Nimira S. Alimohamed

Change in Neutrophil-to-lymphocyte Ratio in Response to Targeted Therapy for Metastatic Renal Cell Carcinoma as a Prognosticator and Biomarker of Efficacy

BACKGROUND Neutrophil-to-lymphocyte ratio (NLR), if elevated, is associated with worse outcomes in several malignancies. OBJECTIVE Investigation of NLR at baseline and during therapy for metastatic renal cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 1199 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC cohort) and 4350 patients from 12 prospective randomized trials (validation cohort). INTERVENTION Targeted therapies for metastatic renal cell carcinoma. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS NLR was examined at baseline and 6 (± 2) wk later. A landmark analysis at 8 wk was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate using Cox or logistic regression models, adjusted for variables in IMDC score and NLR values at baseline. RESULTS AND LIMITATIONS Higher NLR at baseline was associated with shorter OS and PFS (Hazard Ratios [HR] per 1 unit increase in log-transformed NLR = 1.69 [95% confidence interval {CI} = 1.46-1.95] and 1.30 [95% CI = 1.15-1.48], respectively). Compared with no change (decrease < 25% to increase < 25%, reference), increase NLR at Week 6 by 25-50% and > 75% was associated with poor OS (HR=1.55 [95% CI=1.10-2.18] and 2.31 [95% CI=1.64-3.25], respectively), poor PFS (HR=1.46 [95% CI=1.04-2.03], 1.76 [95% CI=1.23-2.52], respectively), and reduced objective response rate (odds ratios = 0.77 [95% CI=0.37-1.63] and 0.24 [95% CI=0.08-0.72], respectively). By contrast, a decrease of 25-50% was associated with improved outcomes. Findings were confirmed in the validation cohort. The study is limited by its retrospective design. CONCLUSIONS Compared with no change, early decline of NLR is associated with favorable outcomes, whereas an increase is associated with worse outcomes. PATIENT SUMMARY We found that the proportion of immune cells in the blood is of prognostic value, namely that a decrease of the proportion of neutrophils-to-lymphocytes is associated with more favorable outcomes while an increase had the opposite effect.

Contemporary treatment of metastatic renal cell carcinoma

The introduction of targeted therapy has revolutionized the treatment of patients with metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Over the past few years, research exploring novel targeted agents has blossomed, leading to the approval of various targeted therapies. Furthermore, results from the CheckMate025 and the METEOR trials have brought about two additional novel options: the programmed cell death 1 (PD-1) checkpoint inhibitor nivolumab and the MET/VEGFR/AXL inhibitor cabozantinib, respectively. With the variety of therapeutic agents available for treatment of mRCC, research examining appropriate sequencing and combinations of the drugs is ongoing. This review discusses the role of prognostic criteria, such as those from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. It also covers the current standard of treatment for mRCC with targeted therapy in first-, second-, and third-line setting. Additionally, the novel mechanism of action of nivolumab and cabozantinib, therapeutic sequencing and ongoing clinical trials are discussed.

A Population-Based Overview of Sequences of Targeted Therapy in Metastatic Renal Cell Carcinoma

BACKGROUND Several TTs are available to treat mRCC; however, the optimal sequence of therapy remains unknown. PATIENTS AND METHODS Consecutive population-based samples of patients with mRCC treated with TT were collected from 12 cancer centers via the International Metastatic Renal Cell Carcinoma Database Consortium. Patient characteristics, first-line and second-line progression-free survival rates and overall survival data were collected based on sequencing of TT. Multivariable analysis was performed when there were significant differences on univariable analysis. RESULTS A total of 2106 patients were included with a median follow-up of 36 months; 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics were well matched among different sequences apart from more patients with non-clear-cell histology in the vascular endothelial growth factor (VEGF) to mammalian target of rapamycin (mTOR) group compared with the VEGF to VEGF group sequence. When adjusting for the Heng risk criteria and non-clear-cell histology, the hazard ratio for death for the VEGF to mTOR group versus the VEGF to VEGF group was 0.833 (95% confidence interval [CI], 0.669-1.037; P = .1016). More specifically, the adjusted hazard ratio for death for the sunitinib to everolimus versus sunitinib to temsirolimus sequences was 0.774 (95% CI, 0.52-1.153; P = .2086). CONCLUSION In this large multicenter analysis evaluating different sequences of TT in mRCC, no substantial effect on outcome based on sequence of TT was identified.

Conditional Survival of Patients With Metastatic Testicular Germ Cell Tumors Treated With First-Line Curative Therapy

PURPOSE The International Germ Cell Cancer Collaborative Group (IGCCCG) criteria prognosticate survival outcomes in metastatic testicular germ cell tumor (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment is unknown. PATIENTS AND METHODS We assessed patients eligible for first-line therapy for MT-GCT at five tertiary cancer centers from 1990 to 2012 for 2-year conditional overall survival (COS) and conditional disease-free survival (CDFS), defined as the probability of surviving, or surviving and being disease free, respectively, for an additional 2 years at a given time point since the initial diagnosis. RESULTS For all patients (N = 942), 2-year COS increased from 92% (95% CI, 91% to 94%) at 0 months to 98% (95% CI, 97% to 99%), and 2-year CDFS increased from 83% (95% CI, 81% to 86%) at baseline to 98% (95% CI, 97% to 99%) at 24 months after diagnosis. Two-year COS improved by 2% (97% at 0 months, 99% at 24 months) in the IGCCCG favorable-risk group, by 5% (94% at 0 months, 99% at 24 months) in the intermediate-risk group, and by 22% (71% at 0 months to 93% at 24 months) in the poor-risk group. Two-year CDFS improved significantly at 12 months for each risk group (favorable, 91% baseline v 95% at 12 months; intermediate, 84% v 95%; poor, 55% v 85%). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to greater than 2 years post therapy. No significant differences in COS and CDFS were noted between seminoma and nonseminoma; patients ≥ 40 years old had inferior 2-year COS from 0 to 12 months, but no differences were noted at 18 months. CONCLUSION Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. Patients with MT-GCT who survived and remained disease free more than 2 years after the diagnosis had an excellent chance of staying alive and disease free in additional subsequent years, regardless of the initial IGCCCG risk stratification.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate‐resistant prostate cancer (mCRPC).

Clinical Outcomes of First-line Abiraterone Acetate or Enzalutamide for Metastatic Castration-resistant Prostate Cancer After Androgen Deprivation Therapy + Docetaxel or ADT Alone for Metastatic Hormone-sensitive Prostate Cancer

Background The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone‐sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first‐line treatment for metastatic castration‐resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone. Patients and Methods A cohort of patients with mCRPC treated between 2014 and 2017 with first‐line AA or E for mCRPC was identified from 3 hospitals’ institutional review board‐approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014, and it inherently entailed a short follow‐up time on AA/E. The endpoints included overall survival from ADT start, overall survival from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log‐rank test. Results Of the 102 patients with mCRPC identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow‐up of 24.4 and 29.8 months, respectively. Conclusion In a cohort of ADT/ADT+D‐treated patients with mCRPC with short times to first‐line AA/E and follow‐up, the efficacy of AA/E is similar regardless of previous use of D. Micro‐Abstract Although an androgen deprivation therapy plus docetaxel regimen was shown to extend the survival of some patients with metastatic hormone‐sensitive prostate cancer compared with androgen deprivation therapy alone, currently, there is no report in the literature investigating the impact of upfront docetaxel on subsequent first‐line abiraterone acetate or enzalutamide for metastatic castration‐resistant prostate cancer. This study showed that their activity is maintained regardless of previous use of docetaxel for metastatic hormone‐sensitive prostate cancer. These findings can aid treatment decision‐making.

Prognostic and predictive clinical factors in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel

INTRODUCTION Cabazitaxel is one of several treatment options available for patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel. Little is known about clinical factors that influence prognosis or treatment response for patients receiving cabazitaxel. Identifying prognostic and predictive factors could contribute to the optimal selection of patients for treatment after docetaxel. METHODS A retrospective review of patients enrolled on the cabazitaxel Canadian Early Access Program (C-EAP) was performed. Clinical factors were analyzed by univariable and multivariable Cox proportional hazards and logistic regression analysis to identify independent predictors of prognosis and response. RESULTS Forty-five patients from five centres in Canada were included in this study. On multivariable analysis, lower hemoglobin was associated with shorter survival. No other factors were independently associated with survival, prostate-specific antigen (PSA) response, or primary PSA progression. CONCLUSIONS Clinical factors predicting survival or treatment response were not identified for men with castration-resistant prostate cancer receiving cabazitaxel. Larger studies may be necessary to identify clinical factors and biomarkers that identify whether patients should or should not receive cabazitaxel.

Neoadjuvant Chemotherapy Before Bladder-Sparing Chemoradiotherapy in Patients With Nonmetastatic Muscle-Invasive Bladder Cancer

Background Cisplatin‐based neoadjuvant chemotherapy (NAC) before cystectomy improves survival in muscle‐invasive urothelial bladder cancer (MIBC). The use of NAC before chemoradiation (CRT) has been limited, as these patients are often elderly, frail, and ineligible for cisplatin. However, the role of NAC in fit, cisplatin‐eligible patients who opt for bladder preservation warrants further evaluation. Patients and Methods Patients with MIBC treated with NAC followed by CRT at the Princess Margaret and Durham Regional cancer centers from 2008 to 2017 were retrospectively reviewed. Gemcitabine–cisplatin NAC was given for 2 to 4 cycles, followed by reassessment for CRT. External‐beam radiotherapy (60‐66 Gy) over 6 weeks was given with concurrent weekly cisplatin at 40 mg/m2. Kaplan‐Meier method was used for survival analyses. Results We identified 57 consecutive patients. Median age was 72 (range 45‐87), and all had an Eastern Cooperative Oncology Group performance status of 0 (60%) or 1 (40%). Stage II disease (65%), stage III disease (25%), and regional nodal metastases (11%) were included. Most completed planned NAC (95%). All patients completed external‐beam radiotherapy, and 84% completed at least 60% of the planned concurrent weekly cisplatin doses. Median (range) follow‐up was 19.3 (4.8‐96.1) months. Median overall survival (OS) was not reached. Two‐year OS and disease‐specific survival rates were 74% (95% confidence interval, 57.7‐84.9) and 88% (95% confidence interval, 78.5‐98.1), respectively. Two‐year bladder‐intact disease‐free survival was 64%. Salvage cystectomy was performed in 14%. Distant relapse occurred in 11%, and 9% died of metastatic disease. OS was associated with baseline hydronephrosis and with bladder‐intact disease‐free survival with residual disease on cystoscopy. Conclusion NAC followed by CRT can result in encouraging outcomes and tolerability in cisplatin‐eligible patients. Micro‐Abstract The evidence for using neoadjuvant chemotherapy (NAC) before bladder‐sparing chemoradiotherapy for patients with muscle‐invasive urothelial bladder cancer (MIBC) has been limited. This retrospective cohort study of 57 MIBC patients demonstrated that this approach can achieve encouraging overall survival and disease‐specific survival comparable to contemporary radical cystectomy and bladder‐preservation series. Our results support offering NAC for appropriately selected patients who opt for a bladder‐sparing approach.

Real world outcomes in advanced urothelial cancer and the role of neutrophil to lymphocyte ratio.

e16020Background: Advanced urothelial carcinoma (UC) patients have a poor prognosis. In the first and second line UC treatment setting, we investigated real world outcomes and evaluated the prognos...

Real World Outcomes in Advanced Urothelial Cancer and the Role of Neutrophil to Lymphocyte Ratio

&NA; In the first‐ and second‐line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real‐world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR). A retrospective analysis was performed on 233 mUC patients. In this real‐world mUC analysis, first‐line outcomes were lower than expected. Low NLR in the first‐ and second‐line is associated with improved mTTF and mOS. Introduction: In the first‐ and second‐line metastatic urothelial carcinoma (mUC) treatment setting, we investigated real‐world outcomes and evaluated the prognostic role of neutrophil to lymphocyte ratio (NLR). Methods: A retrospective analysis was performed on patients with mUC treated with systemic therapy. Overall response rates (ORRs), median time to treatment failure (mTTF), and median overall survival (mOS) were calculated. The association between baseline NLR (using a literature‐derived cut‐off of 3, as well as the best cut‐off NLR value of 5.45 as identified by X‐Tile software from this dataset) and mTTF and mOS were evaluated using Cox regression analysis. Results: We evaluated 233 patients. In the first‐line, the ORR was 25%. mTTF and mOS were 6.9 months and 9.0 months, respectively. Low baseline NLR was significantly associated with improved 8.3‐month mTTF, in contrast to 5.8 months for patients with high NLR (P = .046). Low NLR was significantly correlated with a longer mOS of 13.1 months, compared with high NLR (8.2 months; P = .007). In the second‐line, an ORR of 22%, an mTTF of 4.1 months, and an mOS of 8 months were observed. Low NLR in the second‐line was significantly associated with improved mTTF at 7.9 months versus high NLR patients (3.3 months; P = .023). Second‐line low NLR was significantly associated with a longer mOS of 12.2 months, in comparison to 6.8 months with high NLR (P = .003). Conclusion: In this real‐world analysis of patients with mUC, first‐line outcomes were lower than expected. Low NLR in the first‐ and second‐line is associated with improved mTTF and mOS.