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1.  Refining Patient Selection for Neoadjuvant Chemotherapy before Radical Cystectomy 
The Journal of urology  2013;191(1):40-47.
We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy.
Materials and Methods
We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection. We evaluated survival (disease specific, progression-free and overall) and rate of pathological up staging. An independent cohort of patients from another institution was used to confirm our findings.
We identified 98 high risk and 199 low risk patients eligible for analysis. High risk patients exhibited decreased 5-year overall survival (47.0% vs 64.8%) and decreased disease specific (64.3% vs 83.5%) and progression-free (62.0% vs 84.1%) survival probabilities compared to low risk patients (p <0.001). Survival outcomes were confirmed in the validation subset. On final pathology 49.2% of low risk patients had disease up staged.
The 5-year disease specific survival of low risk patients was greater than 80%, supporting the distinction of high risk and low risk muscle invasive bladder cancer. The presence of high risk features identifies patients with a poor prognosis who are most likely to benefit from neoadjuvant chemotherapy, while many of those with low risk disease can undergo surgery up front with good expectations and avoid chemotherapy associated toxicity.
PMCID: PMC4158919  PMID: 23911605
urinary bladder neoplasms; cystectomy; neoadjuvant therapy; risk; outcomes assessment
2.  Plasmacytoid Urothelial Carcinomas – A Chemo-sensitive Cancer with Poor Prognosis, and Peritoneal Carcinomatosis 
The Journal of urology  2012;189(5):1656-1661.
Plasmacytoid urothelial carcinoma (PUC) is a rare variant histology with poorly defined clinical behavior. We report clinical outcomes information on patients with predominant PUC.
Materials and Methods
Retrospective analysis of treatments and outcomes in patients with predominant PUC seen at MD Anderson Cancer Center from 1990–2010. Kaplan-Meier method was used to calculate Overall (OS) and progression-free survival (PFS).
31 patients were identified (median age:63.5yrs; 83.3% male; TNM stage:cT1N0,n=4;cT2N0,n=7;cT3b-4aN0,n=5; cT4b, N+ or M+ n = 15). Median OS for all patients was 17.7months (Stage I-III vs IV: 45.8 vs 13.3mo). Of 16 patients with potentially surgically resectable PUC (<=pT4aN0M0) 5 received neo-adjuvant chemotherapy, 10 had initial surgery, and one was treated with TURBT alone. Despite pathologic downstaging in 80% of patients treated with neo-adjuvant chemotherapy, relapses were common and there was no difference in survival between patients treated with neo-adjuvant chemotherapy compared to initial surgery, even though adjuvant chemotherapy was given in 7 patients. Surgical upstaging with positive margins was also common with surgery alone. The most common site of recurrence was in the peritoneum (19/23), with relapses occurring even in those with pCR at surgery. In patients presenting with metastatic disease who were treated with chemotherapy, the median survival was 12.6 months.
PUC is a very aggressive subset with overall poor outcomes. Although downstaging is seen with neoadjuvant chemotherapy, there are few long-term survivors. There is a strong predilection for recurrences along the peritoneal lining.
PMCID: PMC4243847  PMID: 23159581
survival; plasmacytoid; urothelial carcinoma
3.  Neoadjuvant Chemotherapy in Small Cell Urothelial Cancer Improves Pathologic Downstaging and Long-term Outcomes: Results from a Retrospective Study at the MD Anderson Cancer Center 
European urology  2012;64(2):10.1016/j.eururo.2012.04.020.
Small cell urothelial carcinoma (SCUC) is a rare, aggressive malignancy with a propensity for early microscopic metastases. Data suggest that neoadjuvant chemotherapy may lead to improved survival compared with initial surgery.
To determine the influence of neoadjuvant chemotherapy on survival of SCUC patients in a large single-institution cohort.
Design, setting, and participants
Between 1985 and 2010, 172 patients were treated for SCUC at MD Anderson Cancer Center (MDACC). Clinical, pathologic, and surgical data were collected and analyzed.
Outcome measurements and statistical analysis
Overall survival (OS) and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. Multivariable Cox proportional hazards models were used to evaluate the effects of neoadjuvant chemotherapy on survival.
Results and limitations
Of 125 patients with resectable disease (≤cT4aN0M0), 95 were surgical candidates. Forty-eight received neoadjuvant chemotherapy, and 47 underwent initial surgery. Neoadjuvant treatment was associated with improved OS and DSS compared with initial cystectomy (median OS: 159.5 mo vs 18.3 mo, p < 0.001; 5-yr DSS: 79% vs 20%, p < 0.001). Neoadjuvant chemotherapy resulted in pathologic downstaging to ≤pT1N0 in 62% of tumors compared with only 9% treated with initial surgery (odds ratio: 44.55; 95% confidence interval, 10.39–191). Eight patients with clinically node-positive disease had surgical consolidation with cystectomy and extended lymph node dissection after clinical complete response to chemotherapy. Median OS and DSS in this group of patients were 23.3 mo and 21.8 mo, respectively, with 5-yr OS and DSS of 38%.
Neoadjuvant chemotherapy is associated with a high rate of pathologic downstaging and correlates with significantly higher survival compared with historical expectations. Although limited by a small sample size and retrospective analysis, in the context of a rare disease, this experience suggests neoadjuvant chemotherapy as a standard approach in treating SCUC.
PMCID: PMC3815632  PMID: 22564397
Small cell urothelial cancer; Bladder cancer; Neoadjuvant; Surgery; Chemotherapy
4.  Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer 
Clinical features characteristic of small-cell prostate carcinoma (SCPC), (““anaplastic””) often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden or short response to androgen deprivation therapy.
Experimental Design
A 120-patient phase II trial of frontline carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after 4 cycles of CD and EP, respectively. Median overall survival (OS) was 16 months (95% CI, 13.6-19.0 months). Of the 7 “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase (LDH) strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with CRPC and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
PMCID: PMC3699964  PMID: 23649003
Small-cell; neuroendocrine; castration-resistant; prostate carcinoma; platinum chemotherapy
5.  Survival outcomes for men with mediastinal germ-cell tumors: The University of Texas M. D. Anderson Cancer Center experience✩ 
Urologic oncology  2010;30(6):879-885.
Primary mediastinal germ-cell tumors are rare, and the effect of newer drugs and treatment strategies in this disease on overall survival is not known. We retrospectively assessed treatment outcomes at a single institution.
Materials and methods
We identified men seen at our institution from 1998 through 2005 for mediastinal germ-cell tumors. Medical records were reviewed for patient characteristics, histology, tumor markers, treatment, and survival outcome.
Thirty-four patients met study criteria, of whom 27 had nonseminomatous germ-cell tumor (NSGCT) and 7 had pure seminoma. Eleven patients (41%) with NSGCT were alive at last contact with a median overall survival time of 33.5 months. Among 13 patients with NSGCT referred to us at initial diagnosis, 7 (54%) were alive and recurrence-free at a median follow-up of 56.5 months. Progression-free survival was associated with absence of risk factors (any histology other than endodermal sinus tumor, β-hCG > 1000 mIU/mL, or disease outside the mediastinum). For the patients whose disease progressed (n = 5) or who had been referred to us for salvage treatment (n = 14), the 3-year overall survival from the date of first progression was 23%. Conversely, patients with seminoma did uniformly well with platinum-based chemotherapy; most did not undergo radiation or surgery.
Chemotherapy given to maximum effect followed by surgical consolidation resulted in long-term progression-free survival for 54% of patients with mediastinal NSGCT. The number of risk factors present at diagnosis may be associated with survival outcome and should be studied in a larger test group.
PMCID: PMC3956468  PMID: 20933444
Mediastinal neoplasms; Germ-cell neoplasms; Seminoma; Tumor markers; Resection; Outcome
7.  Evaluation of Viable Dynamic Treatment Regimes in a Sequentially Randomized Trial of Advanced Prostate Cancer 
We present new statistical analyses of data arising from a clinical trial designed to compare two-stage dynamic treatment regimes (DTRs) for advanced prostate cancer. The trial protocol mandated that patients were to be initially randomized among four chemotherapies, and that those who responded poorly were to be rerandomized to one of the remaining candidate therapies. The primary aim was to compare the DTRs’ overall success rates, with success defined by the occurrence of successful responses in each of two consecutive courses of the patient’s therapy. Of the one hundred and fifty study participants, forty seven did not complete their therapy per the algorithm. However, thirty five of them did so for reasons that precluded further chemotherapy; i.e. toxicity and/or progressive disease. Consequently, rather than comparing the overall success rates of the DTRs in the unrealistic event that these patients had remained on their assigned chemotherapies, we conducted an analysis that compared viable switch rules defined by the per-protocol rules but with the additional provision that patients who developed toxicity or progressive disease switch to a non-prespecified therapeutic or palliative strategy. This modification involved consideration of bivariate per-course outcomes encoding both efficacy and toxicity. We used numerical scores elicited from the trial’s Principal Investigator to quantify the clinical desirability of each bivariate per-course outcome, and defined one endpoint as their average over all courses of treatment. Two other simpler sets of scores as well as log survival time also were used as endpoints. Estimation of each DTR-specific mean score was conducted using inverse probability weighted methods that assumed that missingness in the twelve remaining drop-outs was informative but explainable in that it only depended on past recorded data. We conducted additional worst-best case analyses to evaluate sensitivity of our findings to extreme departures from the explainable drop-out assumption.
PMCID: PMC3433243  PMID: 22956855
Causal inference; Efficiency; Informative dropout; Inverse probability weighting; Marginal structural models; Optimal regime; Simultaneous confidence intervals
8.  Phase III Trial of Androgen Ablation With or Without Three Cycles of Systemic Chemotherapy for Advanced Prostate Cancer 
Journal of Clinical Oncology  2008;26(36):5936-5942.
We conducted a phase III trial in patients with previously untreated metastatic prostate cancer to test the hypothesis that three 8-week cycles of ketoconazole and doxorubicin alternating with vinblastine and estramustine, given in addition to standard androgen deprivation, would delay the appearance of castrate-resistant disease.
Patients and Methods
Eligible patients had metastatic prostate cancer threatening enough to justify sustained androgen ablation and were fit enough for chemotherapy. The primary end point was time to castrate-resistant progression as shown by increasing prostate-specific antigen, new radiographic lesions, worsening cancer-related symptoms, or receipt of any other systemic therapy.
Three hundred six patients were registered; 286 are reported. Median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (P = .39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; P = .41). Prostate-specific antigen kinetics at the time of androgen ablation and the nadir after hormone treatment were strongly correlated with survival. Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events.
There is no role for ketoconazole and doxorubicin alternating with vinblastine and estramustine before emergence of a castrate-resistant phenotype.
PMCID: PMC3864402  PMID: 19029421

Results 1-8 (8)