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.

Assessment of Intrathoracic Extent of Disease 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).

Diagnostic Imaging
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 detect enlarged nodes but has inadequate sensitivity and specificity to supplant mediastinoscopy. The major role of CT at this time is to direct the thoracic surgeon to abnormal nodes and to detect synchronous/metastatic cancers that are not visible on the chest radiograph. Conventional radiological tomography has no role in mediastinal assessment.

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

Positron emission tomography (PET) scanning is a new technology that is not routinely available within British Columbia at this time but arrangements for appropriate cases are possible. Its role in the routine staging of lung cancer has not been established but preliminary reports indicate that it may be useful in selected cases.

Mediastinoscopic evidence of metastases to N3 lymph nodes indicates inoperability (Stage IIIB). Mediastinoscopic evidence of metastases to N2 position nodes (Stage IIIA) 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 6.4.1.2.2)

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).

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.

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.

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.

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. ASCO Special Article: Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 15:2996-3018, 1997  
2. Pugatch RD: Radiological evaluation in chest malignancies. A review of imaging modalities. Chest 107:S294-S297, 1995 (suppl 6)  
3. Quint LE, Francis IR,Wahl RL, et al: Preoperative staging in non-small cell carcinoma of the lung: Imaging methods. AJR 164:1349-1359, 1995

The Canadian Lung Oncology Group: Investigation for mediastinal disease in patients with apparently operable lung cancer. Ann Thorac Surg 60:1382-1389,1995.

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.

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