Immunotherapy shows promise not only in metastatic melanoma but also in curative treatment. Ipilimumab can help improve survival in stage III melanoma.1 Postoperative radiation may help build on immunotherapy’s success in several ways. Here are 10 reasons why we should look at postoperative radiation for regional disease.
1. Radiation can damage melanoma cells and may help immunotherapy work better. When radiation causes melanoma cells to die, the dying cells may expose certain proteins or other molecular targets that helps immunotherapy target melanoma cells not only in the area irradiated but throughout the body.2
This phenomenon, called the abscopal effect ("out of the scope" or location of radiation treatment), is rare on its own. But reports do suggest that for metastatic melanoma we can see regression throughout the body after radiation. Here is a case report from the New England Journal of Medicine as an example of radiation interacting with CTLA-4 inhibitor ipilimumab.3
2. Radiation before immunotherapy may improve survival in metastatic cancer. Let’s look at non-small cell lung cancer, where radiation is used more commonly than melanoma. The phase I KEYNOTE-001 trial evaluated PD-L1 inhibitor pembrolizumab tolerance. An unplanned analysis shows that radiation used before the drug was linked to a doubling of disease control and for overall survival. It was only 98 patients, and could be other factors that explain it. But it’s possible that radiation and immunotherapy interact to prevent disease progression and patients may live longer.4
Retrospective data suggest the same may hold true in melanoma, with better response rates and survival.5 Good reason to pursue clinical trials in metastatic melanoma, but let’s look further.
3. Ipilimumab improves survival after surgery for patients with melanoma with involved lymph nodes. A European multicenter trial, EORTC 18071, randomly assigned 951 patients to either ipilimumab or placebo. At 5 years, more patients receiving immunotherapy were alive (65.4% vs 54.4%) and without metastatic disease (48.3% vs. 38.9%).1 The study was industry-sponsored so it deserves further scrutiny, but it does offer hope for effective treatment after surgery. The caveat: all patients had a lymph node dissection to be eligible.
4. Lymph node dissection doesn’t improve outcomes in melanoma. A large randomized trial of 3,531 patients just published shows that more surgery doesn’t help patients with melanoma with involved nodes live longer .6 Cancer-specific and overall survival were essentially the same. There was a higher 3-year risk of nodal recurrence without dissection than with it (23% vs 8%), but also a lower risk of lymphedema (6.3% vs 24.1%). If there were only a way to lower regional recurrences without surgery…
5. Radiation can provide good regional control with less lymphedema compared to surgery. It’s worth taking a look at the breast cancer experience. Axillary lymph node dissection has become less common if the nodes aren’t detectable on physical because surgery doesn’t improve outcomes. Though not always needed, radiation can substitute for surgery in clinically node-negative breast cancer. The AMAROS trial found in 4,823 patients with breast cancer had no difference in axillary recurrences and a 5-year lymphedema risk of 11% with radiation versus 23% with surgery.7
Can we expect that radiation will work in melanoma as well as it did in breast cancer? By itself, not necessarily. Two small studies have been done, an Australian trial that showed no regional recurrence benefit and a smaller Moffitt trial that does.8,9 But these were after lymph node dissection, so if limited surgery were done would the results be different?
6. Postoperative radiation and immunotherapy may offer synergistic benefits. Surgery doesn’t improve melanoma outcomes; ipilimumab does. Some of the research I already cited suggests radiation may make ipilimumab work better in the postoperative setting. Combining nivolumab with ipilimumab increased serious toxicities in melanoma to 54% vs 20% with ipilimumab alone.10 Although it requires careful study, it may be better to try adding radiation rather than another systemic drug.
7. Radiation is cheap compared to newer systemic therapies. Radiation is a free drug, where the cost is the technical methods of delivery. A full course of radiation treatment may cost less than a single dose of immunotherapy.11
Not true with drugs. A recent study shows Merck could save patients and insurance companies $825 million annually with patient-specific dosing for pembrolizumab.12 Similar cost savings likely exist with ipilimumab and argue against adding yet another targeted drug in stage III melanoma. Unfortunately drug prices keep going up, with any clear link to improve outcomes.13
8. If radiation and immunotherapy work together, can we use less of either to lessen toxicity and cost? I have no idea. But a definite reason to consider if we want cost-effective care. This is years down the road, since first there needs to be evidence that radiation and immunotherapy work well together at standard doses.
9. Clinical trials with radiation can go faster than new drugs. Radiation has been tested in melanoma already, just not with immunotherapy. A phase I/II trial could get things going fairly quickly compared to a new targeted agent. If promising, onward to phase III. No in vitro or animal studies needed.
10. Photons are free. Radiation treatments with subatomic particles have no pharmaceutical companies or intellectual property issues to slow things down for FDA approval, patent protections delays, or other intellectual property/regulatory barriers often present for new drugs. There will still be biases in radiation trials, but with smaller-sized financial conflicts of interest that immunotherapy may have.
All of these points need clinical trials to confirm my hypothesis. But the shift away from lymph node dissection in melanoma means an opportunity to re-evaluate postoperative radiation. If radiation can make immunotherapy work better, it may provide new hope to patients with melanoma.
- Eggermont AGG, Chiarion-Sileni V, Grob J-J, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845-55.
- Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25:28-33.
- Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effects in a patient with melanoma. N Engl J Med. 2012;366:925-31.
- Sharverdian N, Lisberg AE, Bornazyn K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE -001 phase 1 trial. Lancet Oncol (in press).
- Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther. 2017;18:36-42.
- Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376:2211-22.
- Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomized, multicentre, open-label, phase 3 noninferiority trial. Lancet Oncol. 2014;15:1303-10.
- 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. Lancet Oncol. 2012;13:589-97.
- Strom T, Torres-Roca JF, Parekh A, et al. Regional radiation therapy impacts outcome for node-positive cutaneous melanoma. J Natl Compr Canc Netw. 2017;15:473-42.
- Hodi FS, Chesney J, Pavlick AC. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558-68.
- Yong JH, McGowan T, Redmond-Misner R, et al. Estimating the costs of intensity-modulated and 3-dimensional conformal radiotherapy in Ontario. Curr Oncol. 2016;23:e228-38.
- Goldstein DA, Gordon N, Davidescu M, et al. A pharmacoeconomic analysis of personalized dosing vs fixed dosing of pembrolizumab PD-L1-positive non-small cell lung cancer. J Natl Cancer Inst. 2017;109:djx063 (in press).
- Barnes TA, Amir E, Templeton AJ, et al. Efficacy, safety, tolerability and price of newly approved drugs in solid tumors. Cancer Treat Rev. 2017;56:1-7.
Samuel Ejadi, MD
Jul, 19 2017 9:18 AM
The effect of RT as an immunopotentiator is on the tumor cells and stroma through multiple mechanisms such as causing cell death which releases antigens, cell constituents which activate DAMP pathways and production of chemokines from the surviving cells. Radiating an empty post-op surgical bed may not be beneficial and there was no added benefit in the past followed by adjuvant interferon in high-risk cutaneous melanoma. Systemic antigen density in the adjuvant setting is most often low to nonexistent and may explain lack of long-term durability with adjuvant immunotherapy in resected low volume disease subpopulations that don't develop irAEs. Agree with above suggestions alluding to "pre-operative" RT (or chemotherapy) if possible, followed by adjuvant combination immunotherapy.
Matthew S. Katz, MD
Jul, 20 2017 5:43 AM
Thanks for your comment Dr. Ejadi. As a non-specialist, I'm sure there are details about the molecular pathophysiology of melanoma that I don't understand well enough. I suspect the only role radiation might fit would be in sentinel node+ patients with a high enough risk of additional positive nodes. Here are a couple of interesting articles to consider
I defer to melanoma experts on trial design, but hopefully stimulating some conversation can be worthwhile.