Michael Granovetter

Benefits of pazopanib over sunitinib for renal cell carcinoma

www.thelancet.com/oncology Vol 17 March 2016 e93 A post-hoc analysis of the findings of a randomised, open-label, phase 3 trial of two angiogenesis inhibitors for meta static renal cell carcinoma has confi rmed the overall clinical advantage of pazopanib over sunitinib. In previous analyses, pazopanib and sunitinib were found to have similar effi cacy in patients with metastatic renal cell carcinoma, but patients who were given pazopanib had a higher quality of life than patients who received sunitinib. However, survival and toxicity were assessed as independent measurements. Lead author, Jennifer Beaumont (Northwestern University, Chicago, IL, USA) explained: “there are many competing endpoints in oncology trials: survival, tumour growth, adverse events, symptoms, and general health and well being. Our goal was to combine these endpoints to gain a clearer picture of the relative overall benefi t of each therapy”. To simultaneously assess the safety and effi cacy of pazopanib over sunitinib, the researchers used the quality-adjusted time without symp toms or toxicity (Q-TWiST) method for patients with renal cell carcinoma treated with either pazopanib (n=557) or sunitinib (n=553). Overall survival was analysed in terms of time in defi ned, mutually exclusive health states in which the effects of adverse events or tumour progression on quality of life were assigned various weights. The diff erences in Q-TWiST est imates for pazopanib and sunitinib ranged from –11 days with grade 3 or 4 toxicity to 43 days after tumour progression or relapse across the range of weighted health-state comb inations, but all stat istically signifi cant diff erences sup ported pazopanib over sunitinib (p<0·05). In general, the Q-TWiST estimate for pazopanib was significantly higher than that of sunitinib when the quality of life assoc iated with tumour progression was higher than the quality of life related to adverse events. “The significant differences occurred when the relative quality of life weight was lower for toxicity because this magnifi ed the observed differences between groups in time spent with toxicities”, Beaumont explained. Nevertheless, according to Joan Minguet (European Institute of Cancer Research, Barcelona, Spain), the implications of the present findings are limited, in part because the data used to compute Q-TWiST were analysed post hoc. “As both drugs are approved for clinical use, observational data collected from a real-world setting may help to clarify any differences in Q-TWiST be tween them”, she noted, adding that “a more interesting study would use established instruments to assess quality of life prospectively and directly from patients”.

Acetyl-L-carnitine ineffective in treatment of CIPN

Previous studies had indicated that Acetyl-L-carnitine (ALC), a natural agent that enhances neuronal protection, might be a useful treatment option for patients with chemotherapy-induced peripheral neuropathy (CIPN). But, results from a recent phase 2 double-blind clinical trial have shown that ALC is not only an ineff ective treatment for CIPN, but it can also reduce patient functionality and increase CIPN over time. The researchers randomly assigned women undergoing adjuvant taxanebased chemotherapy to receive either ALC (n=208) or a placebo (n=201). Each patient’s CIPN and functional status were assessed both before and after taxane therapy and intervention. After 12 weeks of treatment with ALC, no signifi cant eff ect was noted on either CIPN or functionality. And, after 24 weeks of intervention, patients prescribed ALC showed an unanticipated signifi cant increase in CIPN and a signifi cant loss in functionality. “We were very surprised by the results of this study”, said coauthor Dawn Hershman (Columbia University, New York, NY, USA). “So much so that we had the pills re-tested and checked the serum carnitine levels to ensure that the carnitine was active and went up in the treatment group—which is what we found.” While Charles Loprinzi (Mayo Clinic, Rochester, MN, USA) commented that it is unclear why the results of the trial are negative, he nonetheless added, “Given the results of the current trial, caution is urged until published placebo-controlled trials demonstrate benefi t for the use of this drug for treating chemotherapyinduced neuropathy.” At the same time, Rebecca Speck (University of Pennsylvania, PA, USA) expressed the need to study the effi cacy of ALC for CIPN treatment further, noting, “Evaluating the preventive eff ects of ALC in specifi c, homogenous regimens (ie, only weekly paclitaxel) may be worthwhile”. But on the basis of their results, the investigators are currently advising patients with CIPN against taking ALC or other nutritional supplements. “It is one thing to see no benefit from a trial, but to realise that the patients on the supplement did worse was very disturbing”, explained Hershman. “It really confirms the fact that it is critical to do these studies and test agents that are taken commonly by our patients.”

Androgen deprivation associated with acute kidney injury

Despite the fact that androgen deprivation therapy (ADT) is a mainstay treatment of advanced prostate cancer, the results of a recent nested case–control analysis suggest that this intervention might be a cause of acute kidney injury (AKI). Although this analysis was the fi rst population-based study of this association, ADT had previously been linked with metabolic fl uctuations, such as dyslipidemia and hyperglycaemia—two conditions that can impair glomerular function. Other research had suggested that androgens and oestrogens might have a crucial role in the renal system. With the use of information from the UK Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database, 10 250 patients with non-metastatic prostate cancer were selected and followed up for an average of 4 years. Patients who ultimately developed AKI were randomly matched to controls by age, year of cohort entry, and duration of follow-up. A conditional logistic regression of the collected data showed a statistically signifi cant association between use of ADT and increased risk of AKI. But some clinicians are sceptical of the study’s results. “While the authors have attempted to control for confounding variables, they likely did not account for all the variables that would impact the endpoint of interest”, explained Andrew Lee (University of Texas, Houston, TX, USA). “On the whole, the men receiving hormone therapy were not as ‘healthy’ as their non-hormone therapy counterparts.” Likewise, Oliver Sartor (Tulane University, New Orleans, LA, USA) noted that this association is meaningless in the absence of a controlled study. “I am not convinced it is real”, he said. “Combined androgen blockade is used in the worst patients, and problems with kidney function go along with advanced prostate cancer. No control group of patients with advanced prostate cancer not treated with hormonal therapy will ever be studied.” Although co-author Laurent Azoulay (Jewish General Hospital, Montreal, Quebec, Canada) also recognised that the study results will not shift the risk–benefi t ratio for patients with advanced prostate cancer, he still added: “Together with other studies associating ADT with an increased risk of diabetes and cardiovascular outcomes, [they] may lead to a more cautious use in patients with less advanced disease.”