1: Efficacy of cabazitaxel as first-line therapy and lower dose cabazitaxel for men with mCRPC

The TROPIC trial (published in 2010) demonstrated that 25 mg/m2 cabazitaxel offered superior overall survival (OS) compared to mitoxantrone (median OS 15.1 vs 12.7 months; p<0.001) and it is currently recommended as second-line treatment for men with metastatic castrate resistant prostate cancer (mCRPC) previously treated with docetaxel. Two phase III trials published in the Journal of Clinical Oncology this month address whether cabazitaxel can be used as first-line treatment and if it is effective at a lower dose.

FIRSTANA assigned 1,168 men with chemotherapy-naïve mCRPC to first-line treatment with either cabazitaxel 20 mg/m2 (C20), cabazitaxel 25 mg/m2 (C25) or docetaxel 75 mg/m2 (D75). Although the trial was not powered to prove non-inferiority, there were no significant differences between progression free survival or OS with median OS of 24.5 months for C20, 25.2 months for C25 and 24.3 months for D75 arms. 41.2%, 60.1% and 46.0% of men in the C20, C25 and D75 arms respectively, experienced grade 3 or 4 adverse effects, with febrile neutropenia, diarrhea and hematuria more frequently seen in men in the C25 arm and peripheral neuropathy, peripheral edema and alopecia more frequent in D75.

The PROSELICA trial, involving 1,200 patients, looked more closely into the efficacy of low dose cabazitaxel (20 mg/m2) (C20) compared to standard of care, 25 mg/m2 cabazitaxel (C25), for men with mCRPC post-docetaxel. C20 was shown to be non-inferior compared to C25 (median OS 13.4 vs 14.5 months; HR 1.024) and was also better tolerated with 39.7% of C20 patients having grade 3 or 4 adverse events compared to 54.5% of C25 patients.

Taken together, these studies demonstrate that cabazitaxel could be considered as a first-line chemotherapy option for patients who are contraindicated for docetaxel (i.e. those intolerant of docetaxel or who have baseline peripheral neuropathy). In addition, as lower dose cabazitaxel caused fewer toxicities this may be an option for patients who are frail or at high risk for febrile neutropenia and may not tolerate higher doses of cabazitaxel.

 

2: Monitoring patient reported outcomes improves overall survival for patients with metastatic cancer

One of the most exciting trials to report at ASCO (published concurrently in JAMA) was about the benefits of integrating electronic patient reported outcomes (PRO) into clinical practice. The trial, based at Memorial Sloane Kettering, randomised 766 patients who had metastatic cancer (breast, lung, genitourinary and gynaecological) and were initiating chemotherapy, to a usual care or PRO group. Patients undergoing usual care discussed their symptoms during clinical visits and could contact the office by telephone between visits if they had concerns. Patients in the PRO group received a weekly email prompt to self-report on 12 common symptoms using a web-based system. Severe or worsening symptoms triggered an email alert to an appropriate nurse. Longitudinal symptom reports were provided to the oncologist during clinic visits.

With a median follow up of seven years, patients in the PRO group showed improved median overall survival (31.2mo vs 26.0mo, HR 0.83; [CI] 0.70-0.99; p=0.04) which equates to an 8% survival benefit. Remarkably, this exceeds the survival benefit seen for many of the drugs for advanced cancer that received FDA approval last year. In addition to improved survival, a previous publication also demonstrated that patients in the PRO group had increased improvement in health related quality of life at 6 months, reduced visits to the emergency room and longer duration of chemotherapy use (8.2mo vs 6.3mo). Importantly, these studies also show that patients are willing to self-report (73% reported when prompted) and that clinicians will follow up when alerted (nurses responded to email alerts 77% of the time).

So what accounts for the improved survival? The authors hypothesised that by catching problems at an early stage, patients stay mobile and functional for longer and are able to continue with chemotherapy for longer. What is clear from previous studies is that PRO alone isn’t enough - it has to be integrated with clinical care and responsiveness. Therefore, while this is not a cost-free solution, the success of this trial suggests that regular symptom monitoring should be an important aspect of cancer care going forward.

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3: Vasectomy and associated prostate cancer risk: an update on the debate

Whether there is an epidemiological association between vasectomy and an increased risk of prostate cancer has been hotly debated since the 1980s. Meta-analyses conducted on the topic have also not collectively answered this question: a number of studies have supported both sides of the debate. However, these meta-analyses have been criticised for not taking into account any study biases (for example health-seeking behaviour), nor did they evaluate the association between vasectomy and risk of high-grade, advanced-stage, and fatal prostate cancer.

To address this, authors of a meta-analysis published this month in JAMA Internal Medicine paid particular attention to study design and quality, and also separately evaluated studies with a low risk of bias. Following a full-text review of 115 manuscripts, the authors assessed 53 studies: 16 cohort (2,563,519 participants), 33 case-control (44,536 participants) and 4 cross-sectional (12,098,221 participants).

When results were pooled from the 13 cohort studies that used adjusted measures of effect, a small but statistically significant increased risk of prostate cancer among patients with a history of vasectomy was found (adjusted RR, 1.08; 95% CI, 1.02-1.14; P = .006; I2 = 63%). However, this effect was closer to the null when cohort studies with a low risk of bias were exclusively analysed (7 studies; adjusted rate ratio, 1.05; 95%CI, 1.02-1.09; P < .001; I2 = 9%). A similar trend was found when analysing case-control studies: a statistically significant association between vasectomy and prostate cancer was found when incorporating studies with a moderate to high risk of bias (17 studies; adjusted OR, 1.31; 95% CI, 1.12-1.53; P < .001; I2 = 66%)  but a nonsignificant association was found among low risk of bias case-control studies (6 studies; adjusted odds ratio, 1.06; 95% CI, 0.88-1.29; P = .54; I2 = 37%). All 4 cross-sectional studies were found to have a moderate to high risk of bias and were not subjected to analysis.

Among cohort studies, there was no statistically significant association noted between vasectomy and the diagnosis of high-grade prostate cancer (6 studies; adjusted HR, 1.03; 95% CI, 0.89-1.21; P = .67; I2 = 55%), advanced prostate cancer (6 studies; adjusted HR, 1.08; 95% CI, 0.98-1.20; P = .11; I2 = 18%), or fatal prostate cancer (5 studies; adjusted HR, 1.02; 95% CI,0.92-1.14; P = .68; I2 = 26%). Inconsistent definitions of advanced prostate cancer precluded meta-analysis of the case-control studies.

Using pooled effect estimates from the meta-analysis of cohort studies with a low risk of bias, the authors calculated that vasectomy history corresponds to a 0.6% absolute increase in lifetime risk of incident prostate cancer (95% CI, 0.3%-1.2%), or a number needed to harm of 156. At population level, only 0.5% of prostate cancers were estimated to be associated with vasectomy (95% CI, 0.2%-0.9%).

As residual unmeasured bias is still possible owing to the observational nature of pooled studies, the study concluded that any association between vasectomy and prostate cancer, if present, is sufficiently small that it is unlikely to be of clinical importance. Concerns about the risk of prostate cancer should also not prevent vasectomy being offered as a long-term contraceptive, although patients should be appropriately counselled.

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