Hodgkin's Lymphoma Treatment Linked to Risk for Stomach Cancer

Roxanne Nelson

August 30, 2013

People treated for Hodgkin's lymphoma could face an increased risk for the subsequently development of stomach cancer. New data show a dose-dependent increase in the risk for stomach cancer in patients who received subdiaphragmatic radiotherapy and a chemotherapy regimen containing high-dose procarbazine (Matulane).

Results from the case–control study were published online August 26 in the Journal of Clinical Oncology.

The researchers found that the risk for stomach cancer rose with increasing doses of radiation to the stomach (P for trend  < .001) and with an increasing number of chemotherapy cycles containing alkylating agents (P for trend = .02).

Patients who received 25 Gy of radiation or more to the stomach and procarbazine (≥5600 mg/m²) had a 77.5-fold higher risk of developing stomach cancer. However, for patients who received any dose of procarbazine but less than 25 Gy of abdominal radiation, there was no increased risk.

For patients who received less than 5600 mg/m² of procarbazine and abdominal radiation of 25 Gy or more, the risk for stomach cancer jumped 2.8-fold.

For those who received less than 25 Gy of abdominal radiation and dacarbazine (DTIC-Dome), the risk was increased 5.4-fold.

"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," said lead author Lindsay M. Morton, PhD, from the division of cancer epidemiology and genetics at the National Cancer Institute, in a statement.

"Because Hodgkin's 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," she explained. "Clinicians who follow these survivors should be alert to patient complaints related to the gastrointestinal tract."

Who Gets Screened?

Although secondary cancers can be a serious long-term effect of treatment, the absolute risk for stomach cancer is still quite low, said Andrew E. Hendifar, MD, MPH, a gastrointestinal oncologist at Cedar's Sinai Medical Center in Los Angeles, California.

"What this is really compelling is that they were able to isolate a subgroup of patients who were at the highest risk and who received a high dose of procarbazine and radiation to the stomach," he told Medscape Medical News. "It is obvious that the risk is higher in this group, but it is hard to gauge how it relates to entire Hodgkin's lymphoma population."

Dr. Hendifar noted that if he had a such a high-risk patient, he would consider screening. "But at this point, it really is too early to know which patients actually need to be screened," he said. "Screening is invasive; it involves upper endoscopy. We have to consider that, as well as the cost."

Another factor is how often patients would need to be screened, he pointed out. "Is 1 time enough, or should they be screened more often? And at what intervals?"

High Risk for Secondary Cancers

Although Hodgkin's lymphoma has become a highly curable disease, with a 5-year survival rate of 86%, the risk for late treatment effects is high, the researchers note. Secondary malignancies have emerged as an important cause of mortality among patients with Hodgkin's lymphoma, as previously reported by Medscape Medical News.

Dose-Dependent Risk

In their study, Dr. Morton and colleagues evaluated data from Canada, Denmark, Finland, the Netherlands, Norway, Sweden, and the United States. From the 19,882 survivors of Hodgkin's lymphoma diagnosed from 1953 to 2003, 89 patients developed stomach cancer; they were matched with 190 control subjects for the analysis.

The median age at diagnosis of Hodgkin's lymphoma was 30 years, and 44% of the patients were diagnosed in 1975 or later. The majority of patients received radiotherapy (92% cases, 86% controls), with or without alkylating agents.

The case patients received subsequent therapy for Hodgkin's lymphoma more frequently than the control patients (47% vs 27%), and the median time to the development of stomach cancer was 15 years (median age at diagnosis, 50 years). After the diagnosis of stomach cancer, survival was quite poor; 88% of the case patients are known to be deceased (median survival, 6 months).

The researchers note that radiotherapy for stomach cancer with at least some subdiaphragmatic exposure was far more common in the case patients than in the control patients (69% vs 37%; odds ratio, 6.2).

There was a statistically significant association between stomach cancer and treatment with procarbazine (P for trend = .003) or dacarbazine (P for trend = .008), but not with other alkylating agents.

In a multivariate analysis of radiation therapy, procarbazine, and dacarbazine, the odds ratio was significantly higher for radiation at or above 25 Gy (OR, 5.8), for procarbazine at doses of 5600 to 8399 mg/m² (OR, 2.9) or of 8400 mg/m² or higher (OR, 2.3), and for any dose of dacarbazine (OR, 8.8).

The researchers point out that although the number of patients who received dacarbazine was too small to conduct a reliable dose–response analysis (12 cases, 9 controls), its association with stomach cancer does not appear to be "accounted for or modified by exposure to radiation or procarbazine."

"The association between procarbazine and stomach cancer risk was strikingly dependent on the radiation dose to the stomach," the researchers write. They estimate the proportion of stomach cancer cases attributable to treatment to be 99% for patients who received radiation to the stomach of 25 Gy or more and procarbazine at doses of 5600 mg/m² or higher.

The study was supported by the Intramural Research Program of the National Cancer Institute (NCI), as well as through NCI-issued contracts. The authors have disclosed no relevant financial relationships.

J Clin Oncol. Published online August 26, 2013. Abstract

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