Late non-neoplastic events in patients with aggressive non-Hodgkin's lymphoma in four randomized European Organisation for Research and Treatment of Cancer trials

: BACKGROUND: A significant proportion of patients with aggressive non-Hodgkin's lymphoma (NHL) become long-term survivors. A European Organisation for Research and Treatment of Cancer database of patients with aggressive NHL, consistently treated with doxorubicin-based chemotherapy since 1980, afforded the possibility to explore late complications in this patient group. PATIENTS AND METHODS: Of 951 randomized patients, complete data on late complications could be collected in 757 patients who were alive > or = 2 years after the start of therapy and were seen at yearly follow-ups (median follow-up, 9.4 years; range, 2.1-20.4 years). We computed cumulative incidences of late events in a competing risk model by Gray (death being the competing event) to avoid bias caused by the high percentage of NHL-related deaths. Risk factors were estimated in a Cox proportional-hazards model and also evaluated with the Gray test. RESULTS: Late non-neoplastic events were found in 46% of the 757 patients. At 15 years, the cumulative incidences of cardiac disease and infertility were 20% and 29%, respectively. Renal insufficiency (11%), acquired hypertension (8%), and disabling neuropathy (13%) were also frequent. Salvage treatment was a risk factor in most cases. Smoking, age > 50 years during treatment, and preexistent hypertension were the main risk factors for cardiovascular disease. In-field radiation therapy (RT) was related to hypothyroidism, lung fibrosis, hypertension, gastrointestinal toxicity, and renal insufficiency but not to cardiovascular events. Autologous stem cell transplantation and cisplatin- and MOPP (mechlorethamine/vincristine/procarbazine/prednisone)-containing therapies were associated with infertility and renal insufficiency. CONCLUSION: Altogether, almost half the patients with aggressive NHL experienced events addressed as late non-neoplastic complications. Salvage therapy, smoking, age > 50 years, and in-field RT are important risk factor