Novel Radiation Therapy Techniques Should Become Standard in Esophageal Cancer Management

Steven H. Lin, MD, PhD

Technological advancements in the radiation therapy field, including intensity-modulated radiation therapy (IMRT) and proton therapy, have become a novel and more concentrated approach to delivering radiation doses as well as spare patients from life-threatening toxicities. This direction differs from 3D conformal radiation therapy, which remains the current standard of care for radiation therapy delivery, even with its long-term morbidity and mortality risks.

OncLive: Can you give an overview of your talk on advances in radiation therapy?

In an interview with OncLive, Steven H. Lin, MD, PhD, associate professor of radiation oncology, The University of Texas MD Anderson Cancer Center, discussed why IMRT should be adopted as the new standard approach. He also hones in on the benefits of these advanced radiation technologies, specifically for patients with esophageal cancer.Lin: In esophageal cancer management, the most important thing in terms of treatment modality is radiation, along with surgery and chemotherapy. Surgery is still reserved for early-stage cancers; however, for locally advanced diseases, pre-operative chemoradiation followed by surgery is now the current standard of care in patients who are surgical candidates.

For patients who are not surgical candidates, chemoradiation definitively is the standard of care. Radiation is a very important modality for the management of esophageal cancer, however, because of the usual location of esophageal tumors—which is in the chest, surrounded by the heart and lungs—when we deliver the radiation, it’s very important to try and spare the doses to these vital organs as much as possible.

The current standard of care in the community for the delivery of radiation is 3-D conformal radiation therapy, which is simple beam arrangements that deliver higher doses relatively to the heart and lungs. While it delivers cytodoses to the tumor, it unfortunately can potentially have long-term morbidity, as well as mortality, to patients. Not only in the patients who survive long enough from their cancer and then they develop these long-term complications, but also immediately after surgery. More radiation to these structures can potentially increase these post-operative complications.

What advanced technology tries to do is spare the doses as much as possible to these surrounding structures through various ways of delivering the dose, and it modulates the dose so that most of it is concentrated in the tumor, and then relatively low doses go to the heart and lung. IMRT is one way to do it, and certainly for x-ray therapy, it is the most advanced way of delivering x-ray radiation.

What data was looked at in the analysis you performed?

Proton therapy is the next most advanced, because it’s not actually x-rays, it’s charged particles, the protons are hydrogen ions that are accelerated and delivered into the patient. By the physical property of charged particles and its interaction with matter, it delivers energy at a very specific point and not beyond that point. Because of the physical nature of protons, it completely spares the surrounding structures while delivering the high dose to the tumor, and relatively no doses are delivered to parts of the heart and lung compared to even IMRT.We looked at our experience and compared our complications after surgery and long-term outcomes of patients who were treated between 3-D conformal and IMRT. We found that the use of IMRT does seem to improve and reduce toxicities that patients experience in the immediate surgical period in terms of the incidence of pulmonary complications and gastrointestinal complications, but also long-term outcomes, including cardiac mortality, seem to be spared with the use of IMRT.

We also decided to look in the population data, so we looked at 2,500 or so patients in the database, where a subset of patients got IMRT and the larger group got 3-D conformal.

What we know is the adoption of IMRT was fairly rapid, so we looked at the time period between 2002 and 2009, and we found that at the beginning of 2002, only about 2% of clinicians were using IMRT, and 98% of patients were treated with 3-D. Over time, up to 2009, 30% of patients were being treated with IMRT. That kind of technology is going out to the community and clinicians are believing there is a benefit, of course with not much evidence, but they believe there is a benefit to patients, therefore there is a rapid adoption of that technology.

When we looked at those data, we found that the use of IMRT also improves survival. We see that there is an improvement in survival in patients treated with IMRT compared to 3-D conformal. But what is more interesting is that when we looked at the type of deaths in patients, the majority of the time they die from cancer. But there is a subset of patients that don’t die from cancer—what are they dying from? We noticed that patients are dying more frequently from cardiac deaths, but not from pulmonary or infectious deaths.

It seems to bore out even in the population data that we can see this difference in cardiac mortality that’s in excess in patients treated with 3-D conformal. That convinces us that there is a need to adopt IMRT, and since we don’t have a randomized trial to compare 3-D conformal, we think IMRT should be considered standard in the community. We feel that’s a standard, but then we can further improve upon that, so the use of protons is a way to further spare toxicity.

We have started doing proton therapy for a number of our patients, either because it’s part of a trial or patients want protons and physicians feel it will benefit patients. A number of our patients are doing proton therapy at MD Anderson for esophageal cancer and we have accumulated a lot of experience from that. We have analyzed our experience comparing patients in the post-operative setting in terms of complication rates, comparing proton therapy to IMRT. We also found that proton therapy was able to drastically reduce the level and frequency of pulmonary complications that patients suffer from, as well as womb complications in patients that got protons.

How is lymphocyte count impacted with proton therapy compared with IMRT?

It was very interesting when we looked at 90-day mortality comparing patients that got 3-D conformal, IMRT, and protons. There’s no difference between IMRT and 3-D—90-day mortality is about 4% between the 2. What we know is, interestingly enough, only 0.9% of patients had 90-day mortality in the proton group, so a substantial reduction in 90-day mortality. But again, that’s retrospective and maybe there’s some selection bias, but it’s interesting data, suggesting that there is a further potential for improvement in outcome with the use of proton therapy.One of the studies that is related to proton and IMRT is a poster we presented where we compared lymphocyte count in patients that got protons or IMRT. Lymphocytes is one of those blood-based cells that is important for controlling infections, particularly for viral infections, and it’s important for immunologic warfare, lymphocytes are very important for patients treated with immunotherapy. It is super and exquisitely sensitive to radiation therapy, even low doses of radiation.

What we’ve done in our data set is we looked at a large group of patients that got chemotherapy upfront before they started radiation, and then during the course of radiation, as well as afterwards.

What we noticed is that there is no impact on lymphocyte count when they are getting chemotherapy. They are very stable when they’re getting chemotherapy. Neutrophils and monocytes change a little bit. But when you start radiation, even if it’s after the first week of radiation, you see an immediate drop in the lymphocyte count. By the third week, lymphocytes drop to almost the complete bottom for a lot of patients. What we found, curiously, is the patient that got photon IMRT radiation, the lymphocyte count is much lower in terms of the drop in the nadir compared to patients that got proton therapy. That is highly significant.

If you look at the patients who have lower lymphocyte count, it seemed to correlate with a poorer survival. That means that by dropping their lymphocyte count, the lymphocytes are just not available for helping cancer surveillance. There is no direct proof, but it seems to indicate, not only from these data, but from published literature, that the lymphocyte count that is impacted by radiation has an impact on patient survival and prognosis. That is what we see in the patients who got esophageal cancer, but then protons are able to significantly spare lymphocytes that’s in the blood.

One of the organs we felt was a critical contributor to that is the heart because as you can imagine, the majority of tumors that we treat are in the distal portion of the esophagus, and that is exactly where the heart resides. When the radiation beam is on, the heart is pumping blood through the system, carrying live, active lymphocytes or naïve lymphocytes that are getting radiated and killed everyday as a patient is undergoing therapy. The heart is a very significant contributor to that. We find that because protons are able to spare the heart better, it reduces the impact on the lymphocyte count.

What are the next steps with this research?

We think it has significant implication for the future, particularly for the adoption of other therapies, such as immune therapies where you need the immune system to be intact. I think there will be better synergy with the use of better technologies like proton therapy.We are thinking of adopting the use of immunotherapy and then considering proton therapy as potential stratification. Although you can’t say that every patient needs to get proton therapy to get immunotherapy, the utilization of these technologies need to be a stratifying factor in the design of clinical trials. We could eventually see that the utilization of protons yields a better response, potentially, to the use of immunotherapy compared to immunosuppressive therapies, like photon-based radiation.

This is a hypothesis that we hopefully will test in the future. We would certainly like to validate our findings, as our finding is retrospective based on experience. We want to validate this in the prospective randomized trials that we have running now and in the future. When we run these trials, we want to look at these objectively and look at the data to see if this type of difference bores out in the randomized trial setting.