Stage III Melanoma


Stage III melanoma includes cancers of any thickness with tumor spread to regional lymph nodes. The extent or amount of tumor in the lymph nodes is the most important prognostic factor for patients with stage III melanoma. The presence of micrometastases, defined as tumor detected by sentinel lymph node biopsy, is more favorable than the presence of macrometastases, which are defined as clinically detectable nodal metastases. Similarly, one lymph node that contains tumor is more favorable than having four or more involved lymph nodes.

The following is a general overview of treatment for stage III melanoma. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, targeted therapy or some combination of these treatment techniques. Multi-modality treatment, which utilizes two or more treatments, is increasingly recognized as an important approach for improving a patient’s chance of cure or prolonging survival.

As a result of recent drug discoveries many new treatment options have recently become available for the management of melanoma. Clinical trials utilizing these new, innovative therapies may provide the most promising treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17

Surgical Treatment of Stage III Disease

Outcomes of patients with stage III melanoma relates primarily to the extent of lymph node metastasis. Standard surgical treatment for patients with stage III melanoma is removal of the primary cancer with up to 2-centimeter (over an inch) margins of the adjacent skin, depending on the thickness of the primary tumor, and removal of all of the regional lymph nodes. Regional lymph node dissection may be performed in the neck, armpit or groin, depending on the site of the primary tumor and presence of palpable nodes. Chronic side effects of removing lymph nodes vary, depending on the extent of disease, body habits of the patient, and inclusion of postoperative radiation to site, but may include numbness, and swelling of the associated extremity, which is called lymphedema.

Historically, patients with locoregional spread of melanoma (stage III disease) and thick primary tumors have been considered appropriate candidates for adjuvant therapy because of high rates of distant recurrence and subsequent death from disease. Our ability to detect micrometastatic locoregional disease has improved over the past decade with the adoption of new techniques such as sentinel lymph node (SLN) biopsy. In addition, the pathologic assessment of sentinel lymph nodes have improved with the availability of immunohistochemical staining which allows detection of nodal metastases as small as 0.1 mm or even aggregates of a few cells.   For this reason, the current era can be viewed as one of transition, in which patients are being diagnosed with stage III disease earlier with a much better prognosis and lower risk of relapse. The significance of these technologic advances is reflected in the new American Joint Committee on Cancer (AJCC) staging system, which now incorporates pathologic nodal staging.

One of the challenges facing oncologists is assessing the risks for individual patients on the basis of data from previously published studies. Five-year overall survival rates for patients with stage III melanoma have been reported as ranging from 70% for stage IIIA to 27% for stage IIIC disease. In this group of patients, assembled largely during the pre-sentinel lymph node era, patients with stage I and II disease were reported to have 5-year recurrence-free survival rates of 90% and 70%, respectively. The 10% to 30% recurrence rates likely reflect unidentified microscopic disease, which can be detected with present-day techniques.

Adjuvant Treatment of Stage III Disease

It is important to understand that many patients with stage III melanoma are at high risk for disease recurrence because undetectable cancer cells referred to as micrometastases may have already broken away from the primary cancer and travelied through the lymph and blood system to other locations in the body.. The presence of micrometastases are what causes cancer recurrence following treatment with surgery alone. The delivery of cancer treatment following local treatment with surgery is referred to as “adjuvant” therapy and may include radiation therapy, biologic therapy, combination chemotherapy/biologic therapy and/or vaccines.

Radiation Therapy: A subset of patients is known to have a significant risk of locoregional relapse of melanoma following surgery. Features associated with a high risk of recurrence at the primary site are positive microscopic margins, recurrent disease, and thick primary tumors with ulceration or satellitosis. Features associated with high risk for lymph node recurrence following surgical removal of the lymph nodes have also been defined and include involvement of 4 or more lymph nodes, lymph nodes measuring at lease 3 cm, lymph nodes in the neck (cervical region) and evidence of extracapsular extension (tumor beyond the capsule of the normal lymph node). In these circumstances, a short course of radiotherapy to the region is believed to be effective in controlling and “killing” possible residual microscopic disease, decreasing the incidence of recurrence in the region.1

Biologic Therapy: High-dose alpha interferon is a biologic therapy that stimulates the immune system and has been approved by the U.S. Food and Drug Administration for adjuvant treatment of stage III melanoma. Three clinical trials have been completed in which patients with high-risk melanoma and stage III melanoma were treated with either high-dose alpha interferon for one month and lower doses for 48 weeks or no adjuvant therapy. In all 3 trials, there was a 9% to 11% reduction in the incidence of recurrence and in 2 of the 3 trials there was an 8% to 9% improvement in 5-year overall survival. Increasing emphasis has been placed on the “relative value” that patients place on side effects of treatment, in part because of the significant toxicity experienced by 78% of patients in the ECOG 1684 trial.

Table 1: Randomized phase III trials of high-dose interferon alpha adjuvant therapy for patients with high-risk (stage IIB and III) melanoma


Total No. of Patients

Median Follow-up (years)

5-year Disease Free Survival: Interferon Arm

5-year Disease Free Survival: Observation Arm

5-year Overall Survival: Interferon Arm

5-year Overall Survival: Observation Arm








ECOG 1684







ECOG 1690







There have been no benefits associated with using lower doses of alpha-interferon.

Patients with stage III disease appear to have some benefit from adjuvant interferon therapy, however there are a number of ongoing clinical trials evaluating newer biologic, targeted, and other anti-cancer therapies alone or in combination. It is important to consider all of these options before beginning treatment.

Strategies to Improve Treatment

PD-1 Inhibitors Investigational immunotherapy drugs known as anti-PD-1 drugs have produced very promising response rates in early-phase clinical trials. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. These drugs include Keytruda® (pembrolizumab) and nivolumab.6,16

Keytruda® (pembrolizumab) is a targeted immunotherapy and the first anti-PD-1 drug, aimed at re-energizing a patient’s protective immune response to cancer to have received FDA approval in the U.S for the treatment of cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1, such as Keytruda®, may enhance the ability of the immune system to fight cancer. Data from an ongoing trial evaluating Keytruda® has demonstrated promising survival rates among patients with advanced melanoma. Among 365 patients with measureable disease 28% of those who had previously received Yervoy® and 40% of those who had not received Yervoy® had a promising response to treatment.6

New Targeted Therapy Drugs:  Unlike conventional chemotherapy drugs that attack both normal and cancerous cells, targeted therapies are designed to block specific substances or pathways in cancer cells that enable cancer to grow.  A targeted therapy is one that is designed to treat only the cancer cells and minimize damage to normal, healthy cells. Several targeted therapies have been approved for the management of malignant melanoma and doctors are working to determine the best way to use them.

Zelboraf® (vemurafenib)  and Tafinlar® (dabrafenib) belong to a new class of drugs known as BRAF inhibitors. It turns off a genetic mutation called BRAF V600, found in about half of patients with advanced melanoma

As promising as all of the new, targeted therapies are they typically stop working at some point because melanoma cells find another pathway that lets them start growing again. In many cancers, combination therapy improves survival and leads to cures when compared to single agent treatment. Researchers are now testing combinations of two or more targeted therapies.

The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of advanced melanoma will result from the continued evaluation of new treatments in clinical trials.

Patients may gain access to better treatments by participating in a clinical trial. Participation in a clinical trial also contributes to the cancer community’s understanding of optimal cancer care and may lead to better standard treatments. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician.

Researchers are continuing to evaluate novel chemotherapeutic drugs and targeted therapies for the treatment of melanoma. The following are undergoing evaluation in clinical trials based on initial encouraging results.

Tafinlar® plus Mekinist® The COMBI-v clinical trial compared the combination of the BRAF inhibitor Tafinlar® plus the MEK inhibitor Mekinist® with Zelboraf® alone in 704 patients with the BRAF V600mutation.  Overall response rates, duration of response and overall survival were improved with combination therapy. The median overall survival was 17.2 months with Zelboraf alone and had not been reached in the Tafinlar®/ Mekinist® treated patients.5

Vaccines:  Currently, no vaccine has been approved for the treatment melanoma.  Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent.

The experimental cancer vaccine talimogene laherparepvec (T-VEC) has been demonstrated to promote tumor shrinkage, trigger a systemic immune response and prolong survival in some patients with advanced melanoma.  T-VEC is a type of immunotherapy that uses a specially designed virus to destroy cancer cells. It is injected directly into the tumor. After acting locally within the tumor, it is intended to prompt an immune response against cancer cells elsewhere in the body.

Preliminary results showed that 64 percent of injected tumors shrank by half.  The vaccine shrank tumors that were directly injected as well as those that were not injected—indicating that the vaccine was triggering the immune system to fight the distant tumors.17


1 Cancer Facts & Figures 2013. American Cancer Society website. Available at: Accessed January 17, 2014.

2 Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine. 2011;364(26):2507-16. doi: 10.1056/NEJMoa1103782.

3 Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X.

4 Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. New England Journal of Medicine. 2012;367(2):107-14. doi: 10.1056/NEJMoa1203421.

5 Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine.2012;367(18):1694-703. doi: 10.1056/NEJMoa1210093.

6 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.

7 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.

8 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. Paper presented at: 38th Congress of the European Society for Medical Oncology; September 27–October 1, 2013; Amsterdam, Netherlands. Abstract LBA24.

9 Cancer, Vol 88, No 9, pp 2042-2046, 2000)

10 Bottomley A, Coens C, Suciu S et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected Stage III melanoma: A Phase II randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Journal of Clinical Oncology. 2009;27:2916-2923.

11 Rao RD, Holtan SG, Ingle JN et al. Combination of Paclitaxel and Carboplatin as Second-Line Therapy for Patients with Metastatic Melanoma. Cancer. 2006;106:375-82.

12 Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009; 115: 119-127.

13 Journal of Surgical Oncology, Vol 71, No 4, pp 209-213, 1999

14 Kocher M, Soffietti R, Abacioglu U, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: Results of the EORTC 22952-26001 Study. Journal of Clinical Oncology [early online publication]. November 1, 2010.

15 Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. The Lancet Oncology. 2012; 13(6): 589-597.

16 Robert C, Long GV, Brady B, et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. New England Journal of Medicine [early online publication]. November 16, 2014.

17 Andtbacka RH, Ross MI, Delman K, et al: Responses of injected and uninjected lesions to intralesional tal-imogene laherparepvec (T-VEC) in the OPTiM Study and the Contribution of Surgery to Response. Presented at the Society of Surgical Oncology Cancer Symposium in Phoenix, Arizona March 12-15, 2014. Abstract 52.

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