TREATMENT PATHWAY FOR MELANOMA

By Gary M. White, MD


Consensus recommendations are constantly in flux. The following has been recommended in the past and the most recent reports should be consulted.

Complete Skin Examination

Every patient found to have a melanoma should have a total body skin examination (TSE). Just because a patient is found to have one melanoma does not mean s/he can't have two!

Palpable Nodes

If the lesion is a melanoma and the regional lymph nodes are palpable, then wide excision plus lymph node dissection should be done.

Sentinel Node Biopsy

In general, the criteria for offering SLN biopsy is changing with advances in medicine. The latest guidelines say that patients with less than 5% risk of positive SLN should not be offered SLN biopsy.

In the past, if the lesion is a melanoma with a thickness equal to or greater than 1 mm. and the lymph nodes are not palpable, then sentinel node biopsy may be offered. Sentinel node biopsy may also be indicated for any high-risk lesion, e.g. ulceration, mitotic rate ≥ 1 per mm, young age. A systematic review found that patients with regression had a lower likelihood of SLN positivity (OR 0.56) than patient without regression [JAMA Derm 2015;151;1301]. SLNB, as of this writing, is valuable for prognosis and staging, but not reducing mortality. It may be however, that with all the new therapeutic agents that have recently become available, SLNB in the future will prove valuable with regard to treatment. Studies are ongoing.

If the Sentinel Node is Positive, Should Complete Lymphadenectomy be Done?

The debate over this issue is onging, but in general, no. Several clinical trials have not found that completion lymph node dissection in the setting of a positive SLN does not improve overall or melanoma-specific survival, vs observation [Ann Surg Oncol 17:514-520, 2010]. (It does however reduce the risk of local recurrence.) In addition, completion lymph node dissection conveys a risk for lymphedema and wound complications, Therefore, while complete lymphadenectomy reduces the risk of relapse locally, it comes at the cost of more side effects and does not reduce mortality.

Surgical Excision

Surgical excision continues to be the treatment of choice with margins based upon the thickness of the melanoma. In the past, the following has been recommended:

Thickness Surgical Margin
in situ 5-10 mm
< 1 mm 1 cm
1 - 2 mm 1-2 cm
> 2 mm 2 cm

A study of 1587 patients with T3 melanoma (2-4 mm in thickness) at a single institution [Ann Surg 2014;260;1095] found that "a 1 cm surgical margin was not inferior to a 2 cm surgical margin" and that a histopathologic excision margin of 8 mm or more (corresponding to a ≥1 cm surgical excision margin) combined with SLN biopsy (followed by an immediate completion lymph node dissection if positive) provided T3 melanoma patients with optimum local, regional, and distant disease control and resulted in enhanced melanoma-specific survival".

A good argument is made for the more sophisticated surgical approach of Mohs Micrographic surgery with MART-1 imunostaining along with central debulking excision. This technique has low local recurrence rates and the potential for upstaging allowing for SLNBx prior to definitive reconstruction [JAAD 2015;72;840].

Staged excision with permanent section margin control can be used with low recurrence rates for head and neck melanoma [JAMADerm 2017;153;282].

Expeditious surgical removal of stage I melanoma (thickness < 2 mm; no spread to nearby lymph nodes or distant sites) results in improved outcomes, e.g., decrease mortality [JAAD 2018;78;40–46 ]. A reasonable conclusion from that article is that all stage I melanomas should be treated within 30 days of initial biopsy. Stage II and III melanomas did not show the same effect.

Laboratory Data

Other than a vitamin D level (see below), no baseline or follow-up labs or CXR are indicated for primary melanoma without evidence of metastasis unless clinical suspicion directs specific tests. A complete cutaneous examination of course should be done.

Vitamin D

Vitamin D deficiency is associated with the diagnosis of melanoma and poorer prognostic features (e.g. higher mitotic rate and ulceration) [Br J Dermatol 2017;177;282]. Lower vitamin D levels in patients with melanoma are associated with poorer outcomes [J Clin Oncol. 2016 May 20;34(15):1741-7]. For example in that study, patients with melanoma who had a level less than 16 ng/ml were 1.62 times more likely to experience recurrence and were 1.76 times more likely to die as a result of melanoma. Studies are ongoing, but it seems prudent to follow Vitamin D levels in patients with melanoma and supplement orally if patients are deficient.

Should Gene Analysis be Routinely Done?

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (2017) do not recommend testing the primary cutaneous melanoma for the BRAF mutation unless required to guide systemic therapy.

Should Genetic Profiling Be Routinely Done?

A recent workgroup on melanoma concluded the following: "While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiatebenign from malignant neoplasms, or melanomas at low versus high risk for metastasis, routine (baseline) prognostic genetic testing of primary cutaneous melanomas (before or following sentinel lymph node biopsy [SLNB]) is not recommended outside of a clinical study (trial).” [NCCN Guidelines for Melanoma V.1.2018–Panel Meeting on 06/28/17]

DecisionDx-Melanoma Test

DecisionDx-Melanoma (DDM) test (Castle Biosciences) is a gene expression profile (GEP) test that is an independent predictor of metastasis and death for patients with melanoma. The test classifies tumors into two groups: low and high risk. The data so far shows that DDM has a higher predictive value than SLNB and some advocate getting it instead of SLNB.

Followup Visits

Follow-up by a dermatologist in order to: examine and palpate the scar, examine the regional lymph nodes, perform a complete skin examination, educate the patient on the ABCD’s of melanoma, encourage monthly self-examination and lymph node palpation, encourage sun avoidance, and encourage close relatives to have a complete skin examination. See also clinical under metastatic melanoma.

There is no uniformly accepted recommendation for the appropriate number and interval of follow-up visits. In fact, as of this writing, there has been no evidence that a specific follow-up schedule for early recurrence detection results in any survival benefit [British J Dermatology January 2014]. The following is one possible approach:

    THICKNESS      FOLLOW UP        
    In situ      Yearly.
     < 1 mm      Every 4 months for 2  years, then yearly.
     > 1 mm      Every 3 months for the first year. Every 4 months for 2 years, then yearly.

In a 10-year, prospective study of intensive follow up of 290 patients with stage IIB, IIC and III melanoma with the goal of detecting recurrence as early as possible, the following was either concluded or found [JAAD 2016;75;516]:

Risk of Another Melanoma

The risk of another primary melanoma in a patient with a history of melanoma is 2% the first year and 1% per year after that [JAAD 2015;73;630]. The risk stays elevated even after 20 years, so annual TBE should be recommended for life. (If one assumes only the dermatologist finds any subsequent melanoma, then the dermatologist will find one melanoma every 100 TBEs in this population.)

Prevention

Sunscreen

Daily use of sunscreen reduces the risk of melanoma.

Aspirin

Taking aspirin regularly reduced the risk of melanoma in postmenopausal women in a large observational study from the Women's Health Initiative comprising nearly 60,000 women. Acetaminophen (e.g. Tylenol) and other pain killers (e.g. ibuprofen) did not protect. A meta-analysis Oncol Lett. 2015 Mar;9(3):1073-1080 of multiple studies concluded that a daily dose of 50-400 mg aspirin was significantly associated with a reduced risk of skin cancers.

Alcohol

Another study found 20% increased risk of cutaneous melanoma with regular alcohol drinking [British J Dermatology 2014 May].

Melanoma Mortality

SEER data of 49,319 melanomas showed a 10-year mortality as follows in the table below [as reported from the 2016 SID meeting]:

Thickness (mm) Mortality at 10 years
0.01-1.0 3%
1.01-2.00 12%
2.01-4.00 25%
> 4.0 32%

A retrospective analysis of 1804 melanoma patients found that increased BMI was associated with lower overall and melanoma-specific survival (controlling for age, gender, and tumor stage) [N Engl J Med. 2003;348:1625].

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