Melanoma Stage III Decisions

The Doctor Is In…

Dr. Richard Joseph, MD

Richard Joseph, MD, is an assistant professor of medicine/oncology at Mayo Clinic. His Hematology/Oncology fellowship was completed at MD Anderson Cancer Center. He is a voting member of the NCCN (National Comprehensive Cancer Network. He belongs to Melanoma International’s Scientific Advisory Board and received MIF’s Doctor of the Year award for 2015.

I have micromets in one lymph node, the doctor said my prognosis was excellent staging me at 3a, because he removed that node. Is that true or is it possible the melanoma cells are still circulating in my bloodstream?

Dr. Joseph: “Patients with Stage IIIA melanoma generally have a very good prognosis with ~70-80% of patients alive at 10 years from the time of diagnosis. With that being said, a minority of patients who have Stage IIIA disease can ultimately develop metastatic disease. There are choices for patients with Stage III to decrease the rate of recurrence and I will review some of those choices below.”

Another opinion on my 3A status wants me to go on Sylatron. What is that?

Dr. Joseph: “We will review this under question 3. But Sylatron is a type of interferon prescribed for a 5 year period.”

What choices do Stage 3 patients have for adjuvant therapy?

Dr. Joseph: “Adjuvant therapy is treatment that is added after surgical resection of all the tumors that we can see from scans. The goal of adjuvant therapy is to decrease the chance of recurrence. However, finding the successful therapy is difficult if there are no tumors to measure. Still, many studies have been tried in the adjuvant setting and we will briefly review some of the options below.

High dose Interferon:
Adjuvant interferon has been studied in multiple randomized controlled studies in the adjuvant setting for melanoma. Fairly consistently, adjuvant interferon demonstrates increased time in between the diagnosis of melanoma to the development of recurrent disease. What remains inconsistent is the impact interferon has on improving overall survival with some studies demonstrating improvement and other studies not demonstrating. At least one meta-analysis has performed a pooled analysis confirmed an improvement of using interferon in both disease free survival and overall survival, however the impact on overall survival was relatively small and the authors estimate that approximately only 1 person out 29 patients actually benefits from adjuvant interferon. In addition, the toxicity profile of interferon is unacceptable to many patients. It should not be prescribed to anyone with a history of depression, who has difficulty with fertility, or plans on an active lifestyle during treatment.

Pegylated Interferon (Sylatron)
One of the challenges of high dose interferon is the intense toxicity. Pegylated interferon is a long acting interferon that requires less frequent injections that high dose interferon and is reported by some to be better tolerated. One large, randomized study comparing pegylated interferon to observation demonstrated improved relapse free survival favoring pegylated interferon. One bit of caution is that in the design of this study, the pegylated interferon was to be given for five years. Very few patients were able to tolerate treatment for five years with the median duration of therapy was slightly over one year.

Biochemotherapy is a combination of traditional chemotherapy with interferon and another immunotherapy called interleukin-2 (IL-2). Biochemotherapy has demonstrated responses in patients with unresectable or metastatic melanoma providing a rationale to test this combination in the adjuvant setting. One large, randomized study compared biochemotherapy to high dose interferon in the adjuvant setting. In this study, biochemotherapy was compared to high dose interferon and demonstrated that biochemotherapy improved relapse free survival but not overall survival over high dose interferon. This study is not routinely incorporated into clinical practice given the toxicity of the regimen but could be considered an option for patients who are not candidates for high dose interferon.

Adjuvant Summary
The options for adjuvant therapy in melanoma are less than ideal. Given the poor choices, my first choice for a patient with Stage III melanoma is a clinical study especially those studies utilizing less toxic agents like anti-PD1 (pembrolizumab or nivolumab). If a study is not available, patients and doctors should consider if adjuvant therapy is the right decision for them. Watching and waiting through close observation is an acceptable option.”

Will the study on CLND presented at ASCO change the current practice for stage II/III patients?

Dr. Joseph: “To summarize, Leiter et al. presented data on a randomized phase 3 study in patients with a positive sentinel lymph node to undergo either a complete lymph node dissection versus observation. In this study, patients who received a complete lymph node dissection did not have improved survival compared to observation calling into question the utility of removing additional lymph nodes in the setting of one positive node. Removal or complete node dissection has risks of nerve damage, infection and future lymphedema that can affect quality of life. This study has several caveats that patients should be aware of when trying to apply these results to their case.

1. Only patients with a positive sentinel node were included. Patients with nodes that could be felt on exam or seen on scans were not included.
2. The study is relatively small with ~500 patients because recruitment was difficult
3. A United States version of this study is still recruiting patients and is much larger. If the findings are confirmed in the US study, then complete lymph node dissection in patients with early Stage III disease will certainly become more controversial
4. When is complete lymph node dissection (CLND) still appropriate for patients
Related to above, CLND is still an appropriate decision for all patients with lymph node positive disease. I would strongly recommend patients with bulky lymph nodes to consider a CLND. Patients with just one positive sentinel node should continue to be referred to a surgeon to discuss the pros and cons of a CLND. “

What do you think about following a patient with ultrasound of the nodes?

Dr. Joseph: “Ultrasound of the lymph node basin is a safe and effective way of assessing for recurrence. The advantage of ultrasound is that it doesn’t use traditional radiation. Ultrasounds of the lymph nodes will not detect distant recurrence in areas outside of the lymph node basin but is a viable option for follow up.”

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