Risk of Treatment-Related Stomach Cancer Among Hodgkin Lymphoma Survivors
Authors: Morton Lindsay M. , Gilbert Ethel S. , Lynch Charles F. , Hall Per , Dores Graca M. , Curtis Rochelle E. , Storm Hans H. , Johannesen Tom Borge , Stovall Marilyn , Smith Susan A. , Weathers Rita E. , Aleman Berthe M. , Kleinerman Ruth A. , Fraumeni Joseph F. , Holowaty Eric J. , Pukkala Eero , Kaijser Magnus , Hauptmann Michael , Fossa Sophie D. , Joensuu Heikki , Andersson Michael , Belt-Dusebout Alexandra W. van den , Vaalavirta Leila , Langmark Froydis , Travis Lois B. , van Leeuwen Flora E. 
Published: October 2019

Abstract
Abstract 2679

Introduction.
Subsequent malignancies are a leading cause of morbidity and mortality among Hodgkin lymphoma (HL) survivors. Stomach cancer is one of the more common second malignancies occurring after HL, yet few studies have quantified stomach cancer risk in relation to radiation dose, and only one investigation has evaluated potential risks associated with chemotherapy.

Methods.
We conducted a nested case-control study of stomach cancer among 17,447 ≥5-year survivors of HL from six European and North American population-based cancer registries during 1953–2005. Patients included 71 cases diagnosed with HL and subsequent stomach cancer, and 142 individually-matched controls diagnosed with HL only. Data were pooled with a previous hospital-based case-control study from The Netherlands (18 cases, 48 controls), resulting in a total of 89 cases and 190 controls. For all patients, detailed data were abstracted from medical records on HL diagnosis and treatment and, for cases, stomach cancer diagnosis. Based on detailed radiotherapy information, the radiation dose was estimated to the area of the stomach where the case patient's tumor developed and to the comparable location in matched control patients. Chemotherapy data included specific drugs, doses, and number of cycles. The relative risk of stomach cancer was estimated using odds ratios (ORs) derived from conditional logistic regression analyses.

Results.
Median ages of case patients at HL and stomach cancer diagnosis were 32 years (range, 11–83 years) and 50 years (range, 26–89 years), respectively, with a median interval between HL and stomach cancer of 16 years (range, 5–36 years). Most patients received combined modality treatment (chemotherapy + radiotherapy, 56% cases, 44% controls) or radiotherapy alone (36% cases, 43% controls), whereas few patients received chemotherapy alone (8% cases, 13% controls). Stomach cancer risk increased with increasing radiation dose to the stomach tumor location (Ptrend<0.001). Compared with patients receiving <0.5 Gy, radiation doses of 30–39 Gy were associated with 5.3-fold increased risk [95% confidence interval (CI) 2.1–13], whereas radiation doses ≥40 Gy were associated with 2.1-fold increased risk (95%CI 0.8–5.9). Stomach cancer risk also increased with increasing number of cycles of alkylating agent chemotherapy (≥11 cycles versus no chemotherapy, OR=2.8, 95%CI 1.2–7.0; Ptrend=0.042), and was most strongly associated with increasing dose of procarbazine (Ptrend=0.004).

Conclusions.
Past treatment with radiotherapy and alkylating agent-based chemotherapy is associated with dose-dependent increased risk for stomach cancer among HL survivors. Current treatment practices with involved field radiotherapy, lower radiation doses, and alternate chemotherapy regimens may be associated with lower risk, however, patients receiving abdominal radiation and/or alkylating agents may still be at increased risk. Our results highlight the importance of increased awareness among clinicians and patients during long-term follow-up and prompt evaluation of signs and symptoms referable to the upper gastrointestinal tract.

Disclosures:
No relevant conflicts of interest to declare.