One of the most important questions in gastrointestinal radiation oncology is determining what is the comparative benefit of protons over intensity-modulated radiation therapy.
—Theodore S. Hong, MD
The use of radiation therapy in the treatment of gastrointestinal cancer has evolved over the past several decades, in a gradual, stepwise fashion. Since most gastrointestinal cancers are diagnosed at a locally advanced stage, coupled with the inherent sensitivity of most parts of the gastrointestinal tract to high-dose radiation, radiation therapy is most often used as part of multimodality therapy, instead of as a sole curative modality. New developments may change the approach of radiation therapies in these highly complex gastrointestinal cancers. To shed light on the emerging role of radiation in gastrointestinal cancers, The ASCO Post recently spoke with Theodore S. Hong, MD, Associate Professor, Department of Radiation Oncology, Harvard Medical School.
Greatest Advance in Liver Tumors
Over the course of your career, what has been the greatest advance(s) in gastrointestinal radiation oncology?
I think the greatest advance in gastrointestinal radiation oncology has occurred in the treatment of liver tumors. The improved technology both in terms of delivery as well as localization has allowed for a new generation of therapeutic options, in which a small number of high-dose fractions can be accurately targeted to the liver in an ablative fashion.
This advance has led to a number of institutional trials, which have demonstrated that patients with unresectable primary or metastatic liver tumors can have durable local control with high-dose radiation (stereotactic body radiation). And the promising local control and survival that we see in hepatocellular carcinoma and intrahepatic cholangiocarcinoma have led to two randomized clinical trials that are currently open for enrollment.
For hepatocellular carcinoma, RTOG-1112 is looking at sorafenib (Nexavar) plus or minus high-dose liver radiation, and NRG-GI001 is a randomized trial evaluating the addition of liver-directed radiation therapy to chemotherapy with respect to overall survival for patients with unresectable, localized intrahepatic cholangiocarcinoma. Both trials will give us valuable results that will translate to the clinic.
Progress in Limiting Toxicity
The luminal gastrointestinal tract is sensitive to high-dose radiation. Have we progressed in our ability to target tumors in this complex anatomic region?
I believe we’ve made progress in this area, certainly in anal cancer, in which previously all the radiation was delivered from the front and back; this approach led to a fair amount of gastrointestinal toxicity, which manifested as problematic diarrhea.
Also, the development of intensity-modulated radiation therapy (looked at prospectively through the RTOG) was able to demonstrate that with improved radiation targeting, we could substantially decrease the rate of gastrointestinal toxicity. And this development has led to a wide rate of acceptance for intensity-modulated radiation therapy in anal cancer.
In addition, in treating both liver tumors as well as pancreatic tumors, there was always a risk of damaging the luminal gastrointestinal tract. However, multiple publications now suggest that we are indeed getting better at protecting the patient from the acute side effects of nausea and vomiting in upper gastrointestinal cancers and also preventing long-term side effects such as gastrointestinal bleeding.
Advocates of proton-beam therapy contend that it is more tumor-specific than intensity-modulated radiation therapy, leading to less morbidity. Where are we in this debate?
I believe that one of the most important questions in gastrointestinal radiation oncology is determining what is the comparative benefit of protons over intensity-modulated radiation therapy. As we know, protons have a theoretic benefit due to the lack of an exit dose, giving greater tissue-sparing efficacy.
There are very robust data from Japan as well as Loma Linda Cancer Center evaluating proton-beam therapy in primary liver tumors. But there have been no direct comparisons of proton-beam vs intensity-modulated radiation therapy. Currently, we at Mass General, in collaboration with MD Anderson, are designing a proton vs intensity-modulated radiation therapy study to try to determine which one has more benefit in liver cancer.
The other gastrointestinal site where we’ve looked at proton-beam therapy is anal cancer. We are currently conducting a prospective trial evaluating patient-reported quality-of-life metrics, both during and after completion of proton-beam therapy. Given the toxicity profile of chemoradiotherapy, we want to see whether protons offer a better option in this disease. Once we have these prospective data to evaluate, it might help us move to a randomized trial looking at proton-beam therapy against intensity-modulated radiation therapy.
Is there a role for preoperative chemoradiotherapy in certain gastrointestinal malignancies?
There certainly is. Preoperative chemoradiotherapy is standard of care in esophageal and gastroesophageal cancers. This is largely based on the CROSS trial, which demonstrated a substantial benefit to preoperative chemoradiotherapy with carboplatin and paclitaxel followed by surgery. The trial confirmed that preoperative chemoradiotherapy for resectable esophageal cancer is safe and, compared with surgery alone, is associated with pathologic complete responses and prolonged survival.
Another disease site in which neoadjuvant or preoperative chemoradiotherapy is the standard of care is in rectal cancer. There have been two randomized trials that have demonstrated improved clinical outcomes when chemoradiotherapy is given before surgery as opposed to after surgery.
There is an increasing movement toward preoperative therapy in pancreatic cancer; however, the role of radiation in pancreatic disease remains highly controversial.
A Glimpse at Clinical Trials
What is ongoing or planned in the clinical trial setting for gastrointestinal radiation?
Along with the trials I’ve already mentioned, RTOG is also looking at radiation in the context of different chemotherapy regimens for locally advanced pancreatic cancer. One interesting study is going to evaluate outcomes based on whether a patient’s tumor has preserved DPC-4, which seems to be a predictor of patterns of failure.
Another interesting ongoing trial is RTOG-1010, which is a randomized phase III study evaluating the addition of trastuzumab (Herceptin) to neoadjuvant chemoradiotherapy in esophageal or gastrointestinal junction cancer. I think both of these trials highlight that radiation, which has historically been used in a homogeneous way in a given disease, is now moving in the personalized direction that we see in medical oncology. Hence, the integration of targeted therapies and appropriately selected patients to evaluate which patients may benefit from aggressive treatment based on potential patterns of failure.
Active Research Areas
Are any of the newer targeted therapies showing a synergistic benefit with radiation therapy?
Many of the newer targeted therapies have been looked at in gastrointestinal cancers, but unfortunately, no biologic in combination with radiation has been shown to improve clinical outcomes. That said, we have high hopes for the trastuzumab trial, so it remains an active research area. In rectal cancer, we are looking at a drug called midostaurin (a multitarget kinase inhibitor) in a phase I trial.
There’s also a lot of excitement in work that shows the potential of radiation to enhance the ability of the immune system to recognize cancer cells.
Do you have any final thoughts?
This is an exciting time for radiation oncology. The ability to treat liver tumors, which has arisen over the past 10 years, opens up many opportunities for our patients who previously had no curative options.
Moreover, I think our community remains interested in the integration of new drugs with radiation. Even beyond classic radiosensitization, in which we are just trying to enhance the radiospecific site, the idea of enhancing the abscopal effect, which might trigger a widespread immune response to cancer, is very exciting. The field of radiation oncology is exploring new ways to use our powerful tools. ■
Disclosure: Dr. Hong has received research support from Novartis.