For decades lymphoma patients are, whenever possible, treated in clinical trials. This thesis is based on 30 years experience of large clinical trials by the EORTC (European Organization for... Show moreFor decades lymphoma patients are, whenever possible, treated in clinical trials. This thesis is based on 30 years experience of large clinical trials by the EORTC (European Organization for Research and Treatment of Cancer) Lymphoma Group in aggressive non-Hodgkin__s lymphoma (NHL). The consistent use of CHVmP/BV (cyclophosphamide, doxorubicin, teniposide, prednisone, bleomycin and vincristine) in 4 successive trials offered a unique possibility to update outcome, but also late effects in the almost 1000 patients enrolled of this doxorubicin-based chemotherapy regimen and additional treatments. Long-term follow-up in the 4 EORTC trials (1980-1999) shows that more than half of the NHL patients become long-term survivors and encounter problems as premature menopause, infertility, cardiovascular disease, disabling neuropathy, renal insufficiency and hypothyroidism. Doxorubicin and cyclophosphamide, the main drugs in NHL treatment appear to cause significant risk of chronic heart failure and second cancer (MDS/AML and bladder cancer). Young female patients often experience premature menopause, which seems partly to protect against breast cancer, but induces infertility, osteoporosis and higher risk of cardiovascular disease. Salvage treatment and smoking significantly raise risk of cardiovascular disease and second cancer even further. The statistical methods applied for estimation of late complications are evolving and of key-importance. Corrections by competing risk model and person-years analysis are, therefore, in this thesis described in detail. The risk of late complications appeared to be strongly age-dependent; especially young patients (< 45 years) run into very high risk. Similarly, young patients are considered good candidates for more aggressive treatment approaches. In future trials, the marked high risk of congestive heart failure and second cancer, including leukemia, should be, therefore, balanced against any preference for initial high-dose treatment. Additional radiotherapy on the neck can induce hypothyroidism and stroke, and abdominal fields appeared to be related with secondary hypertension and renal insufficiency. The role of additional radiotherapy in risk of cardiovascular disease appeared to be dose dependent and minimal when doses of 30 Gy or less were given. The relatively small fields used did not increase risk of second cancer, but the numbers analyzed were limited. Obviously, for estimation of the role of radiotherapy in late toxicity, data on techniques, dose, and field placement are mandatory and they significantly changed over time. In conclusion, late toxicity in lymphoma treatment is often associated with radiotherapy. In the CHVmP/BV update, the role of additional radiotherapy appears, however, to be important in case of residual disease, while the excess risk of late effects appeared minimal and is moreover overruled by the number of serious late complications due to first line and second line chemotherapy for aggressive NHL. Therefore, when more therapy is needed, additional radiotherapy instead of more intensive chemotherapy should be seriously considered. All patients, but especially patients treated for NHL before the age of 45 years, need lifelong monitoring and should receive information on late consequences of treatment, focused on cardiovascular disease, premature menopause, renal failure and second cancer, including MDS/AML risk. The treating physician needs to address the excess risk of smoking and overweight. Routinely check of blood pressure, lipid-profile and on indication bone mass, thyroid- and renal function during follow-up is recommended, as preventive care can reduce secondary morbidity and even mortality. Fully dosed (within the consensus limits of 400 mg/m2) doxorubicin-based chemotherapy for NHL appears to result in almost three excess cases per year of congestive heart failure per 100 patients followed. Equivalent risks can be expected when full dose doxorubicin-based chemotherapy is given in young patients for other cancer types, like breast cancer. More research in this field, based on long-term follow-up data and comparison to general population incidence rates is needed. As future trials become more and more equivalency trials, the high risk of second cancer and cardiac toxicity in young patients should be balanced against the potential survival benefit: more is not always better. Show less
