Stage III

Overview

Stage III melanoma includes cancers of any thickness that have spread to the 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 some new treatment options for stage III melanoma have recently become available. Clinical trials utilizing 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 inform patients about their treatment options and to facilitate a mutual or shared decision-making process with their doctor.

Surgical Treatment of Stage III Disease

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. Outcomes of patients with stage III melanoma relate primarily to the extent of lymph node metastasis.

Lymphatic mapping and sentinel lymph node biopsy (SLNB) are used to assess the presence of melanoma cells in the regional lymph nodes in order to help determine which patients may require regional lymph node dissections (LNDs) and adjuvant therapy.

SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. If metastatic melanoma is detected, a complete lymph node dissection (CLND) can be performed in a second procedure. Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive.

CLND dissection may be performed in the neck, armpit or groin, depending on the site of the primary tumor and presence of palpable lymph 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 the site, but may include numbness, and swelling of the associated extremity, which is called lymphedema. Patients should discuss the risk of lymphedema and potential benefit of CLND with their doctor as there is some controversy regarding the role of CLNC.1, 2, 3 ,4 ,5

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Patients with local regional spread of melanoma (stage III disease) and thick primary tumors are considered appropriate candidates for adjuvant therapy following surgery because of the high rate of melanoma recurrence and subsequent death following treatment with surgery alone. The ability to detect micrometastatic local regional 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.1, 2, 3 ,4 ,5

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 traveled through the lymph and blood system to other locations in the body. The presence of these micrometastases are what cause cancer recurrence following treatment with surgery alone. The delivery of cancer treatment following local treatment with surgery is referred to as “adjuvant” therapy. There are several types of adjuvant therapy that may be administered individually or in combination.

A subset of patients with stage III melanoma is known to have a significant risk of local regional relapse of 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).1,2,3,4

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. Several 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. These trials have demonstrated a reduction in the incidence of recurrence but no sustained improvement in 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 many patients. There have been no benefits associated with using lower doses of alpha-interferon.6,7,8

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.

Yervoy®(Ipilimumab) is a monoclonal antibody approved for the treatment of advanced melanoma. Yervoy® targets a molecule known as CTLA4. Which is found on the surface of T cells and is thought to inhibit immune responses. By targeting this molecule, Yervoy® may enhance the immune system’s response against tumor cells.

In 2014 a clinical study with 951 patients over 18 years of age who underwent complete surgical removal of a stage III melanoma were treated with either a placebo or Yervoy® and directly compared. At a median follow-up of 2.7 years from the initiation of this phase III trial, Yervoy® when utilized as adjuvant therapy both reduced the risk of melanoma recurrence and improved the duration of survival. Overall 46% of patients treated with Yervoy® were free of disease recurrence compared to 35% of patients treated with placebo. Patients survived without cancer recurrence an average of 26.1 months when treated with Yervoy® compared to only 17.1 months for placebo. This is the first significant advance in the management of earlier stage melanomas in years. Additional clinical trials will evaluate Yervoy® in combination with other novel melanoma therapies to see if outcomes can be further improved.9

Radiation Therapy: A short course of radiotherapy to the region where a melanoma has been removed can also help eliminate residual microscopic disease and decrease the incidence of recurrence in the region.10,11

Strategies to Improve Treatment

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.

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.12,13

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.12

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.14,15

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.16

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

References


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2 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.

3 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.

4 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.

5 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.

6 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.

7 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.

8 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 randomised phase III trial. Lancet 372 (9633): 117-26, 2008.

9 J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9008).

10 Agrawal S, Kane JM, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer [early online publication]. August 21, 2009.

11 Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000.

12 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.

13 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.

14 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.

15 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.

16 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.

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.