Should merkel cell carcinoma patients receive adjuvant radiation following excision? My personal parallel story

By Warren R. Heymann, MD
Sept. 17, 2016

I was 34 years old when I was diagnosed with a stage I seminoma. Following an orchiectomy, I was instructed to see the radiation oncologist (at the same institution) for adjuvant radiation.

“Why are you here today Dr. Heymann?” the radiation oncologist inquired.
 
“My urologist advised me to come to arrange for my radiation, now that I have had my surgery,” I replied.

“Did you ever hear the story about the man snapping his fingers in Central Park? When someone asked him why he was doing that, he said that he was doing it to keep the lions away. When the inquiring person said that there were no lions there, the man snapping his fingers said — you see, it works!”

“Excuse me, doctor, what are you talking about”, I asked.

“What I’m saying is, even though everyone is doing adjuvant radiation following an orchiectomy, you don’t need it — the latest data according to the guru in Toronto says that your prognosis is the same whether or not you get the radiation.”
 
When I went back to my urologist for follow-up, he asked me how I tolerated the radiation.

“I didn’t have it”, I declared.

“WHAT? WHY NOT?” he questioned in an angry voice.

“Because the radiation oncologist you sent me to told me it made no difference!” I yelled back.

“Damn it, go get your radiation!” he demanded.

I was more than a little confused. I called several experts, and everyone was quoting the same study from Toronto. I decided to call the author of that paper and told her my case — she was very gracious and said that if I had radiation, my 10-year cure rate would be 98% and if I did not, it would be 92%. It took me a millisecond to make my decision — I had the radiation therapy (at a different hospital).

Twenty-seven years later, I have absolutely no regrets about my decision. Out of curiosity, I looked to see what the current approach is for patients with a clinical stage I seminoma. Apparently, national treatment guidelines are now recommending surveillance as the preferred post-orchiectomy management decision. Although the rate of post-orchiectomy recurrence of seminoma is 5% at 5 years with either adjuvant chemotherapy or radiation therapy, compared to 15-20% with just surveillance, the latter is the recommendation because of potential adverse reactions to adjuvant treatment, over-treatment of those who don’t need it, and the success of salvage therapy (for recurrent cancer) approaches 99%. Despite the trend toward increased use of post-orchiectomy surveillance for patients with clinical stage I seminoma, a significant number of patients are still receiving adjuvant treatment following orchiectomy (1). Knowing myself, I would make the same decision today that I made in 1989.
 
Treatment of Merkel cell carcinoma (MCC) is complex, and depends on the size of the primary tumor and stage of disease. The current status of therapy is outlined in the following abstract by the excellent article by Cassler et al (2). It would be worth your while to review Figure 1 from the article for the MCC treatment algorithm.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

The viewpoint that adjuvant radiation therapy may not be necessary for small MCCs without evidence of metastasis has been corroborated by Frohm et al who performed a cohort study of 104 patients with MCCs having 105 primary tumors less than 2 cm in diameter. No patients received adjuvant radiation to the primary tumor site, although 8 patients had their regional lymph node basin treated with radiation as part of the initial treatment plan. Two patients who had positive sentinel lymph nodes declined lymph node dissection and were treated with primary radiation to the nodal basin. True local with concurrent in-transit recurrence occurred in 1 patient, satellite with concurrent regional recurrence occurred in 1 patient, 4 additional patients developed in-transit recurrences, 13 patients had regional recurrences, and 4 patients had distant metastases. The authors acknowledge that a limitation of this study is that there was no control group. They appropriately suggest that adjuvant radiation to the primary site of small (<2 cm), low risk MCCs may be unnecessary (3).

Even though the number of patients who had recurrences seems small, when it is you, one is the only number that counts. As a cancer patient (seminoma and melanoma), I know the difficulty in making decisions in the light of uncertainty; it is even harder to live with cognitive dissonance. You assess your choices and hope for the best — if further decisions need to be made, the process is repeated. I taught myself not to think too hard, but I also allowed myself the time to worry periodically (usually when it was time for the follow-up scans). MCCs are the most aggressive skin cancers. Patients with seminomas (and all cancers) deserve the most precise, curative treatment. While more research is necessary to accurately determine the appropriate role, if any, of adjuvant radiation for MCCs,  patients  must be given current information and perspectives to help them decide the therapeutic regimen that is right for them.

1. Matulewicz RS, et al. The evolving management of patients with clinical stage I seminoma. Urology 2016 [Epub ahead of print]
2. Cassler NM, et al. Merkel cell carcinoma therapeutic update. Curr Treat Options Oncol 2016; Jul 17 (7): 36
3. Frohm ML, et al. Recurrence and survival in patients with Merkel cell carcinoma undergoing surgery without adjuvant radiation therapy to the primary site. JAMA Dermatol 2016; 152: 1001-7.

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