by Dr. C.H. Weaver M.D. updated 10/2022
Patients with stage II melanoma have a cancer that is 1 to 2 millimeters with ulceration, or greater than 2 mm with or without ulceration. Stage II melanoma has spread to the lower part of the inner layer of skin (dermis), but not into the tissue below the dermis or into nearby lymph nodes. Ulceration refers to the microscopic presence of continuous epidermis in the tissue overlying the melanoma and is an important prognostic factor for stage II melanoma.
Currently the standard of care for stage II and III Melanoma is surgical resection of the cancer followed by adjuvant immunotherapy treatment.1-4,10
Surgical Treatment of Stage II Melanoma
Treatment of stage II melanoma typically involves a single surgical procedure in which a local excision of the cancer is performed as well as a sentinel lymph node biopsy (SLNB). When melanoma spreads it typically first invades the local lymph nodes so their evaluation is essential for treatment planning. If the lymph nodes are involved with cancer, additional systemic adjuvant treatment may be necessary. Approximately 15% of patients undergoing SLNB have a positive SLN (pathologically stage III).5
Adjuvant Treatment of Stage II Melanoma
Despite undergoing sentinel lymph node evaluations that are negative, some patients with stage II melanoma are at increased risk for having small amounts of cancer that have not been detected. Undetectable areas of cancer are often referred to as micrometastases. The presence of micrometastases is what causes a melanoma recurrence following treatment with surgery alone. Patients with thick melanomas (> 4 mm) who have evidence of ulceration are considered at high risk for recurrence. The delivery of cancer treatment aimed at killing micrometastases following local treatment with surgery is referred to as “adjuvant” therapy.
Immunotherapy treatment of stage II melanoma has become a standard treatment. The immune system is a network of cells, tissues, and biologic substances that defend the body against viruses, bacteria, and cancer. The immune system recognizes cancer cells as foreign and can eliminate them or keep them in check—up to a point. Cancer cells are very good at finding ways to avoid immune destruction, so the goal of immunotherapy is to help the immune system eliminate cancer cells by either activating the immune system directly or inhibiting the mechanisms of suppression of the cancer.10,11,12
PD-1 “Checkpoint Inhibitors”:
PD-1 is a protein that inhibits certain types of immune responses allowing cancer cells to evade an attack by immune cells. Opdivo (nivolumab) and Keytuda (pembrolizumab) are checkpoint inhibitors that block the PD-1 pathway and can enhance the ability of the immune system to fight cancer. Both Keytruda and Opdivo are approved as adjuvant therapy for melanoma because they improve survival. Opdivo has also been shown to be superior to Yervoy (another form of immunotherapy) for the management of stage IIIb/c melanoma following complete surgical resection.10,11,12
The Phase 3 KEYNOTE-716 clinical trial evaluated adjuvant Keytruda treatment in 954 patients with stage IIB and IIC melanoma that had been surgically resected. Following surgery half of the patients received Keytruda and half did not.
At the interim analysis it was determined that Keytruda treatment improved the duration of remission without cancer recurrence. Fewer patients treated with Keytruda experienced recurrence and at 12 months 91% of Keytruda treated patients survived cancer free compared to only 83% of those not treated with Keytruda. Additional follow up information was released at the 2022 American Society of Clinical Oncology annual meeting confirming the initially reported benefit of Keytruda. At two years 81% of Keytruda treated patients remained cancer free compared to 73% of those not receiving Keytruda.10
Treatment of Stage I - IIIA Non-Small Cell Lung Cancer
Update on the management of early stage NSCLC: three trials confirm benefit of immunotherapy yet many patients still not receiving treatment.
COVID-19 Vaccines and Cancer - Evushield "Authorized"
Preventing COVID-19 in Cancer. Answers to frequently asked questions about vaccination and Evushield.
How Precision Medicine in Oncology Has Dramatically Changed the Way Cancer is Diagnosed and Treated
What Patients Need to Know About Biomarker Testing
A Phase 3 clinical trial (CheckMate -76K) evaluated Opdivo (nivolumab) adjuvant therapy and reported that 89% of Opdivo treated patients survived without melanoma recurrence one year from treatment compared to 79% of those that received no systemic treatment. The rates were 93% versus 84% for stage IIB and 84% versus 72% for stage IIC patients.
Alpha interferon is a biologic therapy that stimulates the immune system and is approved by the U.S. Food and Drug Administration for use as adjuvant therapy in patients with high-risk melanoma.6-8 Clinical trials have demonstrated that patients with stage II melanoma treated with high-dose interferon alpha-2b and pegylated interferon can delay the time to cancer recurrence but do not experience improve overall survival.
Questions to ask your physician
Newer precision cancer medicines and immunotherapy have improved the outcomes of patients with stage II and III melanoma. Patients should ask their doctor about these advances and if they should undergo genomic testing of their cancer and /or participate in a clinical trial evaluating newer adjuvant therapy treatments.
Strategies to Improve Treatment
The progress that has been made in the treatment of melanoma has resulted from patient participation in clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of advanced melanoma being developed in clinical trials.
Precision Cancer Medicines: Adjuvant treatment of patients with stage II disease with newer precision cancer medicine and immunotherapy drugs have rapidly become the standard of care because they delay the time to cancer recurrence and prolong survival. Individuals with stage II melanoma should discuss the role of genomic testing and participation in ongoing clinical trials evaluating these medications.9
Chemotherapy: Chemotherapy has not been extensively evaluated as adjuvant therapy for patients with stage I-III melanoma. Chemotherapy in combination with biologic agents is being evaluated in more advanced disease, and if successful, will be evaluated in earlier stages of melanoma.
Vaccines: One strategy for stimulating the immune system to attack cancer cells is the use of vaccines. Cancer cells often display certain small proteins and/or carbohydrates (antigens) on their surface that are not displayed by healthy cells. Vaccines are often comprised of these specific antigens, which can be taken directly from the patient’s cancer cells, other patient’s cells or produced in a laboratory. If these antigens are injected into the patient, the immune system recognizes them as “foreign” and will attack the cancer cells displaying the antigens. Researchers are now evaluating various strategies to enhance the immune response against the injected antigens, including combining the patient’s own immune cells with the specific antigens in a laboratory prior to injection.
- Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
- Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000.
- Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001.
- Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998.
- Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012.
- Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996.
- Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000.
- Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomized phase III trial. Lancet 372 (9633): 117-26, 2008.
- Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Oncol 32:5s, 2014.
- Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. September 10, 2017DOI: 10.1056/NEJMoa1709030.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New England Journal of Medicine. 2011;364(26):2517-26. doi: 10.1056/NEJMoa1104621.