ABSTRACT
BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.
Subject(s)
Carcinoma, Renal Cell , Immunotherapy , Kidney Neoplasms , Humans , Carcinoma, Renal Cell/therapy , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Male , Kidney Neoplasms/pathology , Kidney Neoplasms/immunology , Kidney Neoplasms/therapy , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Female , Middle Aged , Prognosis , Lymphocyte Count , Aged , Immunotherapy/methods , Lymphopenia , Retrospective Studies , Databases, Factual , AdultABSTRACT
AIMS: To evaluate the clinical impact of the Canadian criteria for identifying patients and families at risk for hereditary renal cell carcinoma (RCC). MATERIALS AND METHODS: The Canadian hereditary RCC risk criteria were applied to patients from 16 centres in the Canadian Kidney Cancer information system (CKCis) prospective database. The primary end point was the proportion of patients who met at least one criterion. RESULTS: Between January 2011 and May 2017, 8388 patients were entered in the database; 291 had inadequate risk data; 2827 (35%) met at least one criterion for genetic testing (at-risk population). Most (83%) met just one criterion. The criterion of non-clear cell histology contributed the largest proportion of at-risk patients (59%), followed by age ≤ 45 years (28%). Sixty-one patients had documentation of genetic testing, with 56 being classified at-risk (2% of at-risk). Twenty patients (35%) of the patients at risk and tested for hereditary RCC were found to harbour a germline mutation. CONCLUSIONS: Application of the Canadian hereditary RCC risk criteria to a large prospective database resulted in 35% of patients being identified at risk for hereditary RCC who could qualify for genetic testing. However, the true incidence of hereditary RCC in this population is unknown as most patients did not have documented genetic testing carried out and, thus, the sensitivity and specificity of the criteria cannot be determined. The low proportion of at-risk patients who underwent genetic testing is disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing.
Subject(s)
Carcinoma, Renal Cell/epidemiology , Database Management Systems/standards , Kidney Neoplasms/epidemiology , Adult , Data Management , Female , Humans , Male , Prospective Studies , Risk FactorsABSTRACT
Objectives: In the present study, we explored the real-world efficacy of the immuno-oncology checkpoint inhibitor nivolumab and the tyrosine kinase inhibitor cabozantinib in the second-line setting. Methods: Using the International Metastatic Renal Cell Carcinoma Database Consortium (imdc) dataset, a retrospective analysis of patients with metastatic renal cell carcinoma (mrcc) treated with nivolumab or cabozantinib in the second line after prior therapy targeted to the vascular endothelial growth factor receptor (vegfr) was performed. Baseline characteristics and imdc risk factors were collected. Overall survival (os) and time to treatment failure (ttf) were calculated using Kaplan-Meier curves. Overall response rates (orrs) were determined for each therapy. Multivariable Cox regression analysis was performed to determine survival differences between cabozantinib and nivolumab treatment. Results: The analysis included 225 patients treated with nivolumab and 53 treated with cabozantinib. No significant difference in median os was observed: 22.10 months [95% confidence interval (ci): 17.18 months to not reached] with nivolumab and 23.70 months (95% ci: 15.52 months to not reached) with cabozantinib (p = 0.61). The ttf was also similar at 6.90 months (95% ci: 4.60 months to 9.20 months) with nivolumab and 7.39 months (95% ci: 5.52 months to 12.85 months) with cabozantinib (p = 0.20). The adjusted hazard ratio (hr) for nivolumab compared with cabozantinib was 1.30 (95% ci: 0.73 to 2.3), p = 0.38. When adjusted by imdc criteria and age, the hr was 1.32 (95% ci: 0.74 to 2.38), p = 0.35. Conclusions: Real-world imdc data indicate comparable os and ttf for nivolumab and cabozantinib. Both agents are reasonable therapeutic options for patients progressing after initial first-line vegfr-targeted therapy.
Subject(s)
Anilides/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Nivolumab/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Aged , Carcinoma, Renal Cell/mortality , Databases, Factual , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Male , Treatment OutcomeABSTRACT
BACKGROUND: The risk of suicide is higher for patients with colorectal cancer (crc) than for the general population. Given known differences in morbidity and sites of recurrence, we sought to compare the predictors of suicide for patients with colon cancer and with rectal cancer. METHODS: Using the U.S. Surveillance, Epidemiology, and End Results database, adult patients with confirmed adenocarcinoma of the colon or rectum during 1973-2009 were identified. Parametric and nonparametric tests were used to assess selected variables, and Cox proportional hazards regression models were used to determine predictors of suicide. RESULTS: The database identified 187,996 patients with rectal cancer and 443,368 with colon cancer. Compared with the rectal cancer group, the colon cancer group was older (median age: 70 years vs. 67 years; p < 0.001) and included more women (51% vs. 43%, p < 0.001). Suicide rates were similar in the colon and rectal cancer groups [611 (0.14%) vs. 337 (0.18%), p < 0.001]. On univariate analysis, rectal cancer was a predictor of suicide [hazard ratio (hr): 1.26; 95% confidence interval (ci): 1.10 to 1.43]. However, after adjusting for clinical and pathology factors, rectal cancer was not a predictor of suicide (hr: 1.05; 95% ci: 0.83 to 1.33). In the colon cancer cohort, independent predictors of suicide included older age, male sex, white race, and lack of primary resection. The aforementioned predictors, plus metastatic disease, similarly predicted suicide in the rectal cancer cohort. CONCLUSIONS: The suicide risk in crc patients is low (<0.2%), and no difference was found based on location of the primary tumour. Sex, age, race, distant spread of disease, and intact primary tumour were the main predictors of suicide among crc patients. Further studies and interventions are needed to target these high-risk groups.
ABSTRACT
In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240âmg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HRâ=â0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.
ABSTRACT
BACKGROUND: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. PATIENTS AND METHODS: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. RESULTS: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). CONCLUSION: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. TRIAL REGISTRATION NUMBERS: NCT00638690.
Subject(s)
Abiraterone Acetate/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prednisone/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Abiraterone Acetate/adverse effects , Antineoplastic Agents/adverse effects , Disease-Free Survival , Double-Blind Method , Humans , Male , Prednisone/adverse effects , Proportional Hazards ModelsABSTRACT
BACKGROUND: Studies of clinical outcomes of elderly patients treated with neoadjuvant chemoradiation (nCRT) for locally advanced rectal cancer (LARC) are limited. Our aim was to assess the impact of age on clinical outcomes in a large multi-institutional database. PATIENTS AND METHODS: Data for patients diagnosed with LARC who received nCRT and curative-intent surgery between 2005 and 2012 were collected from five major Canadian cancer centers. Age was analyzed as a continuous and dichotomous variable (< 70 versus ≥ 70 years) and correlated with disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Cox regression models were used to adjust for important prognostic factors. RESULTS: Of 1172 patients included, 295 (25%) were ≥ 70 years, and they were less likely to receive adjuvant chemotherapy (ACT; 60% versus 79%, P < 0.0001), oxaliplatin-based ACT (12% versus 31%, P < 0.0001), less likely to complete nCT (76% versus 86%, P < 0.001), and more likely to be anemic at initiation of nCRT (42% versus 30%, P = 0.0004). In multivariate analyses, age ≥ 70 years was associated with similar DFS [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.68-1.26, P = 0.63], similar CSS (HR 0.81, 95% CI 0.46-1.41, P = 0.45), and similar OS (HR 1.28, 95% CI 0.88-1.86, P = 0.20), compared with the younger age group. As a continuous variable, increasing age was not predictive of DFS (HR 1.00, 95% CI 0.99-1.02, P = 0.49) or CSS (HR 1.002, 95% CI 0.98-1.02, P = 0.88); however, it correlated with an inferior OS (HR 1.02, 95% CI 1.00-1.03, P = 0.04). CONCLUSIONS: Elderly patients (≥ 70 years) who receive nCRT followed by surgery appear to have similar outcomes compared with younger patients. Decisions regarding eligibility for nCRT and surgery should not be based on age alone.
Subject(s)
Adenocarcinoma/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/mortality , Neoadjuvant Therapy/mortality , Rectal Neoplasms/mortality , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Capecitabine/administration & dosage , Chemotherapy, Adjuvant , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prognosis , Quinazolines/administration & dosage , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Retrospective Studies , Survival Rate , Thiophenes/administration & dosage , Young AdultABSTRACT
BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Molecular Targeted Therapy , TOR Serine-Threonine Kinases/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/pathology , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Proportional Hazards Models , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised. METHODS: A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium. RESULTS: This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively). CONCLUSIONS: Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/ethnology , Kidney Neoplasms/drug therapy , Kidney Neoplasms/ethnology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Angiogenesis Inhibitors/adverse effects , Asian People , Carcinoma, Renal Cell/pathology , Cohort Studies , Female , Humans , Kidney Neoplasms/pathology , Male , Middle Aged , Neoplasm Metastasis , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/secondary , Clinical Trials as Topic , Disease-Free Survival , Eligibility Determination , Humans , Indazoles , Indoles/administration & dosage , Kaplan-Meier Estimate , Karnofsky Performance Status , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Middle Aged , Molecular Targeted Therapy , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Pyrimidines/administration & dosage , Pyrroles/administration & dosage , Sorafenib , Sulfonamides/administration & dosage , Sunitinib , Treatment OutcomeABSTRACT
BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are used in a variety of malignancies. Infections have been reported with these drugs. We performed an up-to-date meta-analysis to further characterise the risk of infections in cancer patients treated with these agents. METHODS: Pubmed and oncology conferences' proceedings were searched for studies from January 1966 to June 2012. Studies were limited to phase II and III randomised controlled trials (RCTs) of everolimus or temsirolimus reporting on cancer patients with adequate safety profiles. Summary incidences, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 3180 patients were included. The incidence of all-grade and high-grade infections due to mTOR inhibitors was 33.1% (95% CI, 24.5-43.0%) and 5.6% (95% CI, 3.8-8.3%), respectively. Compared with controls, the RR of all-grade and high-grade infections due to mTOR inhibitors was 2.00 (95% CI, 1.76-2.28, P<0.001) and 2.60 (95% CI, 1.54-4.41, P<0.001), respectively. Subgroup analysis found no difference in incidences or risks between everolimus and temsirolimus or between different tumour types (renal cell carcinoma (RCC) vs non-RCC). Infections included respiratory tract (61.7%), genitourinary (29.4%), skin/soft tissue (4.2%), and others (4.9%). CONCLUSION: Treatment with mTOR inhibitors is associated with a significant increase in risk of infections. Close monitoring for any signs of infections is warranted.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Infections/chemically induced , Infections/epidemiology , Kidney Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/epidemiology , Clinical Trials, Phase II as Topic/statistics & numerical data , Clinical Trials, Phase III as Topic/statistics & numerical data , Humans , Infections/etiology , Kidney Neoplasms/epidemiology , Randomized Controlled Trials as Topic/statistics & numerical data , Risk FactorsABSTRACT
BACKGROUND: Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS: PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. CONCLUSION: The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.
Subject(s)
Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Everolimus , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Risk , Sirolimus/adverse effects , Sirolimus/therapeutic useABSTRACT
PURPOSE: Continuity clinics (ccs) give trainees an opportunity for longitudinal follow-up of a patient cohort. Trainees can function in a semi-autonomous manner and prepare for independent practice. Data about such clinics in Canada are limited. Our objective was to assess the utility of ccs in Canadian oncology training programs. METHODS: Surveys were developed by the authors for medical and radiation oncology program directors (pds) and trainees, to assess the utility of ccs in Canadian oncology training programs.oncology patients, to assess their attitudes toward ccs. The pds were contacted by e-mail, using the Web site of the Canadian Resident Matching Service; the trainees were contacted by e-mail through the pds and their administrative assistants. Surveys were distributed electronically using SurveyMonkey. Patients were approached by staff oncologists during follow-up visits at The Ottawa Hospital Cancer Centre. RESULTS: Completed surveys were received from 33% of trainees and 63% of pds contacted; patient surveys were completed by 95 patients. Participation in a cc was reported by 47% of responding pds and 37% of responding trainees. Among respondents, 80% rated the ccs as "important" or "very important" to training. The biggest challenge identified by trainees and pds was lack of clinic space. Most pds (57%) and trainees (59%) felt that the staff oncologist should review the patient only if the trainee has concerns, but only 37% of patients shared that view (p = 0.0002). However, many patients expressed the desire to participate in trainee education. CONCLUSIONS: Continuity clinics are considered beneficial by pds and trainees. Patients desire more trainee supervision than the trainees themselves and the pds do, a factor that should be considered when implementing a cc.
ABSTRACT
BACKGROUND: The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). METHODS: A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. RESULTS: Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PFS/TTP was associated with a 6% RRR for OS. A 1-month gain in median PFS/TTP was associated with a 1.17-month gain in median OS (95% CI: 0.59,1.76; R(2)=0.28). CONCLUSION: In trials of treatments for mRCC, treatment effects on PFS/TTP are strongly associated with treatment effects on OS.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Disease Progression , Disease-Free Survival , Endpoint Determination , Humans , Molecular Targeted Therapy , Randomized Controlled Trials as Topic , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Renal Cell/drug therapy , Drug Resistance, Neoplasm , Kidney Neoplasms/drug therapy , Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Benzenesulfonates/pharmacology , Benzenesulfonates/therapeutic use , Bevacizumab , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Everolimus , Female , Humans , Indoles/pharmacology , Indoles/therapeutic use , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Logistic Models , Male , Middle Aged , Multivariate Analysis , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/pharmacology , Pyridines/therapeutic use , Pyrroles/pharmacology , Pyrroles/therapeutic use , Risk Factors , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Sirolimus/therapeutic use , Sorafenib , Sunitinib , Treatment OutcomeABSTRACT
Traditionally, overall survival (os) has been considered the "gold standard" for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of the increasing crossover and contamination of trials. As a result, the approval of promising new therapies may be delayed.Many clinicians believe that progression-free survival (pfs) is a more viable option for evaluating new therapies in metastatic and advanced renal cell carcinoma. As with all endpoints, pfs has inherent biases, and those biases must be addressed to ensure that trial results are not compromised and that they will be accepted by regulatory authorities. In this paper, we examine the issues surrounding the use of pfs as a clinical trial endpoint, and we suggest solutions to ensure that data integrity is maintained.
ABSTRACT
Targeted therapy has greatly changed the way in which metastatic renal cell carcinoma (RCC) is treated. Agents that inhibit the vascular endothelial growth factor and mammalian target of rapamycin pathways that otherwise lead to angiogenesis have now become the standard of care. Much research into the sequence and combination of these agents is ongoing, and new anti-angiogenic agents are being developed. This overview covers the standard treatment of metastatic rcc with targeted therapy, immunotherapy, and surgery. Future directions and ongoing clinical trials are also discussed.