Matthew I Milowsky

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (84)460.46 Total impact

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    ABSTRACT: No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature.
    Urologic oncology. 06/2014;
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    ABSTRACT: We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.
    Proceedings of the National Academy of Sciences 02/2014; · 9.74 Impact Factor
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    ABSTRACT: Upper tract urothelial carcinoma (UTUC) is a rare disease in Western countries and garners little focused attention in urologic and oncologic circles. We report highlights from the first symposium on UTUC. All participants were asked to provide a summary of their presentation to be included as part of these proceedings. Submitted summaries were synthesized into this document. All contributors reviewed and provided input on the final draft. Five highlights are included in this report, including landmark research that not only reveals the likely cause of Balkan endemic nephropathy and associated UTUC but also links it directly to UTUC in Taiwan. Because of the ubiquitous use of Aristolochia plants in these herbal remedies, a public health problem of considerable magnitude is anticipated in Asian countries. Gene expression signatures reveal some differential expression in bladder carcinoma, such as CLCA2 and GABRE. Few urinary markers have proven utility for the diagnosis and follow-up of UTUC, and no tissue or blood-based markers are currently undergoing clinical application. Novel endoscopic therapies provide some hope of improving tissue sampling, diagnosis, and kidney-sparing therapeutics, but the greatest potential lies in improving clinical (preoperative) risk stratification, which is critically limited in this disease. Biomarkers, currently untested, hold promise in identifying patients most likely to benefit from perioperative chemotherapy and at high risk from cisplatin-induced nephrotoxicity. Despite its rarity in the West, UTUC is reaching potentially epidemic proportions in the East because of exposure to carcinogenic herbal remedies. Critical trials are needed to improve our understanding and treatment of UTUC. Because of the broad range of comorbid conditions in patients suffering from this disease, it is the consensus of the participants that future clinical trials should be practical in design and applicable to a broad range of patients, diverging from the current dogma of narrow patient selection criteria in clinical trials. Practical designs would maximize accrual for a still uncommon disease, and their findings would be applicable to a larger proportion of patients than current narrowly selected designs.
    Urologic Oncology 01/2014; · 3.65 Impact Factor
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    ABSTRACT: Salvage systemic therapy for advanced urothelial carcinoma has substantial unmet needs. Small phase II trials have been conducted with varying eligibility criteria, which render cross-trials comparisons difficult. Moreover, accrual to trials is hampered by comorbidities, elderly age and poor performance status. Therefore, improvements in clinical trial design may facilitate further advances. This commentary summarizes recent data regarding prognostic factors, which allow us to recommend inclusive, yet rational, eligibility criteria and stratification factors to enhance accrual and improve interpretability of data from phase II trials: 1) allowing either prior perioperative platinum-based chemotherapy within 1 year or prior platinum-based chemotherapy for metastatic disease, 2) allowing ≤2 prior lines of therapy, 3) allow patients regardless of quality of response to prior therapy, 4) allow all sites of primary urothelial malignancy, and 5) a preplanned analysis of outcomes controlled for baseline prognostic factors.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Objectives No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature. Materials and methods A survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network–sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review. Results Most survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease. Conclusions The management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC.
    Urologic Oncology: Seminars and Original Investigations. 01/2014;
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    ABSTRACT: Background Outcomes with concurrent chemoradiation for penile squamous cell carcinoma (PSCC) are unclear and only anecdotal reports have been published. We performed a retrospective analysis of patients who received concurrent chemotherapy and radiotherapy for PSCC. Patients and methods Individual patient level data were obtained from 5 institutions for outcomes with concurrent chemoradiation for PSCC. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted to examine the prognostic impact of candidate factors on progression-free survival (PFS) and overall survival (OS). Results A total of 26 men were evaluable. The mean age was 60.3 years. The clinical stage was ≤3 in 9 patients (36%) and stage 4 in the rest. Soft tissue and visceral metastasis were present in 35% and 20% of patients, respectively. The chemotherapy was cisplatin-based in 92.3% of patients and the median (range) of external beam radiotherapy administered was 4900 cGy (1800-7000). The median OS was 6.9 months (95% CI: 5, 14) and the median PFS was 5.1 months (95% CI: 2.5, 7.0). When excluding patients with M1 disease, the remaining patients (N=21) had a median OS and PFS of 10.0 months (95% CI: 5, 14) and 6.0 months (95% CI: 2.0, 7.0), respectively. Baseline neutrophil by lymphocyte ratio (NLR) was significantly associated with survival and visceral metastasis showed a trend for association with OS. Conclusions Concurrent chemoradiation demonstrated poor outcomes for locally advanced PSCC. Better understanding of tumor biology and study of novel combinations of biologic agents with radiation are warranted.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
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    ABSTRACT: Background The differential impact of number of prior lines of therapy and setting of prior therapy (perioperative, metastatic) is unclear in advanced urothelial carcinoma (UC). Patients and methods Ten phase II trials of salvage chemotherapy and/or biologic agent therapy enrolling 731 patients were available. Data on the number of prior lines of therapy and setting of prior therapy were required in addition to known previously recognized prognostic factors: time from prior chemotherapy, hemoglobin, performance status and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of number of prior lines and prior perioperative therapy with overall survival (OS) as the primary clinical endpoint. Trial was a stratification factor. Results 711 patients were evaluable. The overall median PFS and OS were 2.7 and 6.8 months, respectively. The number of prior lines were 1 in 559 (78.6%), 2 in 111 (15.6%), 3 in 29 (4.1%), 4 in 10 (1.4%) and 5 in 2 (0.3%) patients. 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 (HR 0.99 [95% CI: 0.86-1.14]). Prior peri-operative chemotherapy was a favorable factor for OS on univariable but not multivariable analysis. Conclusions The number of prior lines of therapy and prior perioperative chemotherapy were not independently prognostic in UC patients receiving salvage therapy. Adoption of these data in salvage therapy trials should enhance accrual, the interpretability of results and drug development.
    Clinical Genitourinary Cancer 01/2014; · 1.43 Impact Factor
  • Matthew I Milowsky, William Y Kim
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    ABSTRACT: Bladder cancer is a disease of older patients who often have multiple comorbidities. Although cisplatin-based combination chemotherapy is the standard of care in the neoadjuvant and metastatic settings, outcomes remain poor, and approximately half of patients are ineligible for cisplatin where treatment options are severely limited. Recent comprehensive genome sequencing studies have defined the mutational spectra of high-grade urothelial carcinoma of the bladder. Although there is a high prevalence of potentially actionable genomic alterations, whether these events represent true oncogenic vulnerabilities has yet to be confirmed. Given the demographics and genetics, we propose that bladder cancer represents an ideal model to study the potential of targeted therapy in older patients who are too often unable to receive cisplatin-based therapy and where novel treatment strategies are desperately needed.
    American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting. 01/2014; 34:e192-5.
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    ABSTRACT: To evaluate the association between patterns of care and patient survival for the treatment of muscle-invasive bladder cancer (MIBC) using a large, national database. We identified a cohort of 36,469 patients with MIBC (Stage II) from 1998 to 2010 from the National Cancer Data Base. Patients were stratified into four treatment groups: radical cystectomy, chemo-radiation, other therapy, or no treatment. Overall survival (OS) between groups was evaluated using the Kaplan Meier (KM) method and Log Rank test. A multivariable Cox proportional hazards model was fit to evaluate the association between treatment groups with OS. Among treatment groups, 27% received radical cystectomy, 10% chemo-radiation, 61% other therapy, and 2% no treatment. Unadjusted KM analysis showed significant differences by group, with cystectomy having the greatest median OS (48 months) followed by chemo-radiation (28 months), other therapy (20 months), and no treatment (5 months). When controlling for multiple covariates, OS for cystectomy was similar to chemo-radiation (HR 1.05, 95% CI 0.98, 1.12), but superior to other therapy (HR 1.42; 95% CI 1.35, 1.48), and no treatment (HR 2.40; 95% CI 2.12, 2.72). OS for chemo-radiation was superior to other therapy and no treatment. Radical cystectomy and chemo-radiation are significantly underutilized despite a substantial survival benefit compared to other therapies or no treatment. Future studies are needed to optimize care delivery and improve outcomes for patients with MIBC.
    BJU International 12/2013; · 3.05 Impact Factor
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    ABSTRACT: Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS≥1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS≥1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS≥1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.
    Urologic Oncology 12/2013; · 3.65 Impact Factor
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    ABSTRACT: To determine whether neoadjuvant chemotherapy (NAC) is a predictor of post-operative complications, length of stay, or operative time after radical cystectomy (RC) for bladder cancer. A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC prior to RC from 2005-2011. Bivariable and multivariable analyses were performed to determine whether NAC was associated with 30-day peri-operative outcomes such as complications, length of stay, and operative time. Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. 457 of the 878 patients (52.1%) undergoing RC had at least 1 complication within 30 days, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (p = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (p=0.87), reoperation (p=0.16), wound infection (p=0.32), or wound dehiscence(p=0.32). Using multiple linear regression, NAC was not a predictor of increased operative time (p=0.24), and patients undergoing NAC had decreased hospital length of stay (p=0.02). Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. In light of these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.
    BJU International 11/2013; · 3.05 Impact Factor
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    ABSTRACT: To examine the association of hospital volume and 90-day mortality after cystectomy, conditional on survival to 30 days SUBJECTS AND METHODS: The National Cancer Database was used to evaluate 30- and 90-day mortality for 35,055 bladder cancer cases that received cystectomy at 1,118 hospitals. Patient data were aggregated into hospital volume categories based on average annual number of procedures [<10 low volume hospital (LVH), 10-19, ≥20 high volume (HVH)]. Associations between mortality and clinical, demographic and hospital characteristics were analyzed using hierarchical logistic regression models. To assess the association between hospital volume and 90-day mortality independent from shorter-term mortality, 90-day mortality conditional on 30-day survival was assessed in the multivariate modeling. Unadjusted 30- and 90-day mortality rates were 2.7% and 7.2% overall, 1.9% and 5.7% among HVH, and 3.2% and 8.0% among LVH, respectively. Compared to HVH, the adjusted risks among LVH [OR (95% CI)] of 30- and 90-day mortality conditional on having survived through 30 days from the hierarchical models were 1.5 (1.3-1.9), and 1.2 (1.0-1.4), respectively. Low hospital volume was associated with increased 30- and 90-day mortality. These data support the need for further research to better understand the relatively high mortality rates seen between 30-90 days, which are high and less variable across hospital volume strata. The stronger association between volume and 30-day mortality suggests that quality-reporting efforts should focus on shorter term outcomes.
    BJU International 11/2013; · 3.05 Impact Factor
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    ABSTRACT: Bladder cancer is notable for a striking heterogeneity of disease-specific risks. Among the approximately 75% of incident cases found to be superficial to the muscularis propria at the time of presentation (non-muscle-invasive bladder cancer), the risk of progression to the lethal phenotype of muscle-invasive disease is strongly associated with stage and grade of disease. Given the suggestion of an increasing percentage of low-risk cases in hospital-based registry data in recent years, the authors hypothesized that population-based data may reveal changes in the stage distribution of early-stage cases. Surveillance, Epidemiology, and End Results (SEER) data were used to examine trends for the stage-specific incidence of bladder cancer between 1988 and 2006, adjusted for age, race, and sex, using Joinpoint and nonparametric tests. The adjusted incidence rate of papillary noninvasive (Ta) predominantly low grade (77%) disease was found to increase from 5.52 to 9.09 per 100,000 population (P < .0001), with an average annual percentage change of +3.3. Over the same period, concomitant, albeit smaller, decreases were observed for flat in situ (Tis) and lamina propria-invasive (T1) disease (2.57 to 1.19 and 6.65 to 4.61 per 100,000 population [both P < .0001]; average annual percent change of -5.0 and -1.6, respectively). The trend was most dramatic among patients in the oldest age strata, suggesting a previously unappreciated cohort phenomenon. The findings of the current study should motivate further epidemiological investigations of differential associations of genetic and environmental factors with different bladder cancer phenotypes as well as further scrutiny of clinical practice guideline recommendations for the growing subgroup of predominantly older patients with lower-risk disease. Cancer 2013. © 2013 American Cancer Society.
    Cancer 10/2013; · 5.20 Impact Factor
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    ABSTRACT: PURPOSEWe sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with high-grade bladder cancer to serve as a platform for therapeutic drug discovery. PATIENTS AND METHODS An integrative analysis of 97 high-grade bladder tumors was conducted to identify actionable drug targets, which are defined as genomic alterations that have been clinically validated in another cancer type (eg, BRAF mutation) or alterations for which a selective inhibitor of the target or pathway is under clinical investigation. DNA copy number alterations (CNAs) were defined by using array comparative genomic hybridization. Mutation profiling was performed by using both mass spectroscopy-based genotyping and Sanger sequencing.ResultsSixty-one percent of tumors harbored potentially actionable genomic alterations. A core pathway analysis of the integrated data set revealed a nonoverlapping pattern of mutations in the RTK-RAS-RAF and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways and regulators of G1-S cell cycle progression. Unsupervised clustering of CNAs defined two distinct classes of bladder tumors that differed in the degree of their CNA burden. Integration of mutation and copy number analyses revealed that mutations in TP53 and RB1 were significantly more common in tumors with a high CNA burden (P < .001 and P < .003, respectively). CONCLUSION High-grade bladder cancer possesses substantial genomic heterogeneity. The majority of tumors harbor potentially tractable genomic alterations that may predict for response to target-selective agents. Given the genomic diversity of bladder cancers, optimal development of target-specific agents will require pretreatment genomic characterization.
    Journal of Clinical Oncology 07/2013; · 18.04 Impact Factor
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    ABSTRACT: Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.
    Annals of Oncology 07/2013; · 7.38 Impact Factor
  • David D Chism, Michael E Woods, Matthew I Milowsky
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    ABSTRACT: Neoadjuvant cisplatin-based combination chemotherapy for muscle-invasive bladder cancer (MIBC) has been shown to confer a survival advantage in two randomized clinical trials and a meta-analysis. Despite level 1 evidence supporting its benefit, utilization remains dismal with nearly one-half of patients ineligible for cisplatin-based therapy because of renal dysfunction, impaired performance status, and/or coexisting medical problems. This situation highlights the need for the development of novel therapies for the management of MIBC, a disease with a lethal phenotype. The neoadjuvant paradigm in bladder cancer offers many advantages for accelerated drug development. First, there is a greater likelihood of successful therapy at an earlier disease state that may be characterized by less genomic instability compared with the metastatic setting, with an early readout of activity with results determined in months rather than years. Second, pre- and post-treatment tumor tissue collection in patients with MIBC is performed as the standard of care without the need for research-directed biopsies, allowing for the ability to perform important correlative studies and to monitor tumor response to therapy in "real time." Third, pathological complete response (pT0) predicts for improved outcome in patients with MIBC. Fourth, there is a strong biological rationale with rapidly accumulating evidence for actionable targets in bladder cancer. This review focuses on the neoadjuvant paradigm for accelerated drug development using bladder cancer as the ideal model.
    The Oncologist 07/2013; · 4.10 Impact Factor
  • Sumanta K Pal, Matthew I Milowsky, Elizabeth R Plimack
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    ABSTRACT: Over the past several decades, few new systemic agents have been incorporated into the treatment paradigm for bladder cancer. Platinum-based therapy remains the cornerstone of treatment in the perioperative and metastatic settings. Despite level one evidence, use of cisplatin-based therapy in the neoadjuvant setting has been dismal. Second-line therapy for metastatic disease has only modest activity with no survival benefit. However, the elucidation and investigation of novel molecular targets, new therapeutics, and associated biomarkers with strong biologic rationale are actively changing the landscape in bladder cancer. Although the field is moving rapidly, no new drug approvals are currently pending and a need remains to continue to educate the medical oncology and urology communities on the optimal use of currently available treatments. This article outlines the evidence, including that from prospective studies and meta-analyses, providing the basis for the current recommendations from NCCN, and details previous and ongoing studies of targeted therapy for bladder cancer.
    Journal of the National Comprehensive Cancer Network: JNCCN 07/2013; 11(7):793-804. · 5.11 Impact Factor
  • Allison M Deal, Matthew I Milowsky
    Cancer 05/2013; · 5.20 Impact Factor
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    ABSTRACT: PURPOSE: To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival EXPERIMENTAL DESIGN: In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers RESULTS: 47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced > 50% decline in PSA, 36.2% experienced > 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond CONCLUSIONS: A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising.
    Clinical Cancer Research 05/2013; · 7.84 Impact Factor
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    ABSTRACT: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: No recent advances have been made in the treatment of patients with advanced bladder cancer and, to date, targeted therapies have not resulted in an improvement in outcome. The mammalian target of rapamycin pathway has been shown to be up-regulated in bladder cancer and represents a rational target for therapeutic intervention. In the present phase II study of everolimus, one near-complete response, one partial response and several minor responses suggest that everolimus possesses biological activity in a subset of patients with bladder cancer. To maximize benefit from targeted agents such as everolimus, the preselection of patients based on molecular phenotype is required. OBJECTIVE: To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC). PATIENTS AND METHODS: The present study comprised a single-arm, non-randomized study in which all patients received everolimus 10 mg orally once daily continuously (one cycle = 4 weeks). In total, 45 patients with metastatic UC progressing after one to four cytotoxic agents were enrolled between February 2009 and November 2010 at the Memorial Sloan-Kettering Cancer Center. The primary endpoints were 2-month progression-free survival (PFS) and the safety of everolimus, with the secondary endpoint being the response rate. A Simon minimax two-stage design tested the null hypothesis that the true two month PFS rate was ≤50%, as opposed to the alternative hypothesis of ≥70%. RESULTS: The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. There were 23 of 45 (51%) patients who were progression-free at 2 months with a median (95% CI) PFS of 2.6 (1.8-3.5) months and a median (95% CI) overall survival of 8.3 (5.5-12.1) months. No clear association was observed between mammalian target of rapamycin pathway marker expression and 2-month PFS. CONCLUSIONS: Although everolimus did not meet its primary endpoint, one partial response, one near-complete response and twelve minor regressions were observed. Everolimus possesses meaningful anti-tumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing.
    BJU International 04/2013; · 3.05 Impact Factor

Publication Stats

2k Citations
460.46 Total Impact Points

Institutions

  • 2012–2014
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
    • Vanderbilt University
      • Department of Neurology
      Nashville, MI, United States
  • 2002–2013
    • Weill Cornell Medical College
      • • Division of Hematology/Medical Oncology
      • • Department of Pathology and Laboratory Medicine
      • • Division of Hospital Medicine
      • • Department of Urology
      New York City, NY, United States
  • 2008–2012
    • Memorial Sloan-Kettering Cancer Center
      • • Genitourinary Oncology Service
      • • Department of Surgery
      New York City, New York, United States
  • 2011
    • American College of Surgeons
      Chicago, Illinois, United States
  • 2009
    • New York Presbyterian Hospital
      • Department of Pain Medicine
      New York City, New York, United States
  • 2001–2009
    • Cornell University
      • • Department of Medicine
      • • Department of Urology
      Ithaca, NY, United States