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1.  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
2.  Quantifying the Survival Benefit for Allogeneic Stem Cell Transplantation in Relapsed Acute Myeloid Leukemia 
Allogeneic hematopoietic stem cell transplantation (HSCT) is the recommended therapy for patients with relapsed AML despite little evidence showing a survival benefit for patients who undergo HSCT vs. chemotherapy alone.
Because a prospective randomized trial addressing this issue is unlikely to be conducted we retrospectively reviewed all patients given 1st salvage therapy for AML at M.D. Anderson Cancer Center from 1995–2004, focusing on patients given HSCT or chemotherapy without HSCT (a) as second salvage after 1st salvage failed to produce CR or (b) in 1st salvage-induced CR. Median survival in group (a) was 5.1 months for HSCT (n=84) vs. 2.3 months for chemotherapy (n=200, p=0.004) and, in group (b), was 11.7 months for HSCT (n=46) vs. 5.6 months for chemotherapy (n=66, p<0. 001). HSCT was associated with a survival benefit in each of 8 subgroups defined by age 36 weeks). Our data suggest that HSCT is preferable to chemotherapy alone in these poor prognosis patients with particular benefit noted in patients <50.
PMCID: PMC4067765  PMID: 19822303
Relapsed acute myeloid leukemia; Hematopoietic stem cell transplant; Overall survival
3.  Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia 
Current opinion in oncology  2009;21(0 1):S11-S15.
We hypothesized that standardized systemic drug delivery would improve treatment safety and provide better leukemia control. We therefore developed an intravenous busulfan formulation and combined it with fludarabine instead of cyclophosphamide in preparation for allogeneic stem cell transplantation (alloSCT). We used a Bayesian method to compare the outcomes of 67 acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received intravenous busulfan–cyclophosphamide (BuCy2) with 148 subsequent AML/MDS patients who received busulfan–fludarabine (Bu-Flu). The groups had comparable pretreatment characteristics, except that the Bu-Flu patients were older, more often had unrelated donors and had a shorter follow-up. A greatly improved outcome in the Bu-Flu group is unlikely to be explained by improved supportive care during this time period. Overall, the data support replacing BuCy2 with or without antithymocyte globulin (ATG) with Bu-Flu with or without rabbit-ATG for AML or MDS. We further suggest that the high level of safety and fast recovery from conditioning therapy-related side effects after the Bu-Flu regimen makes it a suitable platform technology for testing additional adjuncts for improved posttransplant immune recovery and long-term disease control in patients who are at high risk of rapidly recurrent disease after alloSCT. The extremely low one-year treatment-related mortality as well as high overall and event-free survival of patients in the Bu-Flu group indicate that it is time to revisit the value of alloSCT compared with conventional maintenance chemotherapy for patients in first complete remission of AML/MDS.
PMCID: PMC4037323  PMID: 19561406
acute myeloid leukemia; allogeneic stem cell transplantation; cyclophosphamide; fludarabine; intravenous busulfan; myelodysplastic syndrome; reduced-toxicity conditioning therapy
4.  A Randomized Phase II Trial of a Preparative Regimen of Bortezomib, High Dose Melphalan, Arsenic Trioxide and Ascorbic Acid 
Cancer  2011;118(9):2507-2515.
Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan.
Among 60 patients enrolled between October 2006 and September 2007, 58 received autologous transplantation with a preparative regimen of melphalan 200 mg/m2 IV, AA 1000 mg/day IV × 7 days and ATO 0.25 mg/kg IV × 7 days. Patients were randomized to receive no bortezomib (group 1), bortezomib 1 mg/m2 × 3 doses (group 2), and bortezomib 1.5 mg/m2 × 3 doses (group 3). Primary endpoints were complete response (CR), grade 4 toxicity, and 90-day treatment-related mortality (TRM). Secondary endpoints were progression-free (PFS) and overall survival (OS).
Median follow-up in all surviving patients was 36 months (range 20–43). CR rates in groups 1, 2 and 3 were 20%, 10% and 10%. Grade 3–4 non-hematologic toxicities and TRM were comparable. Median OS has not been reached in the groups, while median PFS was 17.8, 17.4 and 20.7 months, respectively. PFS and OS were significantly shorter in patients with high-risk cytogenetics (p0.016 and 0.0001) and relapsed disease (p=0.0001 and 0.0001) regardless of the treatment group.
Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant improvement in CR rate, PFS or OS in the bortezomib groups.
PMCID: PMC4015116  PMID: 21887685
Autologous transplant; Myeloma; Bortezomib; Arsenic Trioxide; Melphalan
5.  Adenoviral Infections in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience 
Bone marrow transplantation  2013;48(9):1218-1223.
Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). A better understanding of AI in allo-HCT recipients can serve a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HCT at M.D. Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that, when the joint effects of all covariates were accounted for, a cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm3, and male gender were associated with a higher probability of disseminated AI. The overall survival was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months versus 28 months, respectively, p<0.001) and for patients with ALC ≤ 200/mm3 (p<0.001). Disseminated AI, in patients who received allo-HCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients.
PMCID: PMC4010139  PMID: 23503529
adenovirus; adult; allogeneic stem cell transplant; outcome; absolute lymphocyte count
6.  Propensity score based comparison of long term outcomes with 3D conformal radiotherapy (3DCRT) versus Intensity Modulated Radiation Therapy (IMRT) in the treatment of esophageal cancer 
Although 3DCRT is the worldwide standard for the treatment of esophageal cancers, IMRT improves dose conformality and reduces radiation exposure to normal tissues. We hypothesized that the dosimetric advantages of IMRT should translate to substantive benefits in clinical outcomes compared to 3DCRT.
Methods and Materials
Analysis was performed on 676 nonrandomized patients (3DCRT=413, IMRT=263) with stage Ib-IVa (AJCC 2002) esophageal cancers treated with chemoradiation at a single institution from 1998–2008. An inverse probability of treatment weighting (IPW) and inclusion of propensity score (treatment probability) as a covariate were used to compare overall survival (OS) time, time to local failure, and time to distant metastasis, while accounting for effects of other clinically relevant covariates. Propensity scores were estimated using logistic regression.
A fitted multivariate inverse probability weighted (IPW)-adjusted Cox model showed that OS time was significantly associated with several well-known prognostic factors, along with radiation modality (IMRT vs 3DCRT, HR=0.72, p<0.001). Compared to IMRT, 3DCRT patients had a significantly greater risk of dying (72.6% vs 52.9%, IPW log rank test: p<0.0001) and for local-regional recurrence (LRR) (p=0.0038). There was no difference in cancer-specific mortality (Gray’s test, p=0.86), or distant metastasis (p=0.99) between the two groups. An increased cumulative incidence of cardiac deaths was seen in the 3DCRT group (p=0.049), but most deaths were undocumented (5 year estimate: 11.7% in 3DCRT vs 5.4% in IMRT, Gray’s test, p=0.0029).
Overall survival, locoregional control, and non-cancer related deaths were significantly better for IMRT compared to 3DCRT. Although these results need confirmation, IMRT should be considered for the treatment of esophageal cancer.
PMCID: PMC3923623  PMID: 22867894
IMRT; 3D-conformal radiation therapy; chemoradiation; esophageal cancer; propensity score
8.  Evaluating Joint Effects of Induction-Salvage Treatment Regimes on Overall Survival in Acute Leukemia 
Typical oncology practice often includes not only an initial, frontline treatment, but also subsequent treatments given if the initial treatment fails. The physician chooses a treatment at each stage based on the patient’s baseline covariates and history of previous treatments and outcomes. Such sequentially adaptive medical decision-making processes are known as dynamic treatment regimes, treatment policies, or multi-stage adaptive treatment strategies. Conventional analyses in terms of frontline treatments that ignore subsequent treatments may be misleading, because they actually are an evaluation of more than front-line treatment effects on outcome. We are motivated by data from a randomized trial of four combination chemotherapies given as frontline treatments to patients with acute leukemia. Most patients in the trial also received a second-line treatment, chosen adaptively and subjectively rather than by randomization, either because the initial treatment was ineffective or the patient’s cancer later recurred. We evaluate effects on overall survival time of the 16 two-stage strategies that actually were used. Our methods include a likelihood-based regression approach in which the transition times of all possible multi-stage outcome paths are modeled, and estimating equations with inverse probability of treatment weighting to correct for bias. While the two approaches give different numerical estimates of mean survival time, they lead to the same substantive conclusions when comparing the two-stage regimes.
PMCID: PMC3762505  PMID: 24014891
Causal inference; Clinical trial; Dynamic treatment regime; Treatment policy
9.  Prior Effective Sample Size in Conditionally Independent Hierarchical Models 
Bayesian analysis (Online)  2012;7(3):10.1214/12-BA720.
Prior effective sample size (ESS) of a Bayesian parametric model was defined by Morita, et al. (2008, Biometrics, 64, 595–602). Starting with an ε-information prior defined to have the same means and correlations as the prior but to be vague in a suitable sense, the ESS is the required sample size to obtain a hypothetical posterior very close to the prior. In this paper, we present two alternative definitions for the prior ESS that are suitable for a conditionally independent hierarchical model. The two definitions focus on either the first level prior or second level prior. The proposed methods are applied to important examples to verify that each of the two types of prior ESS matches the intuitively obvious answer where it exists. We illustrate the method with applications to several motivating examples, including a single-arm clinical trial to evaluate treatment response probabilities across different disease subtypes, a dose-finding trial based on toxicity in this setting, and a multicenter randomized trial of treatments for affective disorders.
PMCID: PMC3810292  PMID: 24175005
Bayesian hierarchical model; Conditionally independent hierarchical model; Computationally intensive methods; Effective sample size; Epsilon-information prior
10.  Clofarabine±Fludarabine with Once Daily IV Busulfan as Pretransplant Conditioning Therapy for Advanced Myeloid Leukemia and MDS 
While a combination of IV busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for AML/MDS, recurrent leukemia post transplantation remains a problem. To enhance the conditioning regimen’s antileukemic effect we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Busulfan (Bu) in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT); Patients were adaptively randomized as follows: Arm I - Clo:Flu 10:30 mg/m2, Arm II - 20:20 mg/m2, Arm III - 30:10 mg/m2, and Arm IV - single-agent Clo at 40 mg/m2. The nucleoside analog(s) were/was infused over one hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily AUC of 6,000 μMol-min +/− 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females with a median age of 45 years (range: 6-59). Nine patients had CML (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first CP: 4). Forty two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second CR and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft vs host disease- (GVHD) prophylaxis was tacrolimus and mini-MTX, and those who had an unrelated or one Ag-mismmatched donor received low-dose rabbit-ATG (Thymoglobulin™). RESULTS: All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival of 23 months. Marrow and blood (T-cell) chimerism studies at day +100 revealed that both in the lower dose Clo groups (groups 1+2) and the higher dose Clo groups (groups 3+4) the patients had a median of 100% donor (T-cell)-derived DNA. There has been no secondary graft failure. In the first 100 days one patient died of pneumonia, and one of liver GVHD. We conclude that 1) Clo±Flu with IV Bu as pretranslant conditioning is safe in high-risk myeloid leukemia patients, 2) Clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia, and 3) the median overall survival (OS) of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo±Flu with IV Bu as pretransplant conditioning therapy are warranted.
PMCID: PMC3760472  PMID: 20946966
Clofarabine; Fludarabine; IV Busulfan; CML; AML; MDS; Allogeneic Stem Cell Transplantation
11.  Adaptive Randomization to Improve Utility-Based Dose-Finding with Bivariate Ordinal Outcomes 
A sequentially outcome-adaptive Bayesian design is proposed for choosing the dose of an experimental therapy based on elicited utilities of a bivariate ordinal (toxicity, efficacy) outcome. Subject to posterior acceptability criteria to control the risk of severe toxicity and exclude unpromising doses, patients are randomized adaptively among the doses having posterior mean utilities near the maximum. The utility increment used to define near-optimality is non-increasing with sample size. The adaptive randomization uses each dose’s posterior probability of a set of good outcomes, defined by a lower utility cut-off. Saturated parametric models are assumed for the marginal dose-toxicity and dose-efficacy distributions, allowing the possible requirement of monotonicity in dose, and a copula is used to obtain a joint distribution. Prior means are computed by simulation using elicited outcome probabilities, and prior variances are calibrated to control prior effective sample size and obtain a design with good operating characteristics. The method is illustrated by a phase I/II trial of radiation therapy for children with brain stem gliomas.
PMCID: PMC3385658  PMID: 22651115
Adaptive design; Bayesian design; Clinical trial; Dose-finding; Epsilon-greedy algorithm; Phase I/II clinical trial; Utility
12.  Discussion on “A Hybrid Selection and Testing Procedure with Curtailment for Comparative Clinical Trials” by Elena M. Buzaianu and Pinyuen Chen 
Sequential analysis  2009;28(1):41-43.
Buzaianu and Chen apply strong curtailment to modify the two-stage select-and-test clinical trial design proposed by Thall et al. (1988). The modification reduces the expected sample size while maintaining overall power but requires continuous monitoring in stage 1. I will review the history of this type of design and discuss practical issues related to the use of strong curtailment that arise in trial conduct.
PMCID: PMC2900801  PMID: 20622929
Clinical trials; Generalized power; Phase II-III design
13.  A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity 
The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial design.
PMCID: PMC3249838  PMID: 22228921
Bayesian design; clinical trial; phase II/III design; treatment selection
14.  Optimizing the Concentration and Bolus of a Drug Delivered by Continuous Infusion 
Biometrics  2011;67(4):1638-1646.
We consider treatment regimes in which an agent is administered continuously at a specified concentration until either a response is achieved or a predetermined maximum infusion time is reached. Response is an event defined to characterize therapeutic efficacy. A portion of the maximum planned total amount administered is given as an initial bolus. For such regimes, the amount of the agent received by the patient depends on the time to response. An additional complication when response is evaluated periodically rather than continuously is that the response time is interval censored. We address the problem of designing a clinical trial in which such response time data and a binary indicator of toxicity are used together to jointly optimize the concentration and the size of the bolus. We propose a sequentially adaptive Bayesian design that chooses the optimal treatment for successive patients by maximizing the posterior mean utility of the joint efficacy-toxicity outcome. The methodology is illustrated by a trial in which tissue plasminogen activator is infused intra-arterially as rapid treatment for acute ischemic stroke.
PMCID: PMC3137757  PMID: 21401568
Adaptive design; Bayesian design; Clinical trial; Continuous infusion; Phase I/II clinical trial; Stroke
15.  Defining and Ranking Effects of Individual Agents Based On Survival Times of Cancer Patients Treated with Combination Chemotherapies 
Statistics in medicine  2011;30(15):1777-1794.
An important problem in oncology is comparing chemotherapy (chemo) agents in terms of their effects on survival or progression free survival time. When the goal is to evaluate individual agents, a difficulty commonly encountered with observational data is that many patients receive a chemo combination including two or more agents. Because agents given in combination may interact, quantifying the contribution of each individual agent to the combination’s overall effect is problematic. Still, if on average combinations including a particular agent confer longer survival, then that agent may be considered superior to agents whose combinations confer shorter survival. Motivated by this idea, we propose a definition of individual agent effects based on observational survival data from patients treated with many different chemo combinations. We define an individual agent effect as the average of the effects of the chemo combinations that include the agent. Similarly, we define the effect of each pair of agents as the average of the effects of the combinations including the pair. Under a Bayesian regression model for survival time in which the chemo combination effects follow a hierarchical structure, these definitions are used as a basis for estimating the posterior effects and ranks of the individual agents, and of all pairs of agents. The methods are illustrated by a data set arising from 224 pediatric brain tumor patients treated with over 27 different chemo combinations involving seven chemo agents.
PMCID: PMC3115413  PMID: 21590700
Bayesian analysis; Brain tumors; Hierarchical model; Ranking; Survival analysis
16.  Placental Growth Factor and Soluble c-Kit Receptor Dynamics Characterize the Cytokine Signature of Imatinib in Prostate Cancer and Bone Metastases 
To assess the hypothesis that the dynamics of plasma angiogenic and inflammatory cytokines after docetaxel chemotherapy with or without the c-kit/abl/platelet-derived growth factor receptor (PDGFR) inhibitor imatinib mesylate for prostate cancer are associated with outcome, the kinetics of 17 plasma cytokines before versus after chemotherapy were assessed and associations with progression-free survival (PFS) examined. After adjusting for multiple tests, significantly different declines in placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1 (VEGFR1), VEGF, and soluble c-kit were observed with docetaxel plus imatinib (n = 41) compared to docetaxel alone (n = 47). Based on a piecewise linear regression model for change in concentration of each cytokine as a function of the probability of change in p-PDGFR in vivo, only the dynamics of PIGF (P < 0.0001) and soluble c-kit (P < 0.0001) differed with imatinib therapy. In a Bayesian log-normal regression model for PFS, a rise in human matrix metalloproteinase 9 after docetaxel alone associated with a longer PFS. Distinct plasma angiogenic cytokines are modified by imatinib and partitioned by in vivo p-PDGFR dynamics after docetaxel chemotherapy for metastatic prostate cancer. Plasma PIGF and soluble c-kit kinetics are candidate biomarkers of imatinib effect. The predictive value of human matrix metalloproteinase 9 kinetics for docetaxel efficacy requires prospective validation.
PMCID: PMC3163391  PMID: 21323568
17.  Estimating progression-free survival in paediatric brain tumour patients when some progression statuses are unknown 
In oncology, progression-free survival time, which is defined as the minimum of the times to disease progression or death, often is used to characterize treatment and covariate effects. We are motivated by the desire to estimate the progression time distribution on the basis of data from 780 paediatric patients with choroid plexus tumours, which are a rare brain cancer where disease progression always precedes death. In retrospective data on 674 patients, the times to death or censoring were recorded but progression times were missing. In a prospective study of 106 patients, both times were recorded but there were only 20 non-censored progression times and 10 non-censored survival times. Consequently, estimating the progression time distribution is complicated by the problems that, for most of the patients, either the survival time is known but the progression time is not known, or the survival time is right censored and it is not known whether the patient’s disease progressed before censoring. For data with these missingness structures, we formulate a family of Bayesian parametric likelihoods and present methods for estimating the progression time distribution. The underlying idea is that estimating the association between the time to progression and subsequent survival time from patients having complete data provides a basis for utilizing covariates and partial event time data of other patients to infer their missing progression times. We illustrate the methodology by analysing the brain tumour data, and we also present a simulation study.
PMCID: PMC3298417  PMID: 22408277
Latent variables; Missingness at random; Missing values; Survival analysis
18.  Neoadjuvant Paclitaxel, Ifosfamide, and Cisplatin Chemotherapy for Metastatic Penile Cancer: A Phase II Study 
Journal of Clinical Oncology  2010;28(24):3851-3857.
Men with penile squamous cell carcinoma and regional lymph node involvement have a low probability of survival with lymphadenectomy alone. A multimodal approach to treatment is desirable for such patients. We performed a phase II study of neoadjuvant chemotherapy with the objective of determining the response rate, time to progression (TTP), and overall survival (OS) among patients with bulky adenopathy.
Patients and Methods
Eligible patients had stage N2 or N3 (stage III or stage IV) penile cancer without distant metastases. Neoadjuvant treatment (four courses every 3-4 weeks) consisted of paclitaxel 175 mg/m2 administered over 3 hours on day 1; ifosfamide 1,200 mg/m2 on days 1 to 3; and cisplatin 25 mg/m2 on days 1 to 3. Clinical and pathologic responses were assessed, and patient groups were compared for TTP and OS.
Thirty men received chemotherapy of whom 15 (50.0%) had an objective response and 22 (73.3%) subsequently underwent surgery. Three patients had no remaining tumor on histopathology. Nine patients (30.0%) remained alive and free of recurrence (median follow-up, 34 months; range, 14-59 months), and two patients died of other causes without recurrence. Improved TTP and OS were significantly associated with a response to chemotherapy (P < .001 and P = .001, respectively), absence of bilateral residual tumor (P = .002 and P = .017, respectively), and absence of extranodal extension (P = .001 and P = .004, respectively) or skin involvement (P = .009 and P = .012, respectively).
The neoadjuvant regimen of paclitaxel, ifosfamide, and cisplatin induced clinically meaningful responses in patients with bulky regional lymph node metastases from penile cancer.
PMCID: PMC2940402  PMID: 20625118
19.  Determining the Effective Sample Size of a Parametric Prior 
Biometrics  2007;64(2):595-602.
We present a definition for the effective sample size of a parametric prior distribution in a Bayesian model, and propose methods for computing the effective sample size in a variety of settings. Our approach first constructs a prior chosen to be vague in a suitable sense, and updates this prior to obtain a sequence of posteriors corresponding to each of a range of sample sizes. We then compute a distance between each posterior and the parametric prior, defined in terms of the curvature of the logarithm of each distribution, and the posterior minimizing the distance defines the effective sample size of the prior. For cases where the distance cannot be computed analytically, we provide a numerical approximation based on Monte Carlo simulation. We provide general guidelines for application, illustrate the method in several standard cases where the answer seems obvious, and then apply it to some nonstandard settings.
PMCID: PMC3081791  PMID: 17764481
Bayesian analysis; Computationally intensive methods; Effective sample size; Epsilon-information prior; Parametric prior distribution
20.  Bayesian Models and Decision Algorithms for Complex Early Phase Clinical Trials 
An early phase clinical trial is the first step in evaluating the effects in humans of a potential new anti-disease agent or combination of agents. Usually called “phase I” or “phase I/II” trials, these experiments typically have the nominal scientific goal of determining an acceptable dose, most often based on adverse event probabilities. This arose from a tradition of phase I trials to evaluate cytotoxic agents for treating cancer, although some methods may be applied in other medical settings, such as treatment of stroke or immunological diseases. Most modern statistical designs for early phase trials include model-based, outcome-adaptive decision rules that choose doses for successive patient cohorts based on data from previous patients in the trial. Such designs have seen limited use in clinical practice, however, due to their complexity, the requirement of intensive, computer-based data monitoring, and the medical community’s resistance to change. Still, many actual applications of model-based outcome-adaptive designs have been remarkably successful in terms of both patient benefit and scientific outcome. In this paper, I will review several Bayesian early phase trial designs that were tailored to accommodate specific complexities of the treatment regime and patient outcomes in particular clinical settings.
PMCID: PMC3035990  PMID: 21318084
Adaptive design; Bayesian design; Clinical trial; Dose-finding; Phase I trial; Phase I/II trial
21.  Evaluating the Impact of Prior Assumptions in Bayesian Biostatistics 
Statistics in biosciences  2010;2(1):1-17.
A common concern in Bayesian data analysis is that an inappropriately informative prior may unduly influence posterior inferences. In the context of Bayesian clinical trial design, well chosen priors are important to ensure that posterior-based decision rules have good frequentist properties. However, it is difficult to quantify prior information in all but the most stylized models. This issue may be addressed by quantifying the prior information in terms of a number of hypothetical patients, i.e., a prior effective sample size (ESS). Prior ESS provides a useful tool for understanding the impact of prior assumptions. For example, the prior ESS may be used to guide calibration of prior variances and other hyperprior parameters. In this paper, we discuss such prior sensitivity analyses by using a recently proposed method to compute a prior ESS. We apply this in several typical Bayesian biomedical data analysis and clinical trial design settings. The data analyses include cross-tabulated counts, multiple correlated diagnostic tests, and ordinal outcomes using a proportional-odds model. The study designs include a phase I trial with late-onset toxicities, a phase II trial that monitors event times, and a phase I/II trial with dose-finding based on efficacy and toxicity.
PMCID: PMC2910452  PMID: 20668651
Bayesian biostatistics; Bayesian clinical trial design; Bayesian analysis; effective sample size; parametric prior distribution
22.  Some Geometric Methods for Constructing Decision Criteria Based On Two-Dimensional Parameters 
This paper reviews two types of geometric methods proposed in recent years for defining statistical decision rules based on 2-dimensional parameters that characterize treatment effect in a medical setting. A common example is that of making decisions, such as comparing treatments or selecting a best dose, based on both the probability of efficacy and the probability toxicity. In most applications, the 2-dimensional parameter is defined in terms of a model parameter of higher dimension including effects of treatment and possibly covariates. Each method uses a geometric construct in the 2-dimensional parameter space based on a set of elicited parameter pairs as a basis for defining decision rules. The first construct is a family of contours that partitions the parameter space, with the contours constructed so that all parameter pairs on a given contour are equally desirable. The partition is used to define statistical decision rules that discriminate between parameter pairs in term of their desirabilities. The second construct is a convex 2-dimensional set of desirable parameter pairs, with decisions based on posterior probabilities of this set for given combinations of treatments and covariates under a Bayesian formulation. A general framework for all of these methods is provided, and each method is illustrated by one or more applications.
PMCID: PMC2906756  PMID: 18617987
Bayesian statistics; Clinical trials; Dose-finding; Indifference set; Medical decision making; Phase II clinical trial; Trade-offs
23.  Utility-Based Optimization of Combination Therapy Using Ordinal Toxicity and Efficacy in Phase I/II Trials 
Biometrics  2009;66(2):532-540.
An outcome-adaptive Bayesian design is proposed for choosing the optimal dose pair of a chemotherapeutic agent and a biologic agent used in combination in a phase I/II clinical trial. Patient outcome is characterized as a vector of two ordinal variables accounting for toxicity and treatment efficacy. A generalization of the Aranda-Ordaz model (1983, Biometrika 68, 357–363) is used for the marginal outcome probabilities as functions of dose pair, and a Gaussian copula is assumed to obtain joint distributions. Numerical utilities of all elementary patient outcomes, allowing the possibility that efficacy is inevaluable due to severe toxicity, are obtained using an elicitation method aimed to establish consensus among the physicians planning the trial. For each successive patient cohort, a dose pair is chosen to maximize the posterior mean utility. The method is illustrated by a trial in bladder cancer, including simulation studies of the method’s sensitivity to prior parameters, the numerical utilities, correlation between the outcomes, sample size, cohort size and starting dose pair.
PMCID: PMC2893272  PMID: 19673865
Adaptive design; Bayesian design; Clinical trial; Combination dose-finding; Utility
24.  A Bayesian hierarchical mixture model for platelet derived growth factor receptor phosphorylation to improve estimation of progression-free survival in prostate cancer 
Advances in understanding the biological underpinnings of many cancers have led increasingly to the use of molecularly targeted anti-cancer therapies. Because the platelet-derived growth factor receptor (PDGFR) has been implicated in the progression of prostate cancer bone metastases, it is of great interest to examine possible relationships between PDGFR inhibition and therapeutic outcomes. Here, we analyze the association between change in activated PDGFR (p-PDGFR) and progression free survival (PFS) time based on large within-patient samples of cell-specific p-PDGFR values taken before and after treatment from each of 88 prostate cancer patients. To utilize these paired samples as covariate data in a regression model for PFS time, and because the p-PDGFR distributions are bimodal, we first employ a Bayesian hierarchical mixture model to obtain a deconvolution of the pre-treatment and post-treatment within-patient p-PDGFR distributions. We evaluate fits of the mixture model and a non-mixture model that ignores the bimodality by using a supnorm metric to compare the empirical distribution of each p-PDGFR data set with the corresponding fitted distribution under each model. Our results show that first using the mixture model to account for the bimodality of the within-patient p-PDGFR distributions, and then using the posterior within-patient component mean changes in p-PDGFR so obtained as covariates in the regression model for PFS time provides an improved estimation.
PMCID: PMC2853262  PMID: 20390057
Bayesian analysis; Survival analysis; Markov chain Monte Carlo; Platelet derived growth factor receptor; Prostate cancer
25.  Selenium and Vitamin E: Cell Type– and Intervention-Specific Tissue Effects in Prostate Cancer 
Secondary analyses of two randomized, controlled phase III trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation.
Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 μg of selenium, 400 IU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided.
The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [CI] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% CI = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% CI = 0.7 to 41.8; P = .051).
We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type– and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications.
PMCID: PMC2734116  PMID: 19244175

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