Improving the methodologic and ethical validity of best supportive care studies in oncology: lessons from a systematic review.

PURPOSE: To systematically review the best supportive care (BSC) literature and to evaluate the ethical and methodologic validity issues by using widely acknowledged criteria. METHODS: Two search strings that included both cancer and supportive as terms (with random article type, or review or meta-analysis) explored databases from 1966 to 2008. Citations, abstracts, and papers were reviewed for inclusion criteria, and relevant data were extracted by two independent researchers. Data were validated for accuracy. Ethical and methodologic validity were evaluated by using the criteria derived from the Helsinki Requirements of the WMA; CONSORT statements for the evaluation of reports of randomized, controlled trials; and the universal requirements for ethical clinical research. RESULTS: Forty-three published papers were identified that described 32 studies, 20 of which incorporated the design of treatment plus supportive care (SC) versus SC alone, and 12 of which incorporated the design of treatment versus SC. Most of the studies had poor compliance to critical Helsinki requirements, to methodologic precautions derived from the CONSORT statement for studies involving a nonpharmacologic arm, and to four of seven universal requirements for ethical clinical research. CONCLUSION: Lack of rigor in BSC studies has contributed to a generation of research with widespread ethical and methodologic shortcomings. Ad hoc SC and lack of standardization of SC delivery may be sources of systematic bias or error in BSC trials. Rectifying these shortcomings in future studies demands greater vigilance toward these issues by researchers, institutional review boards, editors, and peer reviewers. Given the prevalence of overlooked problems that are later identified, currently open BSC studies should be reevaluated by institutional review boards and researchers to check for ethical and methodologic validity, and identified shortcomings should be addressed.

An open-label study to evaluate dose and cycle dependence of the pharmacokinetics of pegylated liposomal doxorubicin.

PURPOSE: There are no definitive data in humans on the dose dependence and/or cycle dependence of the pharmacokinetics (PK) of pegylated liposomal doxorubicin (PLD). This study examined the PK of PLD across a twofold dose variation and along 3 cycles. METHODS: Fifteen patients received PLD in successive doses of 60, 30, and 45 mg/m(2) (Arm A) and 30, 60, and 45 mg/m(2) (Arm B), every 4 weeks. Twelve patients, six on each arm, completed all three cycles and were fully evaluable. Plasma levels of doxorubicin were analyzed by HPLC and fluorimetry. PK analysis was done by non-compartmental method. Repeated measures ANOVA and paired tests were used for statistical analysis. RESULTS: There was no significant difference in the PK parameters examined when the dose was increased from 30 to 60 mg/m(2). However, when we analyzed the effect of cycle number on the PK, we found a gradual and significant inhibition of clearance (P < 0.0001) from the 1st through the 3rd cycle of PLD, with a geometric mean increase of 43% in dose-normalized AUC (P = 0.0003). Dose-normalized C(max) and T(1/2) mean values increased by 17 and 18%, respectively between the 1st and 3rd cycles, but only the increase in T(1/2) was statistically significant (P = 0.0017). CONCLUSIONS: While the PK of PLD is not dose-dependent within the dose range of 30-60 mg/m(2), there is evidence of a cycle-dependent effect that results in inhibition of clearance when patients receive successive cycles of PLD. These results suggest the need for dose adjustments of PLD upon retreatment to minimize the risk of toxicity.

Does mammography hurt?

The documented incidence of pain associated with screening mammography varies from 1% to 62%. Some researchers suggest that pain may undermine compliance with screening mammography. As a part of a quality improvement project, we have surveyed women undergoing mammography in 2 centers in Jerusalem to identify the prevalence, severity, and duration of mammography-associated pain, demographic risk factors, and the degree that this may undermine compliance with breast cancer screening. A 23-item questionnaire was administered to 399 women (32% at the Shaare Zedek Medical Center [SZMC] and 68% at the Rachel Nash Comprehensive Breast Clinic [HALA]). Of the total, 77% of the women reported that the procedure was painful. Of those reporting pain, 60% described pain intensity as moderate or severe. In 67%, the pain resolved within 10 minutes. By univariate analysis, the only significant predictor for pain during mammography was cyclic breast pain (P = 0.053). No significant correlation was identified for age, breast size, pre-mammography counseling, and examination center (SZMC vs. HALA). The prevalence of pre-mammography counseling or explanation was low (51%). Despite that, 61% of the respondents expected that mammography would be painful. Indeed, most of those who anticipated pain reported that the actual severity was not greater than the anticipated severity. Even among women who reported pain of moderate or greater severity, less than 5% expressed preference to receive pre-emptive analgesia prior to their next mammogram. A substantial minority of women acknowledged that the experience of their mammography invoked reactions that may impend future compliance; 26% reported anxiety and 12% reported pain as factors that may interfere with ongoing compliance with regular mammographic screening. These data serve to emphasize the need for appropriate pre-test counseling and suggest a possible role for post-test debriefing to address those factors which may interfere with future test compliance.