endobronchial therapy with brachytherapy, lasers or photodynamic therapy may provide symptomatic benefit for patients with bronchial obstruction.

Level of Evidence: II

Grade of Recommendation: B

Brachytherapy

Brachytherapy refers to endobronchial radiotherapy using a high dose rate microselectron. The objective of the treatment is to palliate symptoms of shortness of breath, hemoptysis or cough in patients with obstructive bronchial cancers. The treatment is performed by placing a small plastic catheter into the obstructed bronchial lumen via the biopsy channel of a fiberoptic bronchoscope. The advantage of this treatment over YAG laser therapy lies in its simplicity. The treatment is done under local anesthesia similar to a standard fiberoptic bronchoscopy. In addition, brachytherapy is efficacious in treating the mucosal component of the tumour, it can also treat the submucosal and part of the peribronchial component of the tumour. The treatment is well tolerated by patients who do not present with respiratory distress or failure. The later group of patients are best managed by YAG laser therapy.

YAG Laser

The Neodymium Yittrium-Aluminum-Garnet (YAG) laser is a useful tool for coagulation and vaporization of malignant tissue. It provides an effective means for reopening obstructed tracheal or bronchial lumen in patients with inoperable obstructive endobronchial tumours. The procedure is generally done under general anesthesia using rigid bronchoscopy. Its major indication is in patients presenting with respiratory distress or respiratory failure due to obstruction of the trachea or main carina by tumour. The objective of the treatment is to palliate symptoms of dyspnea, cough or hemoptysis.

Photodynamic Therapy

Photodynamic therapy refers to the use of a photosensitizing drug which selectively accumulates in the tumour such as porfimer (PHOTOFRIN®) in combination with light to treat malignant tumours. The treatment is done under local anesthesia similar to a standard fiberoptic bronchoscopy twenty-four to forty-eight hours after intravenous injection of porfimer. A red laser light is conducted to the tip of the bronchoscope by a fine quartz fibre to activate the porfimer in the tumour tissue to produce a photochemical reaction to destroy the tumour. It is a potentially curative treatment for small early bronchial cancers that are confined to within the bronchial wall. The major indication of photodynamic therapy is in patients with small early lung cancers who are inoperable due to limited pulmonary capacity and in patients with multiple bronchial cancers.

Stents

Stents are silicone tubes with or without a metal spring. They are sometimes helpful in maintaining a patent airway in patients with extrinsic compression of the airway by tumour in patients who have failed radiotherapy.

Key References:

  1. Mostovych M, Mathisen, D. Management of malignant airway obstruction. Lung Cancer: Principles and Practice. Pass HI, Mitchell JB, Johnson DH, Turrisi AT. Lippincott-Raven, Philadelphia, 1996,663.

  2. Lam S, Muller NL, Miller RR, et al. Predicting the response of obstructive endobronchial tumors to photodynamic therapy. Cancer 1986;58:2298

16. Management of Pleural Effusion

​Updated September 2013

Malignant pleural effusion (MPE) is a common clinical problem in the advanced stages of many cancers. The most common malignancies resulting in MPE are lung and breast cancer. For lung cancer patients, 45% will develop a MPE sometime during their illness, and 50% of advanced breast cancer patients will develop an effusion. It is associated with a poorer prognosis and the most common symptoms are dyspnoea and cough.

Treatment options depend on multiple factors including patient symptoms, performance status, prognosis and speed of reaccumulation of the pleural fluid. MPE is likely to reaccumulate in the majority of cases particularly if a patient is not able to be offered further systemic therapy to control disease.

Patients with malignant pleural effusions may also develop complex pleural spaces rapidly with the formation of adhesions, loculations and trapped lung. Adequate assessment involves the use of imaging with chest xray, thoracic CT scan and thoracic ultrasound and the involvement of Respirologists/Thoracic Surgeons who are experienced in the management of MPE. Patients with suspected malignant effusions require early referral for the appropriate assessment due to the likelihood of reaccumulation and possible development of a complicated pleural space. (See below References for Management algorithm and Thoracocentesis checklist.)

Possible treatment options include:

  1. Intermittent thoracocentesis
  2. Talc pleurodesis – thoracoscopic or via chest tube
  3. Tunnelled indwelling pleural catheter eg PleurX system

1. Intermittent Thoracocentesis

An initial diagnostic and therapeutic thoracocentesis is indicated in the patient with a suspected MPE. It can be performed in the ambulatory setting under local anesthesia. Subsequent further use of repeated therapeutic thoracocentesis can be used on an intermittent basis for the rare patient who has a slowly accumulating effusion that only requires drainage every few months for symptom relief. It is also useful in the patient with a poor performance whose prognosis is < 4-6 weeks and the use of a more aggressive treatment option is not appropriate. It is not appropriate to use multiple repeated therapeutic thoracocenteses for symptom relief due to the risk of infection, empyema, pneumothorax and promotion of a complicated pleural space. The use of small pigtail catheters for prolonged drainage is discouraged due to frequent blockage within 72 hours and the promotion of loculations. If pigtail catheters are utilized, removal after 24 hours of fluid drainage is recommended.

2. Talc Pleurodesis

Talc pleurodesis can be performed via thoracoscopy under general anesthesia, pleuroscopy under local anesthesia and conscious sedation or via a chest tube with talc slurry. It requires inpatient hospital admission for a usual duration of 7 days. The patient must have a fully expandable lung for pleurodesis to be achieved and therefore, those with a trapped lung are excluded from this treatment option. Pleurodesis can be achieved in ~70% of patients without trapped lung but there is a risk of ARDS, infection, pneumonia and respiratory failure. Therefore, this option is usually limited to patients with limited comorbidities, good performance status and prognosis who are able to undergo the procedure and hospital admission.

3. Tunnelled Indwelling Pleural Catheters (TIPC)

The implementation of this technique for management of MPE has increased significantly in the last 5 years and it has largely replaced the use of talc pleurodesis for the majority of patients. Initial series reported its benefit in patients with poor performance status, but it has also been shown to be useful in patients with good performance status who may have been traditional candidates for pleurodesis. It remains the only treatment option for patients with trapped lung. In patients without trapped lung, spontaneous pleurodesis has been reported in 30-70% cases within 2-3 months.

Patient selection is important and evaluation with thoracic ultrasound necessary. Therefore, patients require evaluation by trained Respirologists/Thoracic surgeons with expertise in patient evaluation, TIPC insertion as well as longterm follow-up to manage any issues that may arise. The procedure is usually performed in the ambulatory setting under local anesthesia and light conscious sedation. The patient requires prior referral to the Palliative Care Benefits Schedule and the appropriate Community Nursing program at the time of the procedure. It can be inserted during chemotherapy or radiation therapy without increased risk of complications.

TIPC should not be inserted in patients with:

  1. Empyema
  2. Compromised skin at the site of the insertion due to malignancy, infection or radiation change
  3. Multi- loculated pleural space
  4. Anticoagulation, thrombocytopenia or bleeding diathesis
  5. Lack of available Community nursing services
  6. Prognosis < 4-6 weeks
  7. Inability to lie nearly flat for 30 minutes in lateral decubitus position
  8. No symptomatic improvement with previous thoracocentesis

References

Putnam J, Walsh G, Swisher S, Roth J, Suell D, Vaporciyan A, et al. Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg, 2000;69:369-375.

Tremblay A, Michaud G. Single-center experience with 250 tunnelled pleural catheter insertions for malignant pleural effusion. Chest, 2006;129:362-368.

Tremblay A, Mason C, Michaud G. Use of tunneled catheters for malignant pleural effusions in patients fit for pleurodesis. Eur Respir, 2007;30:759-762.

Van Meter M, McKee K, Kohlwes J. Efficacy and safety of tunneled pleural catheters in adults with malignant pleural effusions: a systematic review. J Gen Intern Med, 2010;26:70-76.

Suzuki K, Servais E, Rizk N, Solomon S, Sima C, Park B, et al. Palliation and pleurodesis in malignant pleural effusion: the role for tunneled pleural catheters. J Thorac Oncol, 2011;6:762-767.

MacEachern P, Tremblay A. Pleural controversy: Pleurodesis versus indwelling pleural catheters for malignant effusions. Respirology, 2011;16:747-754.

 

17. Pre-operative Radical Radiotherapy

Guideline: Pre-operative radical radiotherapy has no routine role.

Level of Evidence: II

Grade of Recommendation: B

There is no clear role for pre-operative radical radiotherapy (without concurrent chemotherapy) at this time. Particular subsets of patients may be considered for pre-operative radiotherapy such as those being considered for resection of superior sulcus tumour, or tumour with invasion into the chest wall. Mutual agreement of the radiation oncologist and surgeon is necessary and such cases are appropriate for presentation at lung conference.

Key References:

  1. Curran WJ, Langer CJ, Keller SM, Comis RL. Analysis of clinical trials employing preoperative chemotherapy and/or thoracic radiation therapy for marginally resectable non-small cell lung cancer. J Int Radiat Oncol Biol Phys 1993;27(Suppl 1):189.

  2. Temeck BK, Okunieff PG, Pass HI. Chest wall disease including superior sulcus tumors. Lung cancer: Principles and Practice, edited by Pass HI, MitchellJB, Johnson D, Turrisi A. Lippincott-Raven, Philadelphia, 1996,pp 585.

6.2 Small Cell Lung Cancer

 Updated January 2014

About 10-12% of lung cancer patients have small cell anaplastic pathology (Govindan et al. 2006). The incidence is decreasing from a 20% proportion in the 1980’s. The demographics are changing with more women and an older population affected.

Although small cell lung cancer (SCLC) responds more readily to both chemotherapy and radiotherapy than non-small cell lung cancer, the majority of patients develop incurable recurrences. Palliation of symptoms and prolongation of survival can be achieved with chemotherapy in patients with extensive stage SCLC and about 20-25% of patients with limited stage disease become long-term survivors after combined modality therapy including chemotherapy and radiotherapy.

Although the BCCA recommends adoption of the TNM system for small cell lung cancer (Shepherd 2007), the VA staging system (limited versus extensive) continues to be widely used because of its simplicity and clinical utility (Green 1969). Using current staging procedures, about 40% of SCLC patients have limited stage disease defined as tumor confined to the ipsilateral hemithorax and regional nodes (including ipsilateral supraclavicular) suitable for a tolerable radiotherapy port. The assignment of TNM stage provides more precise nodal staging, which is required for conformal radiation techniques. Limited stage corresponds to TNM stages I through IIIB. Sixty-percent have extensive stage disease defined as tumor beyond the boundaries of limited disease including distant metastases, malignant pericardial or pleural effusion, and contralateral hilar and supraclavicular nodes.

Stage is the major prognostic factor for response, progression-free survival, overall survival and long-term survival (cure). Other important prognostic factors include performance status, gender (female better), number of metastatic sites, weight loss, serum lactate dehydrogenase and serum albumin.

In addition to medical history and clinical examination, patients require a CBC, liver enzymes, electrolytes, LDH, renal function tests, and lung function tests (as required for radiotherapy assessment). Scans should include a CT of brain, chest and abdomen plus a bone scan. A PET scan may be helpful in the absence of obvious distant disease and be of utility in planning radiotherapy volumes for localized cases and occasional cases for surgery (Thomson 2011).

References

1. Govindan R, Page N, Morgensztern D. Et al. Changing epidemiology of small-cell lung cancer in the United States ovewr the last 30 years: analysis of the SEER database. J Clin Oncol 2006:24;4539-44.

2. Shepherd F, Crowley J, Van Houtte P et al. The International Association for the study of lung cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2:1067-1077:2007.

3. Green RA, Humphrey E, Close H, et al. Alkylating agents in bronchogenic carcinoma. Am J Med 46:516-525, 1969

4. Thomson D, Hulse P, Lorigan P et al. The role of positron emission tomography in management of small cell lung cancer. Lung Cancer 73:121-126, 2011

6.2.1 Limited Stage Disease

Updated January 2014

The prognosis of limited stage SCLC patients that receive no therapy is poor with a median survival of only 10-12 weeks. The median survival of patients treated with radiotherapy alone is 5-6 months and long term survivors are uncommon (1-2%). Combined modality therapy as recommended by the BCCA Lung Tumour Group increases the median survival to 18 to 24 months and the probability of long-term (5-year) survival is 20-25%.

Treatment Modalities for Limited SCLC

Guideline: Limited stage small cell lung cancer patients should receive treatment with curative intent combining thoracic irradiation with chemotherapy.

Level of Evidence: I

Meta-analyses of sixteen randomized trials comparing chemotherapy alone versus chemotherapy plus thoracic irradiation for limited stage SCLC demonstrated a highly significant survival benefit for combined modality therapy (Payne, 1992, Pignon 1992). As soon as the diagnosis of limited SCLC is assigned, patients should have consultation from both medical and radiation oncologists for planning of integrated therapy. Since this is a curable neoplasm, therapy should be given according to a published protocol or a clinical trial rather than assembled in an arbitrary fashion. The treatment plan should be commenced without unnecessary delay.

Patients with extensive disease by regional extension (pleural effusion, pericardial effusion, contralateral supraclavicular nodes and equivocal distant disease) should be given the benefit of the doubt with respect to combined modality therapy. Regional radiotherapy may be delayed until the effusions are controlled. The other cautionary note is patients with negative conventional staging but a PET scan demonstrating a small amount of extra-thoracic disease. It may not be appropriate to deny these patients combined modality therapy.

References:

1. Warde P, Payne D. Does thoracic irradiation improve survival and local control in limited stage small-cell lung carcinoma of the lung? A meta-analysis. J Clin Oncol 1992;10:890-895.

2. Pignon JP, Arriagada R, Ihde DC, et al. A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med 1992;327:1618.

1. Thoracic Irradiation for Limited SCLC

​Updated January 2014

Thoracic Irradiation for Limited Stage Small Cell Lung Cancer

Guideline: Thoracic irradiation for limited SCLC should be delivered concurrently with cisplatin/etoposide chemotherapy early (within first six weeks) in the treatment program rather than at a later time or sequentially after chemotherapy completion.

Level of Evidence: I

Integration of Chemotherapy and Radiotherapy

A randomised clinical trial performed by the National Cancer Institute of Canada showed that integration of thoracic irradiation with chemotherapy early in the treatment program (concurrently with cisplatin/etoposide at week 3) was superior to thoracic irradiation delivered at week 15 (Murray, 1993). The median survival and 5-year survival for early thoracic irradiation was 21 months and 22% versus 16 months and 13% for delayed thoracic irradiation. A number of other randomized studies have examined the effect of radiotherapy timing with results that are not entirely consistent. However, several meta-analyses have been performed that demonstrate a superior survival outcome for early thoracic irradiation for median and long-term survival (Fried, 2004, Pijls-Johannesma M). The best survival outcomes have consistently been associated with protocols that deliver cisplatin and etoposide concurrently with early thoracic irradiation (De Ruyscher). Initial concurrent chemoradiation is widely used for a number of locally advanced but non-metastatic cancers (non-small cell lung cancer, brain cancer, head and neck cancer, cancer of the cervix and cancer of the rectum. This model of therapy obeys fundamental radiobiological principles more than induction chemotherapy followed by radiotherapy.

Cyclophosphamide and anthracycline chemotherapy regimens are inferior to cisplatin and etoposide protocols in limited stage disease (Sundstrom). There is no evidence that more than four cycles of cisplatin and etoposide is associated with any survival advantage (BCCA Protocol LUSCPERT).

References:

1. Murray N, Coy P, Pater J, et al. Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. J Clin Oncol 1993;11:336-344.

2. Fried DB, Morris DE, Poole C, et al. Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22:4837-4845, 2004

3. Pijls-Johannesma M, De Ruysscher D, Vansteenkiske J, et al. Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials. Cancer Treat Rev 33:461-473, 2007

4. De Ruyscher D, Pijils-Johannesma M, Bentzen SM, et al : Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24:1057-1063, 2006.

5. Sundstrom S, Bremnes R, Kaasa S, et al. Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up. J Clin Oncol 20:4665-4672, 2002.

Thoracic Irradiation Dose/Fractionation in Limited SCLC

The dose/fractionation scheme traditionally employed in Canada for limited stage small cell lung cancer is 4000 cGy in 15 fractions delivered over 3 weeks. This is usually given concurrently with the first or second cycle of radiotherapy. Prompt referral to a radiation oncologist is encouraged so that arrangements may be made for early thoracic radiotherapy. Altered fractionation schemes have been investigated in limited stage small cell lung cancer. One randomized trial showed that accelerated fractionation (45Gy in three weeks with a twice daily fractionation) was superior to 45 Gy in five weeks with one fraction daily (Turrisi). It is unknown whether longer radiotherapy regimens that give a higher total dose change survival. To date, the evidence suggests that a “short-sharp” radiotherapy regimen is superior.

References:

1. Murray N, Coy P, Pater J et al. Importance of Timing for Thoracic irradiation in the Combined Modality Treatment of Limited –Stage Small-Cell Lung Cancer. Journal of Clinical Oncology 11:336-344, 1993.

2. Turrisi AT, Kim K, Blum R, Sause W, Livingston R, Komaki R, Wagner H, Aisner S, Johnson D. Twice daily compared with once-daily thoracic irradiation in limited stage small-cell lung cancer treated with concurrent cisplatin and etoposide. N Engl J Med 199;340;265-71, 1999

Thoracic Irradiation Volume in Limited SCLC

The volume to be irradiated includes the primary tumour and the affected lymph. Targeting and treating only nodal structures that measure 1 cm or larger on computed tomographic scan, clinically palpable nodes in the supraclavicular fossa and disease found by bronchoscopy constitute an appropriate target. Elective treatment of uninvolved nodes does not have a good rationale, and the risk of normal tissue exposure with toxicity of esophagitis and reduction in lung function militates strongly against expansive volumes. Early concurrent chemoradiation generally treats the pre-chemotherapy volume. When the pre-chemotherapy volume is unduly large, the treating radiation oncologist may reduce the radiation volume after a chemotherapy response. PET scans may useful to refine the radiotherapy volume.

Reference:

  1. Murray N, Turrisi A. A review of first-line treatment for small-cell lung cancer. J Thorac Oncol. 1:270-278, 2006

2. Standard Regimens for Fit Patients with Limited SCLC

​Updated January 2014

Chemotherapy Regimens for Limited SCLC

Combination chemotherapy is mandatory for curative intent therapy of limited SCLC.

Four cycles of EP (LUSCPERT) has become the international standard for good performance status patients with good renal function with limited SCLC. EP is not associated with severe normal tissue toxicity when administered concurrently with full dose thoracic irradiation. The standard interval between cycles is three weeks. Thoracic irradiation should not be interrupted because of neutropenia (regardless of severity) in the absence of clinical evidence of infection.

An advantage for topoisomerase 1 inhibitors (irinotecan or topotecan) plus cisplatin over etoposide and cisplatin has not been confirmed in North American trials of extensive stage disease and this class of agents does not combine well with thoracic irradiation.

References:

1. Ihde DH: Chemotherapy for lung cancer. N Engl J Med 327:1434-1441, 1992

2. Murray N, Turrisi A. A review of first-line treatment for small-cell lung cancer. J Thorac Oncol. 1:270-278, 2006

3. Alternative Chemo Regimens for Frail or Elderly Patients with Limited SCLC

Updated January 2014

Analysis of data on chemotherapy delivery, thoracic irradiation delivery, and treatment efficacy indicates that patient age (at least up to age 75) does not influence survival of good performance status patients with limited small cell lung cancer (Siu, 1996). Potentially curative combined modality treatment should not be withheld on the basis of age. However, because of smoking induced and other co-morbid illness, many elderly patients with SCLC tolerate standard regimens poorly.

Limited SCLC patients with poor performance status or significant co-morbid medical illness may not tolerate four cycles of EP. For patients with impaired renal function (creatinine clearance less than 60 cc’s per minute), carboplatin may be substituted for cisplatin. Substitution of carboplatin for cisplatin in the EP regimen has less gastrointestinal and renal toxicity but the regimen is myelosuppressive.

Even more frail or very elderly (> 75 years) patients with limited SCLC are problematic as their prognosis is poor if they receive thoracic irradiation only and low intensity chemotherapy does not have curative potential. Integrated chemoradiation with four cycles of chemotherapy may be poorly tolerated with risk of severe and life-threatening toxicity. A pilot study from the BCCA prospectively investigated abbreviated chemotherapy with only two cycles of chemotherapy plus thoracic irradiation (Murray, 1998). In a cohort of 55 patients, 5-year survival was 18% suggesting that the first two cycles of chemotherapy are the most important for generating a chance of long-term survival. This model of abbreviated chemotherapy (two cycles) plus thoracic irradiation is suitable for very frail patients with limited SCLC and those that have unacceptable toxicity from early chemoradiation of standard protocols.

References:

  1. Siu LL, Shepherd FA, Murray N, et al. The influence of age on the treatment of limited stage small-cell lung cancer. J Clin Oncol 1996;14:821-828.

  2. Murray N, Grafton C, Shah A, et al. Abbreviated treatment for elderly, infirm, or non-compliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16:3323-3328, 1998​

4. Prophylactic Cranial Irradiation

Updated January 2014


Guideline: Prophylactic cranial irradiation for limited stage patients with response to treatment decreases the risk of brain metastases and prolongs survival.

Level of Evidence: I

The rationale for prophylactic cranial irradiation (PCI) is that most chemotherapeutic agents do not cross the blood-brain barrier into the central nervous system in adequate doses to prevent frequent occurrence of brain metastases. The incidence of brain metastases drops from about 25-30% to 5-10% with the addition of PCI. Neurotoxicity (dementia, ataxia) associated with prophylactic cranial irradiation has been described particularly when chemotherapy is given concurrently or after brain irradiation. However, randomized prospective data demonstrate that the incidence of neurological morbidity is not clearly worse in SCLC cohorts given prophylactic cranial irradiation than those not irradiated. However, the attrition of patients from recurrences leaves a small fraction of long-term survivors for analysis. Late neurologic damage with neurocognitive side effects cannot be excluded particularly in patients existing neurological disease or vascular disease. Meta-analysis on 987 patients randomized to receive or not receive PCI has demonstrated a statistically significant benefit with respect to brain metastases-free survival (RR=0.46), disease-free survival (RR=0.75) and overall survival (RR=0.84). This corresponds to a 5.4% increase in 3-year survival rate (Auperin 1999).

Patient Selection for PCI

PCI is recommended for limited stage patients that have responded to induction therapy and have no pre-existing neurological morbidity (such as cerebrovascular disease, dementia, Parkinson's Disease).

PCI Timing

PCI should be delivered after completion of induction thoracic irradiation and all chemotherapy.

PCI Dose/Fractionation

The dose-fractionation for PCI is 25 Gy in 10 fractions (Le Pechoux 2009).

Reference:

  1. Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. N Engl J Med 1999;341:476-84.

  2. Le Pechoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer in completer remission after chemotherapy and thoracic radiotherapy : a randomised clinical trial. Lancet 10: 467-475, 2009

5. Supportive Care

Updated January 2014

Until lung cancer symptoms are controlled by antineoplastic therapy, appropriate symptomatic treatment is essential not only for patient comfort but these measures may enhance the fidelity of the combined modality program by minimizing protocol violations.

Neutropenia and fever associated with chemotherapy and thoracic irradiation occurs in 10-20% of patients and is a major factor in the 1-2% probability of treatment related mortality. There is evidence from randomized trials that prophylactic antibiotics with co-trimoxazole (one double strength tablet bid) or ciprofloxacin (500 mg bid) reduces the risk of neutropenic fever and sepsis during induction therapy for patients with SCLC. Patients with bronchial obstruction and atelectasis are particularly at risk and prophylactic antibiotics should be considered during the neutrophil nadir. If a patient has an episode of neutropenia and fever, prophylactic antibiotic may be justified for subsequent chemotherapy cycles.

Esophagitis is common during the final phase of thoracic irradiation and during the week after completion of radiotherapy. Supportive care should include diet modification, analgesics and oral mucaine. When esophagitis appears to be aggravated by gastroesophageal reflux, gastric acid suppression may be helpful (H2 blockers or omeprazole). Severe radiation esophagitis may require hospitalization with intravenous supportive care. Dehydration must be avoided to minimize renal impairment and maintain optimal chemotherapy delivery.

According to the BCCA guidelines for use of cytokine support, patients receiving treatment with curative intent can be considered for G-CSF. However, chemotherapy supported with G-CSF plus concurrent thoracic irradiation has been associated with unexpectedly severe hematologic toxicity and should be avoided (Bunn 1995). Similarly erythropoietin support during chemoradiation has been linked with a high risk of vascular events (35%) and poorer survival.

Clinicians must assess the psychosocial needs of lung cancer patients and use the expertise of their health care colleagues specializing in this area. Inadequate psychological support of the patient can undermine the best treatment plan. Smoking cessation after successful treatment of SCLC is associated with fewer smoking-related second primary cancers. These patients must be actively encouraged and assisted to stop smoking.

References:

1. De Jongh CA, Wade JC, Finley RS, et al. Trimethoprim/sulfamethoxazole versus placebo: a double-blind comparison of infection prophylaxis in patients with small cell carcinoma of the lung. J Clin Oncol 1983;1:302.

2. Tjan-Heijnen V, Manegold C, Buchholz D, et al. Reduction of chemotherapy-induced febrile leukopenia by ciprofloxacin and roxithromycin in small cell lung cancer (SCLC) patients: an EORTC phase III study. Proc Amer Soc Clin Oncol 18;469a, 1999, (abst# 1808)

3. Bunn PA, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 13:1632-1641, 1995.

6. Restaging after Induction Therapy in Limited SCLC

Updated January 2014

Patients with limited SCLC who achieve a satisfactory radiographic response of thoracic disease from combined-modality therapy do not require restaging. Repeat bronchoscopy may identify a small proportion of patients with residual disease but in the absence of a proven therapy that can convert partial responders after intensive chemoradiation to durable complete responders, the patient discomfort and additional costs mitigate against restaging bronchoscopy or imaging procedures in asymptomatic patients.

Reference:

1. Feld R, Pater J, Goodwin PJ, et al. The restaging of responding patients with limited small cell lung cancer; is it really useful? Chest 1993;103:1010.

7. Surgery in Limited SCLC

Updated January 2014

If SCLC is identified unexpectedly at the time of thoracotomy, complete resection and mediastinal lymph node biopsies should be taken if possible. There may be a role for surgery in highly selected cases of SCLC who have "very limited" (stage I and II) disease. These patients should have careful preoperative staging including a PET scan and mediastinal lymph node evaluation (mediastinoscopy/EBUS). Adjuvant combination chemotherapy should be given when they have recovered sufficiently from surgery (four cycles of a platinum plus etoposide-Protocol LUSCPE).

Down-staging of limited SCLC with mediastinal lymph node involvement with neoadjuvant chemotherapy followed by radiotherapy and surgical resection has been assessed in a randomized trial performed by the Lung Cancer Study Group. The results were poor and the treatment was toxic. Such therapy is not recommended.

References:

  1. Shepherd FA. Surgical management of small cell lung cancer. In, Lung Cancer: Principles and Practice, Pass HI, Mitchell JB, Johnson D, Turrisi A. Lippincott-Raven Publishers, Philadelphia, 1996, pp899.

  2. Lad T, Thomas P, Piantadosi S. et al. A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 1994;106(6 Suppl):320S-323S.

6.2.2 Extensive Stage SCLC

Updated January 2014

Extensive Stage SCLC

The prognosis for most cases of extensive stage SCLC is guarded and treatment is palliative. Without chemotherapy, the average survival is only 8-10 weeks. Thoracic radiotherapy alone may palliate local symptoms but has little impact on survival. The majority of patients (70-80%) respond to chemotherapy and complete responses occur in 15-20%. Median survival with standard regimens is 8-11 months. Prophylactic cranial irradiation in patients responding to chemotherapy extends survival (Slotman 2007). Almost all patients relapse and only 5-10% are alive at 2 years. The small proportion (1-2%) of long-term survivors usually had low bulk metastatic disease and an exceptional response to chemotherapy.

Standard Chemotherapy of Extensive Stage SCLC

Guideline: Combination chemotherapy is superior to monotherapy in SCLC.

Level of Evidence: I

Monotherapy with oral etoposide has been proved inferior to combination chemotherapy in SCLC (Souhami, 1997). Combination chemotherapy should be recommended to all extensive SCLC patients fit enough to receive it. However, randomized trials of various combination chemotherapy protocols have not demonstrated a superior regimen.

Standard regimens are the same as for limited SCLC (see above 6.4.2.1) including four cycles of sequential platinum plus etoposide (Protocol LUSCPE). Carboplatin-based chemotherapy appears iso-effective compared to cisplatin-based chemotherapy in a meta-analysis (Rossi 2012).

Although cyclophosphamide and doxorubicin regiments (LUSCCAV) perform as well as platinum and etoposide in the extensive stage setting, six cycles of non-platinum containing chemotherapy appear required to generate a similar result (Roth).

A recent meta-analysis of seven randomized studies showed similar results with irinotecan-platinum compared to etoposide-cisplatin. Irinotecan led to more gastrointestinal toxic effects while more hematological toxic effects were observed with etoposide (Shao 2012). Etoposide and platinum remains the standard of care for first line treatment of advanced non-small cell lung cancer suitable for combination chemotherapy.

Frail or elderly patients that are judged unsuitable for intravenous combination chemotherapy or refuse such therapy may derive some palliative benefit from oral etoposide (LUSCPOE).

References:

  1. Souhami RL, Spiro SG, Rudd RM et al: Five day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89:577-80, 1997.

  2. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. J Clin Oncol 30:1692-1698, 2012

  3. Roth B, Johnson D, Einhorn L, et al. Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10:282-291, 1992.

  4. Shao N, Jin S, Zhu W. An updated meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive stage small cell lung cancer. J Thoracic Oncol 7:470-472, 2012

Radiotherapy for Extensive Stage SCLC

Thoracic irradiation is not routinely recommended for patients with extensive stage SCLC that achieve satisfactory palliation with chemotherapy. Integrated chemoradiation may be used for selected patients with equivocal, minimal or "regional" extensive stage (pleural effusion, contralateral supraclavicular nodes, cervical nodes).

Palliative thoracic irradiation after palliative chemotherapy for extensive stage SCLC is indicated for regional disease that is symptomatic. Additionally, if the original local disease was bulky, the cancer is likely to progress first at that site. Palliative radiotherapy to local disease after response to chemotherapy is reasonable particularly if the patient resides at a region remote from a radiotherapy facility. It may prolong time to progression but has no proven effect on overall survival.

Guideline: Prophylactic cranial irradiation for extensive stage small cell lung cancer with response to chemotherapy decreases the risk of brain metastases and prolongs survival.

Level of Evidence: 2

One randomized trial in extensive stage SCLC responding to induction chemotherapy showed PCI to cause an impressive reduction in symptomatic brain metastases, with a hazard ratio of 0.27 (p<0.001). Overall survival was also improved (HR 0.68, p=0.003) with PCI with a 1-year survival from time of randomization of 27.1% in the treated group and 13.3% in the untreated group (Slotman). PCI radiotherapy dose in extensive SCLC responders is 25 Gy in 10 fractions or 20 Gy in 5 fractions.

Patients with brain metastases have traditionally received therapeutic brain irradiation followed by chemotherapy but it is now clear that brain metastases respond to chemotherapy and good performance status patients can be palliated with chemotherapy followed by therapeutic brain irradiation. Urgent therapeutic brain irradiation is recommended for rapidly evolving or more severe neurological deficits.

Palliative radiotherapy for locally advanced or metastatic SCLC is guided by the same principles as NSCLC (see above 6.4.1).

Reference:

1. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-72, 2007

6.2.3 Salvage Therapy for Relapsed SCLC Patients

Updated January 2014

Guideline: Appropriately selected patients with recurrent small cell lung cancer achieve a palliative benefit from second-line chemotherapy.

Level of Evidence: 2

Recurrent SCLC cannot be retreated with curative intent. Patients that have tolerated initial chemotherapy poorly are likely to have worse toxicity with re-treatment. Disease progression within three months is particularly unfavorable. Patients with longer remissions, particularly those that are free from progression for six months to one-year may be considered for combination chemotherapy. When the time to progression is long (a year or more) platinum and etoposide may be repeated. As always, performance status is a powerful prognostic factor and predictor of response plus toxicity.

A number of other drugs have been recommended for recurrent SCLC including topotecan. A randomized trial of patients that were progression-free for at least 2 months compared topotecan to CAV. The results were poor and not significantly different between the arms. Although topotecan has been approved for recurrent SCLC, the five day topotecan regimen is inconvenient and must be monitored carefully for toxicity (Protocol LUSCTOP). Topotecan has never been demonstrated superior to other salvage regimens for improved survival. Other schedules of topotecan such as a weekly regimen may have a better therapeutic index. Oral topotecan has been demonstrated superior to supportive care only in the second-line setting (O’Brien). To date, there is no trial that has shown survival superiority of one salvage regimen over another.

Because of toxicity issues associated with topotecan, irinotecan has been increasingly used by the BCCA lung systemic group. The LUSCPI protocol delivers irinotecan on days 1 and 8 on a 21 day schedule. Irinotecan may be used as a single agent if the time to progression is short. If the time to progression is long and the patient is clinically suitable, irinotecan can be combined with a platinum. This regimen is associated with more predictable myelosuppression and less diarrhea than topotecan (Zatloukal 2010)

Although monotherapy with oral etoposide has been demonstrated inferior to combination chemotherapy as first-line chemotherapy for SCLC, oral etoposide may still be useful in relapsed patients that are reluctant to receive intravenous chemotherapy but would consider oral therapy. Etoposide 50 mg po bid for seven days every three weeks (LUSCPOE) appears less toxic than higher dose regimens. Cyclophosphamide and anthracycline regimens are sometimes used in this setting (Protocol LUSCCAV).

Relapsed SCLC with carcinomatous meningitis has a very poor prognosis that is difficult to change. Improvement in neurological function with intrathecal chemotherapy for carcinomatous meningitis from SCLC is only occasionally observed and such treatment should be considered only for patients with good performance status and reasonably well controlled disease outside the central nervous system. Palliative radiotherapy to areas of symptomatic involvement may be useful in delaying neurological deterioration.

References:

  1. Van Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-667, 1999.

  2. Murray N, Turrisi A. A review of first-line treatment for small-cell lung cancer. J Thorac Oncol. 1:270-278, 2006

  3. O’Brien M, Ciuleanu T, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 24:5441-5447, 2006

  4. Zatloukal P, Cardenal F, Szczesna A, et al. A multicentre international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in small cell lung cancer with extensive disease. Ann Oncol 21:1810-1816, 2010

6.2.4 Targeted Therapy for Small Cell Lung Cancer

Updated January 2014

Despite considerable efforts, there is no phase III evidence at this time that any type of targeted therapy or immunotherapy has any role in the treatment of small cell lung cancer.

Reference:

1 Abidin AZ, Garassino MC, Blackhall F, et al. Targeted therapies in small cell lung cancer: a review. Ther Adv Med Oncol 1:25-37, 2010

2 Murray N, Salgia R, Fossella F. Targeted molecules in small cell lung cancer. Semin Oncol 31:106-111, 2004

6.3 Follow-up Practice Guidelines

The ability to develop evidence-based guidelines for surveillance and follow-up based on the literature suffers from the lack of randomised studies comparing empiric follow-up with specific follow-up strategies.

1. Follow-up of Patients Treated with Curative Intent

Guideline: For patients treated with curative intent, in the absence of symptoms, a history and physical examination should be performed every 3 months during the first 2 years; every 6 months thereafter through year 5; and yearly thereafter. Although it is reasonable to perform periodic chest radiographs as part of routine follow-up, there is no role for routine scanning (CT, MRI, radionuclide bone scan, PET) or bronchoscopy in asymptomatic patients. Smoking cessation and avoidance of occupational and environmental exposure to carcinogenic substances are recommended as effective interventions to reduce the risk of second primary NSCLC in curatively treated patients.

Level of Evidence: III

Grade of Recommendation: C

Patients in this category include those with resected Stage I, II and IIIA NSCLC (with or without post-operative adjuvant radiotherapy), stage III NSCLC patients treated with radical radiotherapy or combined modality therapy and limited stage SCLC patients treated with combined modality therapy. The responsible physician should be explicitly clarified by the doctor in charge at the BCCA. Patients on investigational trials should be monitored at intervals indicated by their respective studies.

The goal of monitoring patients after potentially curative therapy for lung cancer is to detect symptomatic progression of their disease which may benefit from therapeutic intervention or symptom management. Retrospective studies of lung cancer follow-up showed no evidence for an improved outcome from early detection of an asymptomatic recurrence and there was no evidence that more intense follow-up improved any outcome (Walsh 1995, Virgo 1995). Potentially, detection of a second primary could be of value but as with screening (section 3), such investigation has not been proven to reduce cancer mortality. Long-term survivors from lung cancer are potential candidates for early detection studies depending on the general condition of the patient and the likelihood that curative treatment could be undertaken in case of detection of a metachronous lung cancer. Other goals of follow-up include gathering outcome data (toxicity, survival) and provision of reassurance/psychological support.

Some asymptomatic patients or their physicians may seek further reassurance through performance of regular CT or MRI imaging procedures. The study of Walsh et al. showed that only 10% of asymptomatic recurrences and only 2.2% of all recurrences were detected by such tests. About 80% of relapses are detected by history/physical examination. Special investigations are recommended for symptomatic patients who are amenable to undergo therapeutic or symptomatic interventions.

2. Follow-up of Patients Treated With Palliative Intent

For patients treated with palliative intent, follow-up depends on symptomatology and treatment modality used. Efficacy and side effects of therapies deployed should be documented. Understandably, patients enjoying a palliative remission may develop unrealistic expectations for continued remission. A structured follow-up recommendation helps provide the reassurance and psychological support these patients need. The BCCA doctor in charge should explicitly clarify the physician in charge of palliative patient follow-up. For patients followed by their referring physicians, the BCCA physicians will act as consultants if requested.

Key References

  1. Walsh GL, O'Connor M, Willis KM, et al: Is follow-up of lung cancer patients medically indicated and cost-effective. Ann Thorac Surg 60:1563-72, 1995.

  2. Virgo KS, McKirgan LW, Caputo M, et al: Post treatment management options for patients with lung cancer. Ann Surg 222:700-710, 1995.

  3. ASCO Special Article: Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997

3. Follow-up of Patients Treated with Palliative Radiation Therapy

In general, after treatment, patients will be followed through their referring physician or family doctor unless the radiation oncologist involved states otherwise.

Key References:

  1. Sullivan FJ. Palliative radiotherapy for lung cancer. Lung Cancer: Principles and Practice. Pass HI, Mitchell JB, Johnson DH, Turrisi AT. Lippincott-Raven, Philadelphia, 1996,pp775.

  2. Bleehan N. Inoperable non-small cell lung cancer (NSCLC): a Medical Research Council randomized trial of palliative radiotherapy with two fractions or ten fractions. Br J Cancer 1991;63:265.

  3. Medical research Council Lung Cancer Working Party. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Br J Cancer 1992;65:934.

SOURCE: Lung ( )
Page printed: . Unofficial document if printed. Please refer to SOURCE for latest information.

Copyright © BC Cancer Agency. All Rights Reserved.

    Copyright © 2017 Provincial Health Services Authority