Cardiac toxicity and esophageal cancer radiotherapy: What is the risk?
In the past, a diagnosis of esophageal cancer typically meant near-term death, in part because symptoms often don’t surface until stage III or greater. According to the American Cancer Society, only 5% of these patients lived 5 or more years following treatment in the 1960s and ‘70s. While roughly 20% of patients reach that milestone today, they may face another difficult challenge: severe late toxicities as a result of treatment.
Cardiac toxicity in particular is a serious issue in radiation treatment, especially among breast cancer and Hodgkin’s lymphoma survivors. But how it may affect esophageal patients remains uncertain. Unlike breast cancer patients, esophageal patients typically do not survive long enough or in large enough numbers to be formally studied. Compounding the problem, many esophageal patients are over age 60, at high risk for cardiac diseases, have a history of alcohol use and/or smoking, have poor dietary habits and/or obesity, or are diabetic.
To investigate the effects of cardiac toxicity in this patient population, Jannet C. Beukema, MD, a radiation oncologist at the University Medical Center Groingen, The Netherlands, conducted a literature review, published online December 30, 2014 in Radiotherapy and Oncology.1 The studies in the review were published between 1998 and 2012, 12 of which were retrospective analyses. All patients had undergone a concurrent chemoradiation therapy treatment receiving a total radiation dose up to 60 Gy.
The authors identified a crude incidence of symptomatic cardiac toxicity as high as 10.8%. Toxicities corresponded with several dose-volume parameters of the heart. The most frequently reported complications were pericardial effusion, ischemic heart disease, and heart failure during a follow-up period of 26 to 57 months.
“The primary objective of our ongoing research about the incidence of documented radiation-induced cardiac toxicity after multimodality treatment is to improve radiotherapy treatment decision-making,” Dr. Beukema says. “Contemporary advanced radiation delivery techniques such as intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) techniques are reducing dose to the heart. But the optimal distribution of the dose between various organs at risk – especially the lung – remains to be determined.”
Applied Radiation Oncology talked with several radiation oncology gastrointestinal cancer specialists about cardiac toxicity risk. Even though esophageal cancer is the 8th most common cancer worldwide, and studies have identified types of treatment for the best outcomes, patient management guidelines are less well-defined than other types of cancer.
“Treatments differ depending upon the type of esophageal cancer,” explains Bruce D. Minsky, MD, director of clinical research, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston. About 20 to 30 years ago, 85% to 90% of U.S. patients with esophageal cancer were diagnosed with squamous cell carcinoma, he notes. This cancer begins in the tissue that lines the esophagus, particularly in the middle and upper parts of the abdomen. While this type of cancer has declined dramatically in the United States, it remains the most common type of esophageal cancer worldwide, especially in Northern China, India, Iran and Southern Africa. About 85% to 90% of the esophageal cancers treated in Western societies are adenocarcinomas in the distal esophagus near the stomach. Patients with squamous cell carcinoma tend to receive concurrent chemoradiotherapy treatments, and patients with adenocarcinomas undergo chemoradiotherapy followed by surgery.
Historically, radiation oncologists did not pay as close attention to organs at risk as they do now, Dr. Minsky explains. But today’s multimodality therapy of distal esophageal adenocarcinomas, while improving outcomes, has its own complex risk vs. benefit challenges.
Arta M. Monjazeb, MD, PhD, assistant professor, Department of Radiation Oncology at U.C. Davis Comprehensive Cancer Center in Sacramento, CA, and William A. Blackstock Jr., MD, chair and professor of radiation oncology, Wake Forest University Health Sciences in Winston-Salem, NC, say the complexity stems, in part, from comorbidities, the toxic nature of therapies, and only modest improvement of outcomes in escalated therapies—all affecting a patient’s short- and long-term quality of life.2
“The Cancer Treatment Centers of America (CTCA) uses IMRT, tomotherapy, and VMAT to spare radiation exposure to the heart, lungs and other structures,” says Bernard Eden, MD, national director of radiation oncology. “Additionally, we add a naturopathic substances regime to help protect these organs.”
Dr. Eden says very few CTCA patients develop late cardiac toxicity. “However, there is not an overall 100% solution to deliver the dose directly to the tumor in the esophagus and eliminate dose to the heart. Our goal is to minimize risk for each individual patient.”
“The integration of better chemotherapy, radiation therapy and surgical techniques is changing the treatment landscape for esophageal cancer patients and enabling better outcomes,” adds Sarah E. Hoffe, MD, a radiation oncologist at Moffitt Cancer Center in Tampa, FL, and the national course director of ASTRO’s eContouring program. “Staging advanced tumors has become more reliable than ever before, given the integration of PET imaging and endoscopic ultrasound. Target delineation is better. Gastroenterology colleagues perform an endoscopic ultrasound and can implant fiducial markers at the proximal and distal end of mucosal disease, which enables us to know precisely the local tumor extent.
“We also have technology to incorporate a 4D PET/CT, which shows the area of uptake with the distribution as the patient breathes,” she continues. “Then, when we plan the radiotherapy treatment, we incorporate a 4D CT scan. This enables us to know the position of the tumor from maximum inhalation to maximum exhalation and every point in between.”
If motion is significant, placing a compression belt on the patient’s abdomen may decrease the respiratory-associated target motion by up to 50%, Dr. Hoffe notes. Moreover, during daily treatment, radiation oncologists can perform image-guided radiation therapy (IGRT) to ensure that the fiducial markers are aligned properly. Appropriate shifts can be made to ensure reproducibility of the patient’s setup.
“These types of planning techniques are relatively new, but very beneficial to define tight margins and to decrease the healthy amount of tissue exposed to radiation,” she says. “With these advanced treatment modalities, we are truly able to increase the precision of the higher dose delivery targeted to the tumor, potentially leading to higher rates of response. We are also optimizing the protection of the normal tissues such as the heart and the lung.”
Lawrence R. Kleinberg, MD, associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins Kimmel Cancer Center in Baltimore, MD, adds that IMRT and VMAT can greatly modulate the radiation dose that will be received by the anterior portion of the heart and for many of the coronary artery branches.
“The new techniques we use to protect the heart result in radiation aimed at various angles through the body, unlike the radiation techniques…in which a beam was aimed from the front of a patient’s body but went straight through the heart before reaching the esophagus,” Dr. Kleinberg says. “Still there are tradeoffs, and to the best of my knowledge, no data exist to give us any understanding of what these tradeoffs mean.”
A multidisciplinary team including a gastroenterologist, oncologist, radiation oncologist and surgeon is key to successful treatment as well, since collaboration is especially relevant for esophageal cancer patient management.3 In December 2014, Moffitt Cancer Center announced a collaboration with the division of cardiology at the University of South Florida Morsani College of Medicine in Tampa to create a joint cardio-oncology program that provides cardiovascular services for patients undergoing cancer therapy, and follow-up for survivors at risk of cardiac toxicity, says Michael Fradley, MD, program director. “If we identify potential problems early, we may be able to minimize serious problems in the future.”
Such collaboration is precisely what Dr. Beukema and colleagues hope to promote. “We need to collect more data about esophageal cancer patients. Imaging studies and cardiac function parameters during follow-up will help us to identify the most relevant clinical endpoints and critical parts of the heart,” she says. “Current data are insufficient to make prediction models for radiation-induced cardiac toxicity. But this is needed to develop accurate multivariable prediction models on radiation-induced toxicity to estimate the potential added benefits of various techniques.”
References
- Beukema JC, van Luijk P, Widder J, et al. Is cardiac toxicity a relevant issue in the radiation treatment of esophageal cancer? Radiother Oncol. Published online December 30, 2014 [Epub ahead of print].
- Monjazab, AM and AW Blackstock. The impact of multimodality therapy of distal esophageal and gastroesophageal junction adenocarcinomas on treatment-related toxicity and complications.Semin Radiat Oncol. 2013;23(1):60-73.
- Villaflor, VM, Allaix, ME, Minsky B, et al. Multidisciplinary approach for patients with esophageal cancer. World J Gastroenterol. 2012;18(46):6737-6746.
