“Two roads diverged in a wood, and I—
I took the one less traveled by,
And that has made all the difference.”
–Robert Frost
Mohammad K. Khan, MD, PhD, FACRO
One of the first patients I encountered after residency was a 26-year-old woman with a single brain metastasis from melanoma. For anonymity, let’s call her Anna. Anna had just given birth to a daughter, 10 months earlier. She and her husband were both looking toward a long, happy life together to help raise their newborn daughter. The couple touched my heart, since I too had a daughter of similar age.
Anna was in my clinic for a reason. This was in 2012, before the U.S. Food and Drug Administration (FDA) approved many targeted and immunotherapy agents for metastatic melanoma. Going through the RPA (recursive partitioning analysis) brain metastases classification to tell her that she had about a 7.1-month median survival was one of the hardest things I’ve had to do. I had just passed a death sentence. I had just told her husband that he would lose the love of his life and told her newborn daughter that her mom will soon die, despite our best medical efforts. Clearly, these moments are the most difficult for any physician. And often, we carry our patient’s burden home with us.
The hardest thing for me to accept was the inability to provide any meaningful long-term hope for my patient, despite the odds.— Mohammad K. Khan, MD, PhD, FACRO
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This early experience left me questioning my own role as a radiation oncologist within a multidisciplinary melanoma tumor board. My training had taught me that radiation primarily provides “local control” of tumors through DNA double-strand breaks within tumors. Thus, radiation would not influence the overall “systemic” burden of disease in Anna’s case, and death was inevitable. The hardest thing for me to accept was the inability to provide any meaningful long-term hope for my patient, despite the odds.
Radiation Abscopal Pathway: The Path Less Traveled
Perhaps because of this patient’s experience, and others like her, and my own search for thinking “outside the box,” I embarked on studying a less-known phenomenon: the radiation abscopal pathway. I knew that radiation can infrequently induce an abscopal effect, which refers to a less-understood process by which radiation to one tumor site could induce an out-of-field effect to eradicate tumors at a distant, nonirradiated, metastatic site. The “abscopal effect” was first described in 1953, and since then, there have been limited case reports of such events occurring in the medical literature. Many cancer subtypes, including melanoma, have exhibited such rare events.
The technical issue was that radiation abscopal effect has never been well studied and/or clinically proven through clinical trials. Thus, I embarked on studying this pathway, since I thought it would be a way to provide additional hope to my patients in the future, especially since I thought that several immunotherapy agents would eventually receive FDA approval. If we could show that radiation can also induce antitumor immunity, then the future of medicine could incorporate radiation and immunotherapy combination approaches. Perhaps, a rare phenomenon such as the radiation abscopal effect could become more common. Clearly, this path was not easy, since few academicians at the time were studying the radiation abscopal response and/or believed in its potential promise for the future.
Building a team to include immunologists, medical oncologists, radiobiologists, post-docs, residents, and medical students to help drive many of the clinical outcomes, basic sciences explorations, and future clinical trials along this pathway was not easy. There were, and continue to be, many skeptics. Fortunately for me, there are now several high-profile papers in the basic sciences and early phase I/phase II trials recently published that are starting to show that radiation abscopal may actually have a future as part of multidisciplinary approaches. Many phase II and III trials are ongoing and/or in the design phases.
Predicting the Future
Now that many critics are slowly coming around to the idea that radiation, if used properly, can enhance antitumor immunity in combination with immune checkpoint inhibitors and other emerging cytokines, the future looks promising for those who believe in multidisciplinary approaches. If the number of manuscripts published on the topic from 2011 until now is an indicator of the future, one can clearly see that the future looks promising. Many high-profile papers in Science, Nature, The New England Journal of Medicine, The Lancet Oncology, and the Journal of Clinical Oncology have further given credibility that future cancer treatments will involve integration of radiation and immunotherapy. However, for this to be optimally successful, several issues still remain to be addressed: safety, toxicity, timing of radiation with respect to various immunotherapy agents, optimal radiation dose, radiation technique, and radiation fractionation.
It may be that certain immunoresponsive tumor types, such as melanoma, non–small cell lung cancer, and renal cell carcinoma, may benefit from combination approaches, whereas others may not.— Mohammad K.. Khan, MD, PhD, FACRO
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Furthermore, other issues, such as the need for treating the entire tumor vs treating just a portion, using ablative and/or lower doses of radiation, delivering ultrafast microbeam FLASH/GRID radiotherapy vs conventional therapy, minimizing treatments of the lymph nodes, and limiting toxicity to circulating bone marrow and lymphocytes, are just some of the many factors yet to be worked out. Not all tumor types will benefit equally. It may be that certain immunoresponsive tumor types, such as melanoma, non–small cell lung cancer, and renal cell carcinoma, may benefit from combination approaches, whereas others may not. Thus, the future will involve extensive basic sciences and translational research, which will lead to well-designed clinical trials. Trials that are not well thought out and/or are overly optimistic to the extent to which radiation will drive antitumor immunity may be underpowered and fail.
Quest for More Time
In ANNA’s case, I knew the abscopal response could be a possibility but refrained from giving her any unrealistic hope. Despite the RPA classification discussion, she went on to survive for more than 5 years after stereotactic radiosurgery for her single brain metastasis. Her brain disease and her systemic disease were controlled over several years after stereotactic radiosurgery, to the point where she was able to undergo many of the FDA-approved treatment options, including anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) agents, anti–PD-1 (programmed cell death protein 1) agents, dual checkpoint inhibitors, BRAF inhibitors, and even talimogene laherparepvec. After Anna received multiple rounds of stereotactic radiosurgery and even whole-brain radiotherapy, her brain disease continued to remain well controlled. She eventually succumbed to systemic disease, while having good control of her intracranial disease.
I would like to think that perhaps I played some role as a radiation oncologist in extending her survival beyond just providing her “local control.”
DISCLOSURE: Dr. Khan has received honoraria from Cardinal Health and has received institutional research funding from Merck Sharp & Dohme.
Dr. Khan is Associate Professor and Director, Medical Student Clerkship and Radiation Immuno-Oncology; and Co-Leader, Immuno-Oncology, of Winship Cancer Institute, Emory University, Atlanta.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
