Factors associated with cognitive impairment during the first year of treatment for nonmetastatic breast cancer.

BACKGROUND: Women with breast cancer are more likely to develop cognitive impairment (CI), insomnia, fatigue, and mood disturbance than individuals with other cancers. The main objectives of this study were to establish the prevalence of CI and examine the relationships between CI, insomnia, fatigue, and mood over the first year of breast cancer treatment. METHODS: Participants were recruited after diagnosis and completed validated measures of insomnia, objective and perceived CI, fatigue, and mood disturbance at four time points during the first year of treatment. A random intercepts cross-lagged panel model assessed relationships among symptoms over time. RESULTS: The sample included 98 women. Prevalence of objective CI ranged from 3.1% to 8.2% throughout the year, whereas 36.7% demonstrated a clinically meaningful decline in perceived CI from baseline to 4 months, which remained relatively stable. Greater perceived CI was associated with more fatigue (ß = -0.78, z = 17.48, p < .01) and symptoms of insomnia (ß = -0.58, z = 5.24, p < .01). Short-term fluctuations in perceived CI (p < .05), but not fatigue or insomnia, predicted future perceived CI. Fatigue (p < .001) was a significant predictor of future reported symptoms of fatigue and insomnia. CONCLUSION: Subjective CI is more prevalent than objective impairments. Fatigue, insomnia, and perceived CI remain stable and are associated during the first year of treatment. Changes in insomnia and fatigue may have little effect on future perceived cognition. Women with breast cancer likely require targeted intervention for these side effects.

Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma.

BACKGROUND: Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death-ligand 1(PD-L1) pathway have shown antitumour activity in metastatic renal cell carcinoma (mRCC) and are currently being developed in first-line (in combination) and in previously treated patients. The efficacy targeted therapy (TT) after PD-1/PD-L1 blockade is still unknown. METHODS: Medical records of mRCC patients treated with investigational PD-1 or PD-L1 inhibitors at 4 academic institutions were reviewed. Patients who received subsequent treatment with TT were selected to collect outcome measures of subsequent TT. RESULTS: Of 99 patients who received PD-1/PD-L1 blockade as part of clinical trials, 56 patients have received subsequent therapy: 44 patients received vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors and 12 received mammalian target of rapamycin (mTOR) inhibitors as first subsequent TT. Median follow up, from the start of subsequent TT was 16.1 months (range: 0.2, 30.6 months). TT post PD-1/PD-L1 blockade was administered as second-line, third-line or beyond third-line in 9 (16%), 24 (43%) and 23 patients (41%) respectively. Median time to treatment failure on subsequent TT was 6.6 months (range: 0.2+, 23.0). 1-year and 2 year overall survival from the initiation of subsequent TT was 58% (95% confidence interval (CI): 41-72%) and 36% (95% CI: 18-54%), respectively. CONCLUSION: Both VEGF/VEGFR and mTOR inhibitors demonstrate antitumour activity following PD-1/PD-L1 blockade.

Outcomes with abiraterone acetate in metastatic castration-resistant prostate cancer patients who have poor performance status.

BACKGROUND: Although abiraterone acetate (abiraterone) has proven efficacy in two randomised phase 3 trials in metastatic castration-resistant prostate cancer (mCRPC), patients who had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 were either excluded or under-represented in these trials. OBJECTIVE: To compare outcomes in ECOG PS 0-1 and ≥2 in mCRPC patients treated with abiraterone. DESIGN, SETTING, AND PARTICIPANTS: Cancer registries from three Canadian centres were used to retrospectively identify mCRPC patients (postdocetaxel and docetaxel-naïve) treated with abiraterone. ECOG PS, clinicopathologic characteristics, prostate-specific antigen (PSA) response, and survival data were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards modelling was used to examine the effect of clinicopathologic characteristics on overall survival (OS) and time to PSA progression. RESULTS AND LIMITATIONS: A total of 519 patients were identified; 61% (n=318) and 39% (n=201) were ECOG PS 0-1 and ≥2, respectively. ECOG PS 0-1 patients were significantly more likely than PS ≥2 patients to achieve a PSA decline ≥50% from baseline (45% vs 32%; p=0.003, Fisher exact test) and had significantly longer median time to PSA progression (5.2 mo vs 4.1 mo; p=0.023), median treatment duration (7.4 mo vs 4.5 mo; p<0.001), and median OS (20.0 mo vs 9.1 mo; p<0.001). On multivariate analysis, ECOG PS was a significant factor for OS (p<0.001), time to PSA progression (p=0.043), and PSA decline (p=0.002). Potential limitations include the retrospective study design and subjective nature of ECOG PS classification. CONCLUSIONS: ECOG PS ≥2 mCRPC patients treated with abiraterone have inferior outcomes compared with ECOG 0-1 patients, especially in regard to OS. These data indicate that early initiation of abiraterone prior to a decline in PS may be warranted. PATIENT SUMMARY: We found that advanced prostate cancer patients who have worse performance status (PS) derive less benefit from abiraterone, indicating that earlier treatment before PS declines could improve outcomes.

A retrospective, Canadian multi-center study examining the impact of prior response to abiraterone acetate on efficacy of docetaxel in metastatic castration-resistant prostate cancer.

BACKGROUND: Questions about optimal sequencing of systemic therapy in metastatic castration-resistant prostate cancer (mCRPC) and whether cross-resistance occurs between different drugs remain largely unanswered. Previous studies have produced conflicting data on the activity of docetaxel in patients who did not attain a prostate-specific antigen (PSA) response to abiraterone acetate (abiraterone). We investigated whether the biochemical response to abiraterone is associated with efficacy of subsequent docetaxel therapy. METHODS: mCRPC patients treated with docetaxel after abiraterone were retrospectively identified at three Canadian institutions. Patients who had also received docetaxel prior to abiraterone were termed "docetaxel-experienced," while those not treated with docetaxel prior to abiraterone were termed "docetaxel-naïve." Treatment outcomes on docetaxel were stratified by prior response to abiraterone and compared using χ(2) -square test for confirmed PSA response rate (≥ 50% decline from baseline maintained for ≥ 3 weeks) and the log-rank method for progression-free survival (PFS) and overall survival (OS). RESULTS: Eighty-six patients were treated with abiraterone, of whom 49 were docetaxel-experienced and 37 were docetaxel-naïve. Prior PSA response to abiraterone was no decline, <50% decline and ≥ 50% decline in 37%, 26%, and 37% of patients respectively. The overall PSA response rate to docetaxel was 34.9%, median PFS was 4.0 months and median OS was 11.66 months. Notably, no differences were seen in confirmed PSA response rates (38% vs. 36% vs. 31%, P = 0.86), median PFS (4.04 months vs. 3.94 months vs. 4.24 months, P = 0.43) and median OS (11.86 months vs. 15.38 months vs. 11.00 months, P = 0.56) on docetaxel for patients with no PSA decline, <50% decline and ≥ 50% decline on abiraterone respectively. Importantly, PSA response rates to docetaxel were comparable in the docetaxel-experienced and docetaxel-naïve cohorts and were not linked to prior response to abiraterone in either group. CONCLUSION: Activity of docetaxel was not associated with the biochemical response to prior abiraterone therapy. These data suggest that prior response to abiraterone should not influence decisions on subsequent use of docetaxel in mCRPC.

Current management and future perspectives of metastatic renal cell carcinoma.

Over the last number of years, the treatment of metastatic renal cell cancer has evolved tremendously with the advent of targeted therapy. Previously, immunotherapies, such as interferon alpha and interleukin-2, were the only treatment options available for this chemoresistant malignancy. Currently, seven additional agents, including sunitinib, sorafenib, axitinib, pazopanib, bevacizumab, everolimus and temsirolimus, have been approved for use in metastatic renal cell cancer, with several more in development. The efficacy of these agents depends primarily on inhibition of the vascular endothelial growth factor and mammalian target of rapamycin pathways, and have drastically improved the outcomes of patients diagnosed with metastatic renal cell cancer. This article reviews the major treatment advances that have occurred for metastatic renal cell cancer with the advent of targeted treatments, summarizes the evidence to support their use and addresses clinical issues that have arisen with them. To help guide clinicians in their decision-making with these emerging therapeutic choices, the evidence for sequencing and combining these agents, and the need for biomarkers will be addressed. The role of surgical management options, such as cytoreductive nephrectomy and metastectomy, in the era of targeted treatment is also reviewed. Several novel treatments are also on the horizon, which might serve as future avenues for treatment advancement in metastatic renal cell cancer.