Certain Past Regimens for Hodgkin Lymphoma Can Raise Stomach Cancer Risk—Findings Point to Need for Continued Monitoring

Figure: Stomach adenocarcinoma cellsA study by a multinational team of researchers has found an increased risk of stomach cancer in a small number of Hodgkin lymphoma survivors who received certain radiation and chemotherapy regimens between 1975 and 2003. In the study, published in the September 20 issue of the Journal of Clinical Oncology (2013;31:3369-3377), the researchers reviewed the medical records of 17,477 Hodgkin lymphoma patients treated between 1953 and 2003 in the Netherlands, Denmark, Finland, Norway, Sweden, the United States, and Canada, but those treated before 1975 were excluded from the final analysis because the records before 1975 were deemed unreliable. Among the entire 50-year patient sample, 89 individuals were identified who developed stomach cancer—44 percent of whom were diagnosed after 1975. By examining these patients' treatment records the researchers were able to estimate the radiation doses to the stomach and calculate the doses and the types of chemotherapy received. The data were then compared with the treatment regimens given patients who did not develop stomach cancer. Seventy-four percent of patients had stage I or II Hodgkin lymphoma. Most patients received radiotherapy (92 percent of stomach cancer cases and 86 percent of controls), and stomach cancer patients received subsequent therapy for Hodgkin relapses more often than did the controls—47 vs. 27 percent. The median interval from Hodgkin to stomach cancer was 15 years, and the median age at stomach cancer diagnosis was 50. Survival after a stomach cancer diagnosis was poor, with 88 percent of patients dying after a median survival time of just six months. The researchers, led by Lindsay M. Morton, PhD, an investigator in the National Cancer Institute's Radiation Epidemiology Branch of the Division of Cancer Epidemiology and Genetics, said that although the number of affected patients was relatively small and the study did not demonstrate a cause-and-effect relationship, it is the first to suggest that there might be an association between chemotherapy and radiation types and the later development of stomach cancer in survivors of Hodgkin lymphomas. The cumulative incidence of second primary invasive stomach cancer in the study was 0.39 percent at 15 years and 0.92 percent at 30 years, and the median age at diagnosis was 30 (range of 11 to 83). Advances in treating Hodgkin lymphoma since 1975 have led to improved survival, such as different types of chemotherapy and more targeted radiotherapy. According to data from NCI's Surveillance, Epidemiology and End Results Program, the five-year survival rate for patients with Hodgkin lymphoma was 72 percent from 1975 to 1977, but rose to 88 percent for the period of 2003 to 2009. Past studies have linked Hodgkin lymphoma radiation and chemotherapy treatments with stomach cancer risk, but those studies have been more limited in scope, Morton noted. She and her co-investigators were able to narrow down certain common characteristics in patients who developed stomach cancer. The risk increased with higher doses of radiation to the stomach area—i.e., patients who received the highest exposure had a nearly three-fold increase of stomach cancer compared with those who were treated at the lowest levels. The risk associated with radiation was even higher for survivors who also received the procarbazine, which studies have found can damage DNA. The risk was most highly dependent on the doses of radiation and procarbazine administered. “Strikingly elevated” stomach cancer risk was observed among patients who received both 25 Gy radiation to the stomach and high-dose procarbazine (5,600 mg/m2 or greater). In the study, 25 such patients developed stomach cancer versus just two in the control patients who had received a lower dose of procarbazine and the same radiation dose. Treatment with dacarbazine, which was FDA approved in 1975, also increased the risk of stomach cancer (12 cases vs. 9 controls), after being adjusted for radiation and procarbazine doses. Dacarbazine is commonly used to treat Hodgkin lymphoma, but the researchers noted that because so few patients in the study received the drug, additional research is needed. “Our study adds strong support to the growing concern that stomach cancer is a rare but important adverse late effect of treatment for Hodgkin's lymphoma,” Morton said in an NCI news release. “Because Hodgkin lymphoma patients commonly receive treatment in their 20s and 30s, many of the stomach cancers arise before age 50, nearly 20 years earlier than is typical for newly diagnosed patients who have never had cancer. Clinicians who follow these survivors should be alert to patient complaints related to the gastrointestinal tract.” Risk Lower Today Asked for his opinion, Hodgkin lymphoma expert Richard T. Hoppe, MD, the Henry S. Kaplan-Harry Lebeson Professor of Cancer Biology at Stanford University, said he believes the study sufficiently identifies and quantifies the risk of stomach cancer in these patients, but that most regimens for the disease used today carry far less risk. “The findings provide valuable information, but primarily for patients treated in the past, since the greatest risk was with gastric irradiation, which is now not commonly given, and high-dose procarbazine, such as was given in MOPP,” he said. MOPP, developed in the 1960s, was the first combination chemotherapy used in Hodgkin lymphoma (HL), and included mechlorethamine, vincristine, procarbazine, and prednisone. Different chemotherapy combinations are used today, though, said Hoppe, a member of OT's Editorial Board. “Patients included in the study were treated more than 10 years ago. Current treatment programs for HL include more limited and refined radiation fields that usually do not include the stomach, and MOPP is no longer used as a primary therapy,” he said. “ Procarbazine is included in the newer BEACOPP combination, although only as much per cycle as MOPP. This study also identified a possible increased risk related to dacarbazine, which is one of the four drugs in ABVD chemotherapy, the most common chemotherapy in use today for HL patients in North America.” He also said the findings were not a complete surprise because gastric cancers in survivors of HL treatment have been reported in the past—“but this study does define the risk better than has been done before.” What may be a surprise, though, is that procarbazine and dacarbazine were part of the chemotherapy regimen(s) linked to higher risk, he said. “While treatments have already changed, the study emphasizes the importance of long-term follow-up for patients currently being treated to be able to identify how these risks may be altered with newer therapies. “Current management of HL is already well defined and intended to minimize risk, so the findings should not change management of HL patients. For the radiation oncologist though, it will be important to consider the stomach an ‘organ at risk’ when we define our treatment fields, and employ techniques that minimize gastric radiation exposure such as deep inspiration breath-hold or proton therapy.” He added that future research should include continued long-term follow-up of patients with Hodgkin lymphoma currently participating in large trials because identifying and quantifying such late effect risks can take 30-plus years.

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