S. S. Sridhar

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer

BACKGROUNDnAbiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This studys objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.nnnPATIENTS AND METHODSnAll patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.nnnRESULTSnA confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.nnnCONCLUSIONSnA composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.BACKGROUNDnAbiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This studys objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone.nnnPATIENTS AND METHODSnAll patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation.nnnRESULTSnA confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis.nnnCONCLUSIONSnA composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Angiogenesis inhibitors under study for the treatment of lung cancer.

Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.

Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic

Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.

A phase 2 study of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel: Canadian Urologic Oncology Group study P07a

BACKGROUNDnThe purpose of this study was to determine the clinical activity of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.nnnPATIENTS AND METHODSnEligible patients had progressive disease within 6 months of receiving docetaxel. Patupilone was administered 10 mg/m2 i.v. every 3 weeks. The primary end point was the proportion of patients with a confirmed ≥50% prostate-specific antigen (PSA) decline.nnnRESULTSnEighty-three patients were enrolled. At baseline, the median time to progression after prior docetaxel was 1.4 months (range 0-5.7). Gastrointestinal serious adverse events occurred in four of the six initial patients leading to a reduction of the starting dose of patupilone to 8 mg/m2 for subsequent patients. Grade 3-4 toxicity at this dose included diarrhea (22%), fatigue (21%), and anorexia (10%). One patient experienced grade 3-4 hematologic toxicity. A PSA decline of ≥50% occurred in 47% of patients. A partial measurable disease response occurred in 24% of assessable patients. A patient-reported pain response was observed in 59% of assessable patients. Median time to PSA progression was 6.1 months [95% confidence interval (CI) 4.7-8.0] and median overall survival was 11.3 months (95% CI 9.8-15.4).nnnCONCLUSIONSnPatupilone at 8 mg/m2 was tolerable, had antitumor activity, and was associated with symptomatic improvement in patients previously treated with docetaxel.BACKGROUNDnThe purpose of this study was to determine the clinical activity of patupilone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel.nnnPATIENTS AND METHODSnEligible patients had progressive disease within 6 months of receiving docetaxel. Patupilone was administered 10 mg/m2 i.v. every 3 weeks. The primary end point was the proportion of patients with a confirmed≥50% prostate-specific antigen (PSA) decline.nnnRESULTSnEighty-three patients were enrolled. At baseline, the median time to progression after prior docetaxel was 1.4 months (range 0-5.7). Gastrointestinal serious adverse events occurred in four of the six initial patients leading to a reduction of the starting dose of patupilone to 8 mg/m2 for subsequent patients. Grade 3-4 toxicity at this dose included diarrhea (22%), fatigue (21%), and anorexia (10%). One patient experienced grade 3-4 hematologic toxicity. A PSA decline of ≥50% occurred in 47% of patients. A partial measurable disease response occurred in 24% of assessable patients. A patient-reported pain response was observed in 59% of assessable patients. Median time to PSA progression was 6.1 months [95% confidence interval (CI) 4.7-8.0] and median overall survival was 11.3 months (95% CI 9.8-15.4).nnnCONCLUSIONSnPatupilone at 8 mg/m2 was tolerable, had antitumor activity, and was associated with symptomatic improvement in patients previously treated with docetaxel.

A phase II study of cediranib (AZD 2171) in treatment naive patients with progressive unresectable recurrent or metastatic renal cell carcinoma. A trial of the PMH phase 2 consortium

SummaryBackground Inhibition of angiogenesis has emerged as an effective therapeutic strategy in metastatic renal cell cancer (mRCC). In this single arm phase 2 study, we evaluated the efficacy and tolerability of cediranib (AZD2171) a potent angiogenesis inhibitor in first line mRCC. Methods Eligible patients who had no prior systemic therapy received cediranib 45xa0mg orally once daily continuously. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate (ORR plus stable disease (SD)u2009≥u20094xa0months), duration of response, progression free survival (PFS), median overall survival (OS), safety and tolerability. Results Between January 2006 and April 2008, 44 patients were accrued. The median age was 62 (range 44–83) and performance status was either 0 (22 patients) or 1 (22 patients). Of the 39 evaluable patients there were 15 (38xa0%) partial responses (95xa0% CI: 23–55xa0%); 18 stable disease (SD) for a clinical benefit rate of 33/39u2009=u200985xa0% (95xa0% CI: 69–94xa0%) and 6 progressive disease. Median PFS was 8.9xa0months (95xa0% CI: 5.1–12.9); and median OS was 28.6xa0months (95xa0% CI: 18.2–37.3xa0months). The most frequent grade 3 or higher AEs included hypertension, fatigue, hand-foot syndrome and diarrhea. Conclusions Cediranib demonstrated significant anti-tumour activity in first line, treatment-naive mRCC, with efficacy parameters comparable to the other approved agents (sunitinib and pazopanib) in this setting. The main toxicities were fatigue, diarrhea and hypertension. Based on these encouraging results, further evaluation of cediranib in mRCC at a more tolerable dose of 30xa0mg daily appears warranted.

Management of small cell carcinoma of the bladder: Consensus guidelines from the Canadian Association of Genitourinary Medical Oncologists (CAGMO).

Small cell carcinomas (SCC) most commonly arise from the lung.1 These tumours are aggressive, present with early metastasis and are associated with a poorer prognosis compared to non-small cell lung cancer.2,3 Extra-pulmonary SCC was first described by Duguid and Kennedy in 19304 and subsequently has been reported in the gastrointestinal tract,5 head and neck6 and genitourinary (GU) system.7 SCC of the GU system (SCCGU) are uncommon, but can occur in the kidneys,8 renal pelvis,9 ureter,10 bladder,7 urachus,11 urethra12 and prostate.13 Although rare, these cancers are not insignificant. SCC accounts for 0.5% to 0.7% of all bladder cancers diagnosed.14,15 SCCGU also behaves more aggressively than typical GU histological counterparts.16 There is little medical literature to guide the optimal management of SCCGU malignancies and therefore treatment paradigms have by default mirrored those of the more common small cell carcinoma of the lung. Given the rarity of SCCGU tract and the lack of good clinical guidelines, it was clear that a guideline to help Canadian physicians and surgeons manage these patients with SCCGU was needed. This document achieves that goal for small cell carcinoma of the bladder (SCCB).

Nomogram-based Prediction of Overall Survival in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC)

BACKGROUNDnThe available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.nnnOBJECTIVEnTo develop a new model based on real-world patients.nnnDESIGN, SETTING, AND PARTICIPANTSnIndividual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.nnnINTERVENTIONnFirst-line, platinum-based, combination chemotherapy.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.nnnRESULTS AND LIMITATIONSnA total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670).nnnCONCLUSIONSnWe developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC.nnnPATIENT SUMMARYnWe proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

Impact of the Number of Prior Lines of Therapy and Prior Perioperative Chemotherapy in Patients Receiving Salvage Therapy for Advanced Urothelial Carcinoma: Implications for Trial Design

BACKGROUNDnThe differential impact of the number of prior lines of therapy and the setting of prior therapy (perioperative or metastatic) is unclear in advanced urothelial carcinoma.nnnPATIENTS AND METHODSnTen phase II trials of salvage chemotherapy, biologic agent therapy, or both, enrolling 731 patients, were available. Data on the number of prior lines of therapy and the setting of prior therapy were required in addition to known previously recognized prognostic factors: time from prior chemotherapy, hemoglobin level, performance status, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of the number of prior lines and prior perioperative therapy with overall survival (OS) as the primary clinical endpoint. Trial was a stratification factor.nnnRESULTSnA total of 711 patients were evaluable. The overall median progression-free survival and OS were 2.7 and 6.8 months, respectively. The number of prior lines was 1 in 559 patients (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%), and 5 in 2 (0.3%). Prior perioperative chemotherapy was given to 277 (39.1%) and chemotherapy for metastatic disease to 454 (64.1%). The number of prior lines was not independently associated with OS (hazard ratio, 0.99; 95% CI, 0.86-1.14). Prior perioperative chemotherapy was a favorable factor for OS on univariate but not multivariate analysis.nnnCONCLUSIONnThe number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic in patients with urothelial carcinoma receiving salvage therapy. Adoption of these data in salvage therapy trials should enhance accrual, the interpretability of results, and drug development.

The Importance of Surgeon Characteristics on Impacting Oncologic Outcomes for Patients Undergoing Radical Cystectomy

PURPOSEnGiven that the urologist has a major influence on outcomes of radical cystectomy, it is of interest to patients, trainees, urologists and administrators to understand the provider characteristics associated with favorable outcomes. Therefore, we assessed associations between various surgeon characteristics and long-term oncologic outcomes for patients undergoing radical cystectomy for bladder cancer.nnnMATERIALS AND METHODSnA retrospective cohort treated with radical cystectomy for muscle invasive or nonmuscle invasive bladder cancer at University Health Network (Toronto) was assembled. The characteristics studied included years ofxa0experience in independent practice, surgical radical cystectomy volume, subspecialized focus in bladder cancer and uro-oncology fellowship training. The outcomes were overall survival, bladder cancer specific survival and recurrence-free survival. Kaplan-Meier analyses and multivariate Cox proportional hazards models adjusting for patient, tumor and treatment related parameters were used.nnnRESULTSnThe final cohort included 410 patients treated by 11 urologists (median followup 57 months). Bladder cancer focused and uro-oncology fellowship trained urologists performed more extensive lymphadenectomies and more often performed continent diversions, but there was no difference in the use of neoadjuvant chemotherapy. In Kaplan-Meier and univariate Cox analyses, subspecialized bladder cancer focus and uro-oncology fellowship were associated with improved survival outcomes. However, in multivariate Cox models only subspecialized bladder cancer focus was independently associated with improved overall survival (HR 0.68, 95% CI 0.55-0.85, p <0.001), bladder cancer specific survival (HR 0.63, 95% CI 0.41-0.96, p = 0.032) and recurrence-free survival (HR 0.63, 95% CI 0.42-0.95, p = 0.027).nnnCONCLUSIONSnWhile radical cystectomy volume, experience and uro-oncology fellowship are all likely important, we found that subspecialized focus in bladder cancer was independently associated with improved long-term oncologic outcomes. Our data support disease site differentiation among uro-oncologists atxa0large institutions.

The therapeutic ratio is preserved for radiotherapy or cisplatin treatment in BRCA2-mutated prostate cancers

Prostate cancers in patients with a mutation in BRCA2 have earlier disease onset and an aggressive course, often necessitating the use of systemic therapy. However, these tumours are DNA repair-defective and could respond favourably to Parp inhibitors or DNA-damaging agents, depending on the therapeutic ratio (ratio of tumour response to normal tissue toxicity). We describe 3 patients treated with precision radiotherapy or cisplatin who responded favourably to both agents, yet did not suffer undue toxicity. We review the concept of treating such patients with agents that are selectively toxic to repair-deficient tumours.