Purpose-A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. non-randomized) and risk group (low vs. intermediate-high) Methods and materials-Nine published prostate cancer dose escalation studies including 6539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, γ 50 , is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.Results-Non-randomized studies produced a statistically significantly higher γ 50 than randomized studies for intermediate-high risk patients (γ 50 = 1.63 vs γ 50 = 0.93, p=0.03) and a borderline significantly higher (γ 50 = 1.78 vs γ 50 = 0.56, p=0.08) for low risk patients. No statistically significant difference in γ 50 was found between low and intermediate-high risk patients (p=0.31). From the pooled data of low and intermediate-high risk patients in randomized trials, we obtain the overall best estimate of γ 50 =0.84 with 95% confidence interval 0.54-1.15.Conclusions-Non-randomized studies over-estimate the steepness of the dose-response curve as compared to randomized trials. This is probably the result of stage migration, improved treatment techniques and a shorter follow-up in higher-dose patients that were typically entered more recently. This over-estimation leads to inflated expectations regarding the benefit from doseescalation and could lead to under-powered clinical trials. There is no evidence of a steeper doseresponse for intermediate-high risk compared to low risk patients.
PURPOSE The contemporary management of early-stage Hodgkin lymphoma (ES-HL) involves balancing the risk of late adverse effects of radiotherapy against the increased risk of relapse if radiotherapy is omitted. This study provides information on the risk of radiation-related cardiovascular disease to help personalize the delivery of radiotherapy in ES-HL. METHODS We predicted 30-year absolute cardiovascular risk from chemotherapy and involved field radiotherapy in patients who were positron emission tomography (PET)–negative following three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy within a UK randomized trial of PET-directed therapy for ES-HL. Cardiac and carotid radiation doses and chemotherapy exposure were combined with established dose-response relationships and population-based mortality and incidence rates. RESULTS Average mean heart dose was 4.0 Gy (range 0.1-24.0 Gy) and average bilateral common carotid artery dose was 21.5 Gy (range 0.6-38.1 Gy), based on individualized cardiovascular dosimetry for 144 PET-negative patients receiving involved field radiotherapy. The average predicted 30-year radiation-related absolute excess overall cardiovascular mortality was 0.56% (range 0.01%-6.79%; < 0.5% in 67% of patients and > 1% in 15%), whereas average predicted 30-year excess incidence was 6.24% (range 0.31%-31.09%; < 5% in 58% of patients and > 10% in 24%). For cardiac disease, the average predicted 30-year radiation-related absolute excess mortality was 0.42% (0.79% with mediastinal involvement and 0.05% without) and for stroke, it was 0.14%. CONCLUSION Predicted excess cardiovascular risk is small for most patients, so radiotherapy may provide net benefit. However, for a minority of patients receiving high doses of radiation to cardiovascular structures, it may be preferable to consider advanced radiotherapy techniques to reduce doses or to omit radiotherapy and accept the increased relapse risk. Individual assessment of cardiovascular and other risks before treatment would allow personalized decision making about radiotherapy in ES-HL.
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