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Melanoma

1. Melanoma Incidence, Demographics, Predisposing Factors and Prevention

​Revised 14 Februrary 2013

Melanoma is an important cancer in terms of individual person-years of life lost, since the incidence is over a broad age range, diagnosis frequently occurs in young adults, and at a time of intense family responsibility and financial commitment. However, melanoma is both potentially preventable (section 6.1) and curable (section 6.2), if detected early (section 3).

 Link to Skin Cancer Atlas. 

Incidence

The incidence rates of malignant melanoma continue to increase in men over age 45 and women over age 65 in B.C., but have stabilized or are declining at younger ages. Mortality rates continue to increase in men and women over age 65. It is estimated that there will be over 800 new cases of malignant melanoma in B.C. in 2009, and over 4,500 new cases in Canada, per annum.

See BCCA cancer statistics.

Causes and Prevention

Epidemiologic studies have shown that excessive exposure to sunlight plays the major role in the development of melanoma. Intermittent exposure to intense sun exposure in recreational and vacation activities is the main hazard. Exposure to other sources of ultraviolet radiation, for example from sunbeds, also increases the risk. First exposure to sunbeds prior to age 35 carries a particular increased risk. Fair skinned individuals who tan poorly and burn readily are at the greatest risk. Other identifiable risk factors include the presence of dysplastic nevi, increased number of melanocytic nevi, and family history of melanoma.

As a public health measure everyone needs to be aware of the risks of excess sun exposure. These risks can be minimized through the reduction of intense exposures, particularly during summer and on vacations, by seeking shade, avoiding exposure during the middle hours of the day, wearing UV protective clothing and using sunscreens as described in the section on other skin cancers.

The skin cancer risk of sun tanning salons is well established and therefore should be discussed with the patients.

Screening of Average Risk People

General population screening for cutaneous malignant melanoma either by regular clinical assessment or by self-screening is not recommended, as no trials have demonstrated that such screening decreases mortality.

Surveillance of High Risk Individuals

Individuals at high risk are those with a previous melanoma or a strong family history of melanoma (2 or more first degree relatives with the disease), who may carry a p16(INK4A) germline mutation, predisposing to the disease, and those with atypical nevus syndrome (formerly Dysplastic Nevus Syndrome). Such individuals should be under regular (for example, annual) surveillance, ideally by a dermatologist.

2. Potential Precursors of Melanoma

Revised July 2014


While melanomas can occur in childhood, they are rare. Clinicians should be alert, as melanomas in childhood can be confused with a benign Spitz nevus. A careful review of pathology may spare disfiguring surgery.

1. Common Acquired Melanocytic Nevi

Evidence for the role of common acquired nevi as precursors of melanoma is at present morphological and depends on the histological identification of benign nevus cells in contact with melanoma cells. The frequency with which benign acquired melanocytic nevi develop into melanoma is extremely low given the average number of nevi per person and the relatively low rate of melanoma around the world.

2. Atypical Nevi 

Atypical nevi were first recognized as an autosomal dominant condition in the setting of hereditary melanoma. It is now recognized that atypical nevi may also appear in a non-hereditary setting. In both these situations, atypical nevi are markers for individuals at increased risk to develop melanoma. The clinical features of atypical nevi are generally: - >6 mm; colour - multiple shades of brown, or red-brown; shape - irregular; surface - pebbly or centrally raised; border - poorly demarcated. The diagnosis of atypical nevi should be based on clinical and histologic criteria. However, the correlation between clinical and pathologic diagnosis is rather poor. This could be in part due to the focal nature of the pathology which may be missed on routine histologic sections. The problems in diagnosis suggest clinical diagnostic criteria need to be refined.

Atypical nevi are potential precursors of melanoma. This has been documented clinically with photographs. Histologically, atypical nevi have been found in continuity with melanoma in a number of reported series. In addition, atypical nevi are markers for increased melanoma risk on normal skin on the affected individuals. Patients with atypical nevi need regular skin surveillance. 

See: Management ​of atypical nevi.

3. Congenital Melanocytic Nevi

Congenital melanocytic nevi (CMN) can be arbitrarily classified into 4 categories according to size: giant, >40 cm in diameter, large, between 20 cm and 40 cm in diameter; medium, between 1.5 cm and 20 cm in diameter, and small, <1.5 cm in diameter. CMN are usually raised and hairy. The incidence of CMN in the general population is about 1%. CMN carry an increased risk for developing melanoma. The magnitude of melanoma lifetime risk for small and medium CMN has not been conclusively determined but is likely <1%. For large and giant nevi, the risk of melanoma appears to be approximately 2%.

See: Management ​of congenital melanocytic nevi​

3. Surveillance and Early Detection in High Risk Patients

Revised May 2014


Importance of Early Detection

Screening of high risk individuals to facilitate early detection is of vital importance in the management of melanoma. Survival is directly related to the depth of tumour invasion.

Clinical Clues for Early Detection (but these signs apply more generally)

The most reliable and most widely used criteria to identify lesions that require a biopsy to rule out melanomas is the “ABCDE” acronym.

A: Asymmetry in the shape
B: Border irregularity
C: Color variegation
D: Diameter greater than 6 mm (not absolute)
E: Evolving morphologically or symptomatically (such as growth faster than other lesions, pruritus, pain, bleeding and crusting).

Any nevus or a "mole" that undergoes a significant change in, shape or color, and a mole that causes symptoms of itching or burning should be suspect to be a melanoma. If there is a substantial concern about melanoma, excisional biopsy is indicated. Partial biopsy (such as a punch or incisional biopsy) of an acquired nevus is, because of sampling error, not generally recommended.

4. Diagnosis

​Revised March 2014

1. Classification Criteria

Melanoma may be classified into the following groups based on clinical and histologic criteria: 
         
            Growth Pattern                                            Frequency
a) Superficial spreading melanoma (SSM)                      65%
b) Nodular melanoma (NM)                                               25%
c) Acral-lentiginous melanoma (ALM)                               5%
d) Lentigo maligna melanoma (LMM)                                5%

SSM may arise in a pre-existing mole with a radial growth phase prior to vertical growth phase and invasion, while NM lacks an identifiable radial growth phase. ALM often masquerades as either subungual hematoma, or hematoma of the sole of the foot. Delay in diagnosis can be avoided by having a high index of suspicion. LMM is a relatively indolent melanoma occurring in chronically sun-damaged skin on the head and neck.

2. Diagnostic Pathology

Biopsy and Pathological Assessment

Pathological assessment of atypical or malignant melanocytic lesions is required to confirm the diagnosis, and if malignancy is present, to provide prognostic information.

An appropriately placed biopsy is important, as melanocytic lesions tend to be polyclonal and quite variable from one area to another. An excisional biopsy, which includes normal tissue around the periphery, is desirable whenever clinically feasible. If it is not possible for cosmetic or functional reasons then a single or multiple incisional or punch biopsies may provide adequate information. Superficial shave biopsy is strongly discouraged.  If there is considerable variation in pigmentation, it is recommended that more than one area be sampled. Any palpable tumour with elevation of a portion of the lesion or a nodular component, whether it is pale, pink or pigmented should be sampled.

The best predictor of recurrence from histologic evaluation of the primary lesion is depth of invasion, measured by micrometer (Breslow depth) and histological ulceration. Dermal mitotic activity has been identified as an important prognostic factor in thin melanomas (1 mm. or less in thickness) and is included in the staging system. (Balch CM et al. Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol. 2009; 27(36):6199-206).  Other features such as the Clark’s level of invasion, lymphatic invasion, and lymphocytic response all contribute to the prognosis but are of lesser significance.

A checklist of the details required in a pathology report of melanoma is available from the College of American Patholgists website. (Frishberg D et. al. (2013, October). Protocol for the Examination of Specimens From Patients With Melanoma of the Skin. Retrieved from http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2013/SkinMelanoma_13protocol_3300.pdf

Fine needle aspiration cytology is not recommended for diagnosis of primary lesions although it may be useful in the assessment of metastatic disease such as satellite skin nodules or in regional lymph nodes.

In some patients, the diagnosis of malignant melanoma, dysplastic nevi or Spitz nevi may pose a very difficult problem. The pathologists in the Skin Tumour Group, who provide a provincial consultative service, may be most helpful with these problems.

5. Staging

Revised June 8, 2016


1. Classification Criteria Used for Melanoma Staging

Please refer to the2010 edition of the AJCC staging system and see references.

Primary Tumour

T Classification

Thickness (mm)

Ulceration Status/Mitotic Rate

T1

≤ 1.0

a: without ulceration and <1 mitosis/mm2
b: with ulceration or ≥ 1 mitosis/mm2

T2

1.01 - 2.0

a: without ulceration
b: with ulceration

T3

2.01 – 4.0

a: without ulceration
b: with ulceration

T4

>4.0

a: without ulceration
b: with ulceration

TX primary tumour cannot be assessed; T0 no evidence of primary tumour; 
Tis melanoma in situ

Regional Lymph Nodes

N Classification

Number of Metastatic Nodes

Nodal Metastatic Mass

N1

1 node

a: micrometastasis
b: macrometastasis

N2

2-3 nodes

a: micrometastasis
b: macrometastasis
c: in transit met(s)/satellite(s) without metastatic nodes

N3

4 or more nodes, or matted nodes, or in transit met(s) with metastatic nodes

 

 

Distant Metastasis

M Classification

Site

Serum LDH

M1a

Distant skin, subcutaneous or nodal metastases

Normal

M1b

Lung metastases

Normal

M1c

All other visceral metastases
Any distant metastasis

Elevated

 

Clinical Staging

Stage 0

Tis

N0

M0

Stage IA

T1a

N0

M0

Stage IB

T1b
T2a

N0
N0

M0
M0

Stage IIA

T2b
T3a

N0
N0

M0
M0

Stage IIB

T3b
T4a

N0
N0

M0
M0

Stage IIC

T4b

N0

M0

Stage III

Any T

≥N1

M0

Stage IV

Any T

Any N

M1


2 Investigations for Staging

The initial staging work-up should include a thorough history and physical examination, with special attention to the skin and lymph nodes. Any abnormal finding should direct the need for further studies to detect regional and distant metastases. In asymptomatic patients with localized melanoma of any thickness, routine blood tests and imaging studies are not recommended. LDH is an insensitive marker for metastatic disease and is not clinically useful. Routine surveillance chest x-ray, computed tomography (CT) and positron emission tomography (PET) are limited by a low yield for the detection of metastases and a relatively high false-positive rate. Imaging studies should be performed only as clinically indicated for the investigation of suspicious signs or symptoms which may alter clinical management.

Sentinel lymph node biopsy (SLNB) is a staging procedure for melanoma that is optional. For a discussion of its role in melanoma staging, see section 6.2

Referen​​​​ces:

  1. NCCN Clinical Practice Guidelines in Oncology: Melanoma. V.3. 2011.
  2. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. Melanoma of the skin. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer-Verlag; 2010.

6.1 Melanoma Precursors

Revised January 2008


Link to Skin Cancer Atlas

Common Acquired Melanocytic Nevi
An average adult has 20-40 nevi. An individual with an increased number of common acquired melanocytic nevi has an increased risk of developing melanoma and should be counseled to avoid excessive sun exposure and to have regular skin examinations. As the risk of melanoma transformation in a common acquired melanocytic nevus is extremely low, prophylactic removal is not warranted.

Atypical Nevi
The exact risk of melanoma transformation in atypical nevi has not been established. Not all atypical nevi will evolve into melanoma. In fact, most atypical nevi will remain clinically stable and never progress to melanoma. It is recommended that those atypical nevi that appear clinically very atypical be excised (i.e., lesions with very irregular shape, marked pigment variegation, asymmetry in shape or pigment distribution). These atypical nevi may be clinically indistinguishable from melanoma. Nevi with slightly atypical features (i.e. symmetrical lesions with two-shades of brown, slightly fuzzy borders, or slightly irregular shape) generally do not warrant prophylactic excision. When in doubt, a Dermatologist should be consulted.

As discussed, atypical nevi are both potential precursors and markers for melanoma. In people with these lesions, melanoma can develop both from atypical nevi or de novo in normal appearing skin. These individuals should be advised to have regular follow-up skin examinations at 6 to 12 month intervals and to avoid excessive sun exposure. Atypical nevi may occur sporadically or be inherited in an autosomal dominant fashion. Therefore, it is suggested that first degree relatives be examined to determine if they too have atypical nevi.

Congenital Melanocytic Nevi (CMN)
It is recommended that large CMN be excised as early as possible, as the risk of melanoma transformation in infancy is high. Frequently, the complete excision will be carried out in several stages. Surgical excision significantly decreases, but does not completely eliminate the risk of melanoma as the CMN cells may be deep to the fascia or in leptomeninges that are not surgically accessible. Therefore, these patients should be kept under surveillance. Follow-up examination at 6 to 12 month intervals is generally recommended.

The management of small and medium CMN is controversial because the exact magnitude of the melanoma risk is unknown. Some experts recommend prophylactic excision while others recommend periodic observation only.

6.2 Biopsy Proven Malignant Melanoma

Revised September 2016​

Link to Skin Cancer Atlas

All patients are alerted that further surgery may be recommended, counseled about the possible appearance of a subsequent second primary and advised to avoid excess sun exposure and employ sun screen agents.

6.2.1 Management of the Primary Tumour

Documentation of the planned excision margin should be documented in the operative report. If SNLB is being considered, it would be advisable to perform the wide excision after the SLNB so as not to affect the accuracy of the SLNB.

1. Minimal Risk Non-Invasive Disease (Severe Atypical Nevi and Melanoma in-situ)

Lesions in this category include severe atypical nevi (with features suggesting possible in-situ melanoma), and in-situ melanoma. Such lesions are best excised with a 0.5 to 1 cm margin. In selected cases of lentigo maligna of the face, where the cosmetic results of surgery would likely be disfiguring, radical superficial irradiation is an alternative treatment.

2. Depth of invasion ≤ 1 mm 

For primary invasive melanoma 1.0 mm or less in thickness, wide excision with 1 cm margin is recommended.

3. Depth of invasion ≥ 1 – 2 mm

Based on consensus opinion, an excision margin of 1-2 cm is recommended with considerations given to tumour location, function and cosmesis.

4. Depth of invasion >2 mm

An excision margin of 2 cm is recommended. This can usually be accommodated with primary closure and an excellent cosmetic result. Primary closure is encouraged where possible. Flap repairs may assist in obtaining a good cosmetic repair. When a split thickness skin graft is used, the donor site should not be on the same extremity as the primary site. The excision should extend down to, and may include, the underlying fascia. Sometimes the recommended margin is not practical, particularly on the face, and narrower margins may be appropriate (consult BCCA oncologist). 

For tumours of the digits, amputation at the proximal joint is often indicated. Adequate excisions may require general or regional anesthesia. Consultation with the Melanoma Clinic may be especially helpful for problem cases. Where clinical or pathological features (eg neurotropic pattern) suggest local control may be problematic, wider margins may be recommended.

6.2.2 Management of Regional Lymph Node Basins

1. Prophylactic regional lymph node dissection (PRLND) is NOT recommended

In randomized phase III clinical trials PRLND has not been shown to be of therapeutic benefit (Balch, Ann. Surg 224:255; 1996). Routine PRLND is not recommended. Exceptions can be made if the primary tumour overlies the regional nodes, making future follow-up technically difficult.

2. Sentinel Lymph Node Biopsy (SLNB) and Completion Lymphadenectomy

While the status of sentinel lymph node has been found to be the best prognosticator, SLNB followed by completion lymphadenectomy, if the node is positive, has not been shown to improve overall survival. Thus, SLNB is considered a staging procedure which is optional. Whether early detection of occult nodal disease and completion lymphadenectomy provides greater regional control has not been definitively shown. 

SLNB is not recommended for patients with melanoma in situ or Stage 1A melanoma.

In patients with Stage 1B melanoma according to the 2009 AJCC Classification (i.e. T1b: melanoma ≤ 1 mm with presence of increased mitotic rate or ulceration), the benefit of SLNB for prognostication is untested. 

SLNB should be discussed with patients with Stage 2 or higher melanoma (melanoma >1 mm). Patients should be informed that it is an optional procedure which provides prognostic information but has not been shown to affect overall survival so that they can participate in the informed decision process.

SLNB should be performed in strict accordance with published standard technique. SLNB for head & neck melanomas is technically more challenging and requires special considerations and expertise. The BCCA melanoma group is available for consultations if necessary.

Patients with documented distant or regional metastasis should not undergo SLNB..

3. Therapeutic/Selective Regional Lymph Node Dissection

Patients with documented regional lymph node involvement (palpable or found with SLNB) should be considered for regional lymphadenectomy. The therapeutic benefit of completion lymphadenectomy for micrometastasis <0.2 mm (defined as metastatic focus found in SLNB) is controversial. Discussion of the management of these cases at BCCA Melanoma Conference is encouraged.  

Prior to surgical intervention, a CT scan of the abdomen/pelvis, chest +/- brain should be done to rule out metastatic disease. PET imaging may also be helpful in selected cases. In the setting of suspected distant metastatic disease, a regional lymphadenectomy is only recommended in selected cases, and consultation with a member of the BCCA Skin Tumour Group would be advised.

A full Level I-III dissection is recommended for axillary involvement. Groin involvement should be treated with an inguinal +/- iliac lymph node dissection (an iliac dissection is suggested if there is radiographic disease evident on CT or PET, and can be considered if there are greater than 3 inguinal lymph nodes involved). Head and neck melanomas should be treated with a level II-V dissection +/- level I / superficial parotidectomy depending on the location of the primary lesion.

4. Adjuvant Systemic Therapy

Interferon 

The role of adjuvant high dose interferon (SMAJIFN) has been studied extensively. A meta-analysis of individual patient data in 13 trials of interferon in different doses and schedules showed an improvement in overall survival by an absolute value of 3% (95% confidence intervals 1-6%) at 5 years. The benefit was unrelated to dose or schedule of interferon, or disease stage, primary site, age or gender (Wheatley et al, Proc ASCO 2007). SMAJIFN was introduced in BC after the first ECOG trial (E1684) showed a survival benefit (Kirkwood JM, et al. J Clin Oncol 1996; 14: 7-17). A subsequent analysis of this trial, presented in abstract form, demonstrated that with longer follow-up, the overall survival difference was no longer significant (p = 0.09). Individual trials of low dose interferon have not generally shown an overall survival benefit.

A more recent trial evaluated whether 1 month induction of high dose interferon was equally efficacious but less toxic than 1 month induction followed by 48 weeks of subcutaneous interferon (Pectasides et al, 2009 ). The event-free and overall survival was similar in the treatment groups, however, the induction dose of interferon used was only 15 million units (versus 20 million units), confounding interpretation of the study results. In addition, the results of the ECOG/NCIC study ME10 were recently reported (ASCO 2011) in which intermediate risk melanoma (T3/T4 and/or SNL positive) patients were randomized to the standard dose interferon or observation and the study was stopped prematurely due to a futility analysis. These results question the efficacy of interferon, however, if used, the one year course should be planned if tolerated. 

High dose interferon should only be offered after complete regional lymph node dissection and to patients with no residual disease.  Currently, the BCCA will fund interferon in patients with macroscopic nodal involvement that has been resected but other high risk cases can be considered on a case by case basis.  If radiation is planned, use of interferon should be avoided during radiation therapy and initiated after full recovery (4-6 weeks). Notable side effects for interferon include, severe flu-like symptoms, hepatic toxicity and neutropenia particularly in the induction phase. Depression and autoimmune phenomena have also been reported. Caution in elderly patients as this group has not been well studied. 

5. Radiation Therapy of Clinically Positive Lymph Nodes

Following lymph node dissection, high dose post-operative irradiation should be considered for any of the following: 

  • Microscopic identification of extranodal extension
  • Microscopic evidence of residual disease
  • Extensive nodal disease (where complete resection is unlikely)
    • One or more involved parotid nodes
    • Two or more cervical or axillary nodes
    • Three or more inguinal nodes
  • Resected, but bulky nodal disease with the largest mass >3cm diameter

Where regional lymph node disease is considered unresectable or inoperable for the patient, palliative radiation therapy may be considered to achieve local control.

Reference:

Burmeister BH, Henderson MA, Ainslie J, Fisher R, Di Iulio J, Smithers BM, Hong A, Shannon K, Scolyer RA, Carruthers S, Coventry BJ, Babington S, Duprat J, Hoekstra HJ, Thompson JF: Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomized trial. Lancet Oncol 2012; 13:589-97.

6.3 Recurrent and/or Metastatic Disease

Revised September 2016

Surgery 


Locally recurrent or in-transit metastatic disease may be well treated with surgical excision, especially if the disease is limited and there has been a long disease-free interval. This does not necessitate a wide margin. Since further recurrences are not uncommon, consideration should be given to referral for isolated limb infusion, radiation, or possible trial enrollment in the setting of multiple recurrences, or unresectable disease.

Surgical intervention is only occasionally recommended for distant metastatic malignant melanoma. Metastases of melanoma to brain are usually multiple, even if the initial presentation is of a single lesion. However, consideration should be given to surgical excision of an apparent solitary brain metastasis, especially when there is no known further metastatic involvement of other organs. Under these restricted conditions, there has been a prolonged disease-free interval with excision of a surgically accessible apparent single brain metastasis. A similar case can be made for apparent solitary lung, bowel or solitary liver metastasis when there has been an extended disease free interval, long doubling time and control of all other sites. It is emphasized that excision of solid organ metastases in melanoma has not yielded the benefit experienced when the same strategy is employed for sarcomas. Patients being considered for metastatectomy should be thoroughly investigated with CT or MRI, and PET. Referral to the BCCA Skin Tumour Group for consultation is highly recommended. Please see also radiation oncology section for stereotactic radiotherapy.

Radiation Therapy

Although not all patients will respond to irradiation, a substantial proportion will do so. Palliative irradiation is the most effective treatment for local control of symptomatic metastatic disease. Its use is considered when local disease produces local symptoms which are potentially reversible by irradiation. Examples are painful or about to ulcerate/bleed subcutaneous nodules, painful bone metastases, spinal cord compression, haemoptysis and brain metastases. Stereotactic radiation therapy may be considered for a solitary / oligometastatic unresectable brain metastasis or for a solitary small recurrence after resection and whole brain radiation.

Systemic Therapy

Historically, patients with metastatic melanoma have a median survival of approximately 6 months (Korn et al JCO 2008) and in those with high risk disease with visceral metastases such as liver or CNS, the survival is typically 3-4 months. Patients with limited metastases particularly in lung, skin or soft tissue should be considered for metastatectomy as long-term survival has been reported. Patients with solitary metastases with good performance status and typically long duration of remission from primary disease, should also be considered for surgical resection.

For surgically incurable metastatic melanoma, participation in clinical trials is the preferred course. To determine the status of ongoing studies consult a medical oncologist at one of the BCCA Centres.

Targeted Therapy

BRAF mutations have been identified as the most frequent mutation in cutaneous melanoma, with approximately 40-60% of cases carrying mutations in BRAF V600 kinase with higher frequencies observed in younger patients. Mutations in the BRAF V600 kinase leads to constitutive activation of the downstream MAPK pathway (Hoeflich et al, Cancer Res. 2009). BRAF and MEK tTargeted therapies are only effective in tumors that are BRAF mutation positive.

BRAF mutations have been identified as the most frequent mutation in cutaneous melanoma, with approximately 40-60% of cases carrying mutations in BRAF V600 kinase with higher frequencies observed in younger patients. Mutations in the BRAF V600 kinase lead to constitutive activation of the downstream MAPK pathway (Hoeflich et al, Cancer Res. 2009). BRAF and MEK targeted therapies are only effective in tumors that are BRAF mutation positive. 

Testing for the V600E BRAF mutation status:  Single BRAF gene testing is available at the VCC-BCCA through the Molecular Genetics Laboratory and performed on paraffin-embedded formalin fixed tissue. BRAF mutation requests should only be performed in stage 4 metastatic melanoma or stage 3 unresectable melanoma as the role of BRAF inhibitors in the adjuvant setting is unknown at this time..In addition, oncopanel, which tests a variety of targetable mutations across solid tumors, is also recently available as a preferred option for BRAF testing as it detects the more uncommon variants and also provides KIT and NRAS mutation status.    Access the Pathology Request Forms through Laboratory Services here.

Vemurafenib

Vemurafenib is an oral (960 mg twice daily) potent and selective inhibitor of mutated BRAF that has been shown to inhibit cell proliferation and induce cell death. Vemurafenib has demonstrated statistically significant clinical benefit and manageable safety profile in treatment-naïve and previously treated metastatic melanoma patients whose tumors (primary or metastatic) are positive for mutated BRAF V600. BRIM3, a randomized controlled study comparing vemurafenib to DTIC in untreated patients with unresectable or metastatic melanoma with the V600E mutation, demonstrated improvement in overall survival and progression-free survival (5.3 months vs 1.6 months P<.001) (Chapman et al, NEJM 2011). Overall survival was significantly prolonged with vemurafenib compared with dacarbazine (13.6 versus 9.7 months, HR 0.70, 95% CI 0.57-0.87).  Progression-free survival was also significantly prolonged (6.9 versus 1.6 months, HR 0.38, 95% CI 0.32-0.46). The best ORR (BORR) was 48.4% in the vemurafenib arm versus 5.5% in the dacarbazine arm. The FDA approved Vemurafenib (trade name Zelboraf) for untreated and previously treated metastatic melanoma last year and in February 2012, Health Canada also approved the drug. Late 2012, the BCCA approved funding for vemurafenib through the Compassionate Access Program (CAP) in BRAF mutant metastatic melanoma. Patients receive vemurafenib until progressive disease or unacceptable toxicity.

Further support for the efficacy of vemurafamib comes from the phase II BRIM 2 multicenter trial evaluating the efficacy of vemurafenib in BRAF V600E mutation positive metastatic melanoma patients who have received at least one prior systemic therapy (n=132) (Ribas et al, JCO 2011). With a median follow-up of 12.9 months, (Sosman et al, NEJM 2012) the  confirmed overall response rate was 53%, with a 6% complete response. The median DoR by IRC was 6.7 months and median PFS was 6.8 months and the median OS was 15.9 months (95% CI, 11.6 to 18.3).

In both studies, the most common side effects are photosensitivity, arthralgia, rash, fatigue, alopecia, nausea, and diarrhea as well as excisable keratocanthoma or cutaneous squamous-cell carcinoma. Patients who haven’t had a recent skin evaluation should see a dermatologist.  Rare QT prolongation can occur and patients require periodic ECG monitoring.   

Dabrafenib

Dabrafenib is another BRAF inhibitor with significant activity in patients with advanced melanoma compared with dacarbazine chemotherapy. It was also Health Canada approved for the treatment of patients with advanced melanoma with the V600 BRAF mutation. 

In the pivotal phase III trial (Hauschild et al., Lancet, 2012), patients with BRAF mutation positive unresectable stage III or IV melanoma were randomized to either dabrafenib (150 mg orally twice a day) or dacarbazine. Dabrafenib increased progression free survival compared with dacarbazine (median 5.1 vs. 2.7 months, HR 0.33, 95% CI 0.20-0.54). Overall survival favored patients treated with dabrafenib but was not statistically significant, although crossover was allowed. 

Treatment was generally well tolerated. The most frequent grade 2 or greater toxicities were dermatologic. Other grade 2 or greater toxicities observed included arthralgia, fatigue, headache, and fever. 

The BCCA has also endorsed funding for Dabrafenib and treating physicians can choose either Vemurafenib or Dabrafenib in BRAF mutant metastatic melanoma in untreated and previously treated patients with choice based on different side effect profiles. Although they have never been compared, efficacy across studies is similar.

Combination BRAF/MEK Inhibitors 

There are two different combinations of BRAF inhibitors plus MEK inhibitors which have shown to yield a higher response rate, longer progression-free survival, and longer overall survival compared with BRAF inhibition alone.

One such combination is dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor). Two phase III studies have been conducted (COMBI-d trial and COMBI-v trial). The COMBI-d trial (Long et al., Lancet 2015) compared dabrafenib plus trametinib to dabrafenib plus placebo in treatment naive patients with advanced melanoma with a V600 mutation. ORR was significantly improved (69 vs. 53%) and the CR rate was 16 vs 13%, respectively. Progression-free survival (median 11.0 vs. 8.8 months, HR 0.67, 95% CI 0.53-0.84) and overall survival (median 25.1 vs. 18.7 months, HR 0.71, 95% CI 0.55-0.92) was improved with the combination. Cutaneous toxicities were more common in the dabrafenib arm including dry skin, pruritis, hyperkeratosis, hand-foot syndrome, alopecia, and skin papilloma. SCC were seen in 9% with dabrafenib vs. 3% with the combination. Combination therapy was associated with higher risk of diarrhea, fever, and chills. 

The COMBI-v trial (Robert et al., NEJM 2015) compared dabrafenib plus trametinib to vemurafenib in BRAF mutated advanced melanoma. Overall survival was significantly increased with the combination arm (one-year survival rate 72% vs. 65%, HR for death 0.69, 95% CI 0.53-0.89). Median progression-free survival was significantly increased (11.4 vs. 7.3 months, 95% CI 0.46-0.69) as was the ORR (64 vs. 51%). The incidence of cutaneous SCC and keratoacanthoma was significantly decreased with combination therapy compared with vemurafenib alone. 

Another combination therapy is vemurafenib and cobimetinib, as studied in the coBRIM clinical trial (Larkin et al., NEJM 2014). This trial evaluated patients with previously untreated advanced melanoma randomly assigned to vemurafenib plus cobimetinib or vemurafenib plus placebo. Progression-free survival was significantly increased with combination therapy compared with vemurafenib plus placebo (median 12.3 vs. 7.2 months, HR 0.58, 95% CI 0.46-0.72). The overall ORR was increased with combination therapy (70 vs. 50%) as was the CR rate (16 vs 11%). There was a trend toward longer overall survival with combination therapy although longer follow up is required. 

In August 2016, the BCCA will launch funding of dabrafenib and trametinib in BRAF mutant metastatic melanoma and this is an option over BRAF monotherapy alone at the treating physicians discretion in previously treated or untreated patients.    Vemurafenib and cobimetinib has been Health Canada approved for the same indication and currently, cobimetinib can be accessed through the drug company.  Treatment with either dabrafenib and trametinib or vemurafenib and cobimetinib is at the discretion of the treating physician and largely guided by differences in the side effect profile.  

Immunotherapy

Ipilimumab

Ipilimumab (trade name Yervoy) is an anti-CTL4A antibody, which counters host immunosuppression associated with advanced melanoma. Phase 3 trials in first and second-line therapy have demonstrated improved OS with Ipilimumab. In the previously treated population comparing Ipilumumab to Ipilimumab + GP100 vaccine and GP100 vaccine alone, the median OS was 10 months with Ipilumumab vs 6.4 months with GP100 alone with no improvement seen with drug combination (Hodi et al NEJM 2010). This was the first trial to demonstrate an overall survival benefit with any treatment for metastatic melanoma. The front-line phase III randomized trial used a higher dose of Ipilimumab (10 mg/kg) in combination with DTIC versus DTIC alone in addition to a maintenance phase in the Ipilumumab-containing arm and similarly showed a superior OS (11.2 vs 9.1 months) using Ipilumumab (Roberts et al, 2011).

The approved dose in previously treated patients is Ipilimumab 3 mg/kg given each 3 weeks for 4 doses. Although Ipilimumab is not associated with a higher response rate than standard therapies, some patients have prolonged disease control.  Collectively, prior studies support that approximately 20% of patients achieve durable remissions and even cure with Ipilimumab.   Due to interference with T-suppressor cell function, the main side effects are autoimmune in nature with a predictable time course.  Rash occurs early followed by diarrhea which can progress to colitis, with pathologic changes reminiscent of Crohn’s disease, peak at 7 weeks and early steroid administration is critical or patients can be at risk of colonic perforation and even death. Other side effects can include endocrinopathy (panhypopituitarism, thyroid abnormalities, adrenal suppression), dermatologic (rash, rare severe stevens-johnson syndrome), hepatitis and neurologic dysfunction.  It is critically important that patients meet protocol eligibility criteria for Ipilimumab therapy and that it is given by oncologists at centres knowledgeable about adverse event management. Ipilimumab is not suitable for patients with rapidly progressive disease and/or performance status 2-4. Some patients with disease control after Ipilimumab may be eligible for re-treatment at the time of progression.

Ipilimumab was originally approved in pre-treated patients with metastatic melanoma in 2012 and in July 2015 it was launched at the BCCA in previously untreated with unresectable or metastatic melanoma.  However, with the approval and funding of the PD1 inhibitor pembrolizumab at the BCCA in June 2016, Ipilimumab is no longer funded in patients previously treated with these agents due to a lack of efficacy data in this population and poor cost effectiveness. Ipilimumab remains a treatment option for previously untreated patients, however, with the superior efficacy of PD1 inhibitors in this setting, there will be little role for ipilimumab in this group of patients.  

Anti-PD-1 Antibodies

Nivolumab and pembrolizumab are antibodies that target PD-1 (programmed death 1 protein), an immune checkpoint receptor expressed by activated T cells.  Activation of the PD1 pathway through interaction with the PDL ligands expressed on tumor cells results in melanoma tumor evasion.  By blocking this receptor, these agents restore the anti-tumor T-cell response against melanoma.  Similar to Ipilimumab, autoimmune (AI) toxicities can occur, however, the frequency of severe AI toxicities is much less.  In addition, as a class, PD1 inhibitors can also cause pneumonitis. 

Pembrolizumab 

Pembrolizumab is an anti-PD-1 antibody that has been studied in both the ipilimumab naïve and previously treated patients. In a phase I study (KEYNOTE-001), patients were treated with pembrolizumab in 4 cohorts using one of 3 dose schedules (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks). The ORR was 33%. The median OS was 24 months and the 3 year survival rate was 40%. There was no significant differences in outcomes between dose schedules.  Side effects were manageable with the most common toxicities being fatigue, rash, diarrhea, and arthralgias. 

Two phase III trials were conducted. In the KEYNOTE-002 study, patients with ipilimumab refractory advanced melanoma were randomized to pembrolizumab or chemotherapy. By central review, PFS was significantly improved with pembrolizumab compared with chemotherapy. ORR was higher for pembrolizumab when compared to chemotherapy. Pembrolizumab was well tolerated with the most common adverse events being fatigue, pruritis, and rash. Serious immune related toxicities were rare. In the pivotal KEYNOTE-006 study, patients were randomized to pembrolizumab at a dose of 10 mg/kg every 2 weeks or every 3 weeks or four doses of Ipilimumab at 3 mg/kg every 3 weeks. The estimated 6 month PFS rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for Ipilimumab. Estimated 12 month survival rates were 74.1%, 68.4%, and 58.2%, respectively. Response rates were improved with pembrolizumab every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%). Efficacy was similar in the 2 pembrolizumab groups. Treatment related events were lower in the pembrolizumab groups than in the ipilimumab group. 

Nivolumab

Nivolumab is not yet funded at the BCCA for metastatic melanoma.  

Updated results from the phase I/II study looking at nivolumab showed that the median overall survival was 17 months and the objective or partial responses were observed in 32% (Hodi et al., 2016 AACR Meeting). Based on the earlier studies, three phase III studies were conducted.

The CHECKMATE 066 study was conducted in previously untreated patients with BRAF wild type metastatic melanoma. Patients were randomly assigned to nivolumab (3 mg/kg every 2 weeks) or dacarbazine chemotherapy (1000 mg/m2 every 3 weeks) (Long et al., NEJM 2015). Overall survival was significantly increased in those treated with nivolumab. The one year survival rate was 73% vs. 42%, HR 0.42. PFS was also increased with nivolumab (median 5.1 vs. 2.2 months). The ORR was 40% vs. 14%.

The CHECKMATE 037 study randomized previously treated patients to receive either nivolumab or investigator’s choice chemotherapy (Weber et al., Lancet Oncology 2015). All patients had received prior anti-CTLA-4 therapy and a BRAF inhibitor if a V600 mutation was present. Interim analysis showed that objective responses were higher with nivolumab (32% vs. 10%). Median duration of response was longer with nivolumab (not reached versus 3.7 m) although median PFS was only marginally better with nivolumab (4.7 m vs 4.2 m). Responses were also seen in patients with BRAF mutation positive metastatic melanoma who had progressed on a prior BRAF inhibitor. 

The combination of nivolumab and ipilimumab was studied in the phase III CHECKMATE 067 study in previously untreated BRAF mutant and BRAF WT metastatic melanoma, (Larkin et al., NEJM 2015). The median PFS was longer for the combination compared to ipilimumab (11.5 vs 2.9 months) and numerically higher than nivolumab alone (6.9 months) although the study was not statistically powered for this comparison.  Similarly the ORR was also higher with the combination (57.7% vs 19%) (43.7% for nivolumab). However, combination therapy was associated with a rate of 55% grade 3 and 4 toxicities and the need for treatment discontinuation. Interestingly, the outcome was comparable in patients who had to stop treatment due to toxicity.   Combination therapy is currently available through an expanded access program.  

On June 1 2016, pembrolizumab was launched at the BCCA in previously untreated patients with metastatic melanoma and is accessed through the CAP program.  Subsequently, for BRAF mutant positive patients, pembrolizumab can also be used in patients who have been previously treated with BRAF +/- MEK inhibitors with the sequence chosen at the discretion of the treating physician.  For legacy patients who have been previously treated with ipilimumab and develop recurrent disease, pembrolizumab can be requested through CAP.  However, currently, for all other patients, pembrolizumab is not funded in patients who have previously received ipilumumab after June 2016.

Chemotherapy

Dimethyl triazeno imidazole carboxamide (DTIC) is the only approved chemotherapy agent for the management of metastatic melanoma, however, it has never been shown to have an overall survival benefit. The effectiveness of treatment is influenced by the site and extent of disease, but the overall response rate ranges from 9-29% with more recent trials with stringent response criteria showing responses of only 5-10% and complete remissions of < 3% (Cochrane review 2009). Patients with good performance status and non-visceral metastases are more likely to respond. Patients with mucosal and ocular primaries rarely respond to DTIC in the metastatic setting. Combination chemotherapy regimens have not proven superior to single agent DTIC in comparative trials.

Temozolomide, like DTIC, is a pro-drug of MTIC. However it does not require metabolism, has 100% oral bioavailability and penetrates the blood brain barrier. A randomized study showed a superior PFS but not OS and thus use is limited to patients with CNS metastases or intolerance to DTIC through the Compassionate Access Program.

Previous phase 2 studies have also shown a modest response rate of carboplatin and taxol in metastatic melanoma and may have a higher ORR than DTIC although these treatments have never been directly compared. CCNU has limited efficacy with CNS penetration and can be used in the relapsed setting.  Physicians can request carboplatin/taxol and CCNU can be accessed through CAP.  

Other Systemic therapies

Interferon has shown modest activity in malignant melanoma. The single agent response rate is modest (15%) and there is significant associated toxicity. Combinations of DTIC with interferon have not proved superior to DTIC alone.  Select cases may be considered through the Compassionate Access Program.

Prior to Ipilumumab, IL-2 was used, particularly in the U.S. The composite results of 8 clinical trials have previously demonstrated that high dose Interleukin 2(IL-2) has a low overall response rate (16%) with rare complete remissions (5%). A limited number of highly select patients with predominantly subcutaneous metastases demonstrated durable remissions (Atkins MB et al, J Clin Oncol 1999). However, these results have never been confirmed in a phase 3 trial. Further, IL-2 is associated with severe toxicity including hypotension, capillary-leak syndrome, sepsis, renal insufficiency and myocarditis, thus requiring ICU support. Bio-chemotherapy, which combines DTIC-based chemotherapy regimes with IL-2 and interferon has not fulfilled its early promise of superior survival, in spite of yielding higher response rates (Ives NJ et al., Proc ASCO 2007). IL-2 is not approved for use at the BCCA. 

Whole Limb Perfusion

Whole limb perfusion/infusion may be worthwhile for selected patients with unresectable in-transit metastases. This procedure is associated with significant morbidity and referral to Cancer Centre should be arranged prior to treatment. Whole limb perfusion/infusion should only be performed by surgeons/institutions with extensive experience in this type of treatment. Currently, B.C. patients are referred to Calgary after approval at the multidisciplinary melanoma conference.

Biological Response Modifiers

The use of biological response modifiers in metastatic melanoma remains investigational.

Topical imiquimod cream may be considered for large/non-surgically resectable lentigo maligna where radiotherapy would not be appropriate.

Intra-lesional BCG has been employed in the treatment of isolated cutaneous metastases from melanoma. Care must be taken with BCG treatment as fatal anaphylactic reactions have occurred.

References

  1. Korn EL, Liu PY, Lee SJ. Meta-analysis of phase II cooperative group trials in metastatic melanoma to determine progression-free and overall survival benchmarks for future phase II trials. JCO 2008 Feb 1; 26(4): 527-34
  2. Hoeflich KP, Herter S, Tien J, et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res 2009; 69(7): 3042-51
  3. Chapman PB, Hauschild A, Robert C et al. Improved survival with vemurafenib with BRAF V600E mutation. NEJM 2011; 364: 2507-16. 
  4. Ribas A, Kim KB, Schuchter LM et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. JCO 2011; 29(suppl):15s. abstr 8509.
  5. Sosman JA, Kim KB, Schuchter L., et al. Survival in BRAF V600 mutant advanced melanoma treated with vemurafenib. NEJM 2012 Feb 23;366(8):707-14. 
  6. Hauschild A, Grob J, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet 2012; 380: 358-65
  7. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386: 444-51
  8. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. NEJM 2015; 372(1): 30
  9. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. NEJM 2014; 371(20): 1867
  10. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with Ipilimumab in patients with metastatic melanoma. NEJM 2010; 363(8):711-723
  11. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. NEJM 2011; 364 (26):2517-2526
  12. Weber JS, Kuhler KC, and Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. JCO 2012; 30: 2691-2697
  13. Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Abstract 9503, ASCO 2016
  14. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumb versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002); a randomized, controlled phase 2 trial. Lancet Oncology 2015; 16(8); 908
  15. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. NEJM 2015: 372(26): 2521
  16. Hodi FS, Kluger H, Sznol M, et al. Durable long term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial (abstract CT001). 2016 AACR meeting.
  17. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. NEJM 2015; 372(4): 320
  18. Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomized, controlled, open-label, phase 3 trial. Lancet Oncology 2015; 16(4): 375
  19. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. NEJM 2015; 373(1); 23

6.4 Follow-up

Revised 22 Feb. 2011​​

​In the follow-up history special attention is paid to possible local, regional or distant recurrences, development of new or unusual pigmented lesions especially where there are changes in shape, colour, elevation, irregular pigmentation, pruritus, ulceration or bleeding. Areas of special interest on physical examination include the primary site, possible in transit metastases, regional lymph nodes and sites where distant metastases tend to appear (skin, lymph nodes, lung, liver, brain). The interval of follow-up surveillance varies depending on individual tumour characteristics:

1) Stage I   ​


First and Second Years
History and physical examination every 6 months. At each visit, particular attention should be directed to the skin and lymph nodes. 

Subsequent Years
Annual history and physical examination, including a complete skin assessment. Patients with low risk melanomas may have late recurrences (>10 years after treatment). Also, melanoma patients have an approximate 5% risk of developing a second melanoma. Therefore, melanoma surveillance should be life long.

Patients with a history of atypical mole or a strong family history of melanoma may require more frequent follow up.

2) Stage II, III  ​


First Two Years
  • History and phy​sical examination every 3 to 6 months
Third and Fourth Years
  • History and physical examination every 6 months
Subsequent to Fourth Year
  • Annual history and physical examination

3) Meta​​static Disease


Follow up as clinically indicated.

Referral Info for the New Patient

​Updated 23 January 2012 


Patients with uncomplicated, low risk melanoma (depth of invasion  1.0 mm, non-ulcerated) generally do not need to be referred to the BCCA. For patients with intermediate to high risk melanoma (depth of invasion > 1.0 mm, ulcerated,  1 mitosis/mm2), regional or distant metastatic disease, complicated lesions involving face or digits, referral to the BCCA is encouraged. 

Appointments for referral of patients can be made by telephoning the Admitting Department of any of the Cancer Centres: 

New patient referral form

Reports required for a new patient appointment

SOURCE: Melanoma ( )
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