Phase II, Multicenter, Randomized Trial of Docetaxel plus Prednisone with or Without Cediranib in Men with Chemotherapy-Naive Metastatic Castrate-Resistant Prostate Cancer.

LESSONS LEARNED: The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. BACKGROUND: Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. RESULTS: The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). CONCLUSION: Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.

A phase II trial of ganetespib, a heat shock protein 90 Hsp90) inhibitor, in patients with docetaxel-pretreated metastatic castrate-resistant prostate cancer (CRPC)-a prostate cancer clinical trials consortium (PCCTC) study.

INTRODUCTION: Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. METHODS: Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. RESULTS: Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. CONCLUSIONS: Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

High incidence of severe acute graft-versus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients.

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients.

PURPOSE: Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. METHODS AND MATERIALS: Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. RESULTS: Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). CONCLUSIONS: Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate-Resistant Prostate Cancer.

Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T. SIGNIFICANCE: Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.

Anti-thymocyte globulin (thymoglobulin), tacrolimus, and sirolimus as acute graft-versus-host disease prophylaxis for unrelated hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in patients undergoing unrelated hematopoietic stem cell transplantation. We prospectively evaluated the efficacy of intermediate-dose rabbit anti-thymocyte globulin (Thymoglobulin® a total of 4.5 mg/kg given over days -3, -2, and -1) in combination with tacrolimus and sirolimus for the prevention of aGVHD. We enrolled 47 recipients who underwent unrelated hematopoietic stem cell transplantation. Patients received daily granulocyte colony-stimulating factor starting on day +6 until neutrophil engraftment (median duration, 11 days; range, 9-15 days). Twenty-two patients received HLA 8/8 and 25 received 7/8 matched grafts, respectively. The median follow-up duration was 23.6 months (range, 18.8-27.9 months). The cumulative incidence of grade II to IV aGVHD was 23.4% (95% confidence interval, 12.4-36.3). At 2-year follow-up, the cumulative incidence of nonrelapse mortality was 31.9%, cumulative incidence of relapse was 24.6%, and cumulative incidence of chronic GVHD was 33%. Progression-free survival at 1 year was 54%, with a median of 17.7 months. Overall survival at 1 year was 65%, with no median reached. These results suggest that the combination of Thymoglobulin, tacrolimus, and sirolimus in patients undergoing unrelated hematopoietic stem cell transplantation is well tolerated and associated with a low incidence and severity of aGVHD and chronic graft-versus-host disease.

MRI- and PET-Based Assessment of Radiological and Clinical Factors Associated With Cervical Cancer Response to External Beam Radiation Therapy.

Introduction In the era of MRI-guided external beam radiation therapy (EBRT), complete radiological response (CR) is often seen in cervical cancer (CC) with 4-6 weeks of chemotherapy and EBRT. The clinical and radiological factors associated with this observation were investigated in this study. Materials and methods One hundred and twenty-four CC patients treated with concurrent chemotherapy, EBRT, and brachytherapy (BT) from January 2008 to July 2015 were retrospectively screened. Initial primary gross tumor volume (GTVINITIAL) was estimated after contouring on a planning CT scan registered with pre-EBRT PET and MRI. The maximum standardized uptake value (SUV) of GTVINITIAL from each PET scan report was collected. Spearman's rank correlation coefficient (rho) values were calculated to assess the relationships among age, tumor size, and SUV. Tumor radiological response during EBRT prior to BT was calculated by contouring the final primary gross tumor volume (GTVFINAL) using MRI obtained prior to BT. CR rates during EBRT were estimated from GTVINITIAL and GTVFINAL and compared by the level of various factors using Fisher's exact test (two-sided).  Results Forty-eight patients met the inclusion criteria of the study with a median age of 50 years. The median GTVINITIAL was 82 cc. The median SUV was 14.9. A significant correlation was seen between SUV and GTVINITIAL with a larger tumor size associated with a higher SUV. CR rates were numerically higher for patients who were aged <50 years, or with >37.5 Gy radiation dose at or before the second MRI, or with GTVINITIAL <100 cc, or with no nodes involved or with stages IB or IIA. Conclusions Our study identified higher CC primary tumor CR rates during EBRT in younger patients (<50) with smaller tumors (100 cc) without nodal involvements as well as a positive correlation between PET FDG (18F-fluorodeoxyglucose)-SUV and CC primary tumor size.

Safety and efficacy of molecularly targeted agents in patients with metastatic kidney cancer with renal dysfunction.

Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and the efficacy of these agents in patients with renal insufficiency (RI). This is clinically relevant, especially as about one-third of patients with mRCC have renal dysfunction. The primary objective was to assess the safety and efficacy of targeted agents in patients with mRCC with RI. Medical records of patients with mRCC at Wayne State University, started on sunitinib, temsirolimus, everolimus, or bevacizumab, were reviewed. Patients with a calculated creatinine clearance of less than or equal to 60 ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function. RI was observed in 33% of our patients with mRCC. The incidence of toxicities, responses, time to progression, and overall survival were not significantly different in patients with RI compared with patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with mammalian target of rapamycin inhibitors, than did patients with normal renal function. In conclusion, RI was commonly observed in our patients with mRCC. Molecularly targeted agents are well tolerated, and efficacy seems to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for patients receiving sunitinib and bevacizumab.

Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation.

Given the limited information on Clostridium difficile infection (CDI) during hematopoietic stem cell transplantation (HSCT), we examined the recent epidemiology of CDI in HSCT recipients at our institution. During the two-yr retrospective study period (2005-2006), 361 transplants were performed: 60% allogeneic and 40% autologous. Among all hospitalized patients in a non-outbreak setting, CDI rates in HSCT recipients were ninefold higher than those in general patients and 1.4-fold higher than those in patients with cancer (24.0 vs. 2.6 vs. 16.8/10,000 patient-days respectively). Sixty-two episodes of CDI occurred in 51 (14%) HSCT recipients: 39 (18%) allogeneic vs. 12 (8%) autologous (p = 0.01). Almost half of CDI episodes occurred within 30 d post-HSCT and 22% before HSCT. Clostridium difficile toxin assay was initially positive in 28% of the first, 31% of the second and 27% of the third stool samples tested. All but one patient responded to therapy with metronidazole or vancomycin. Severe CDI occurred in one patient and recurrent CDI in two patients. CDI is common during HSCT especially in allogeneic transplants during the peri-HSCT period. Prospective studies to better define the epidemiology and identify unique risk factors for CDI and more accurate tests to confirm the diagnosis in this population are needed.

A Phase 1 study Combining Pexidartinib, Radiation Therapy, and Androgen Deprivation Therapy in Men With Intermediate- and High-Risk Prostate Cancer.

PURPOSE: This study aimed to evaluate a combination of radiation therapy (RT), androgen deprivation therapy (ADT), and pexidartinib (colony-stimulating factor 1 receptor [CSF1R]) inhibitor in men with intermediate- and high-risk prostate cancer. CSF1R signaling promotes tumor infiltration and survival of tumor-associated macrophages, which in turn promote progression and resistance. Counteracting protumorigenic actions of tumor-associated macrophages via CSF1R inhibition may enhance therapeutic efficacy of RT and ADT for prostate cancer. METHODS AND MATERIALS: In this phase 1 study, the treatment regimen consisted of pexidartinib (800 mg, administered as a split-dose twice daily) and ADT (both for a total of 6 months), and RT that was initiated at the start of month 3. RT volumes included the prostate and proximal seminal vesicles. The delivered dose was 7920 cGy (180 cGy per fraction) using intensity modulated RT with daily image guidance for prostate localization. The primary objective was to identify the maximum tolerated dose based on dose-limiting toxicities. RESULTS: All 4 enrolled patients who were eligible to receive RT had T1 stage prostate cancer, 2 were intermediate risk, and 2 were high risk. The median age was 62.5 years, and the prostate-specific antigen levels were in the range 6.4 to 10.7 ng/mL. The patients' individual Gleason scores were 3 + 3, 4 + 3, 4 + 4, and 4 + 5. All 4 patients reported ≥1 adverse events before RT. Grade 1 hypopigmentation was observed in 1 patient, and grade 3 pulmonary embolus in another. One patient experienced fatigue and joint pain, and another elevated amylase and pruritus (all grade 3 toxicities). Five of the 6 adverse events noted in 3 patients were all grade 3 toxicities attributable to pexidartinib, qualifying as dose-limiting toxicities and ultimately resulting in the study closure. CONCLUSIONS: The combination was not well tolerated and does not warrant further investigation in men with intermediate- and high-risk prostate cancer.

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial.

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706.

Should all prostate needle biopsy Gleason score 4 + 4 = 8 prostate cancers be high risk? Implications for shared decision-making and patient counselling.

OBJECTIVES: To estimate the probability of downgrading to Gleason score ≤7 at radical prostatectomy for men with a prostate needle biopsy demonstrating Gleason score 8 (4 + 4). METHODS: This is a retrospective review of men with Gleason score 8 (4 + 4) prostate cancer on needle biopsy who then underwent a radical prostatectomy at the Karmanos Cancer Institute or the University of Michigan. Men with any pattern 5 on the diagnostic biopsy were excluded. The objective was to estimate the proportion of patients whose tumors were downgraded to Gleason score ≤7 at radical prostatectomy and to identify clinical and biopsy parameters associated with downgrading. RESULTS: Median age of our cohort was 63 years (IQR: 59, 67.5) and median follow-up was 15 months (IQR: 7, 37). Of the 105 men that met inclusion criteria, 59% (62/105) were downgraded to Gleason score ≤7 at radical prostatectomy. Having ≤2 cores demonstrating Gleason score 8, ≤50% maximal tumor involvement of any individual core positive for Gleason score 8, or the presence of Gleason pattern 3 (such as 3 + 4, 4 + 3, or 3 + 3) in other biopsy cores were all independently associated with downgrading in our multivariable model. Depending on the absence, presence, or combination of these 3 factors, patients had an estimated 6% to 82% probability of having their tumor downgraded at radical prostatectomy. CONCLUSIONS: Men with low volume Gleason 8 (4 + 4) and/or the presence Gleason pattern 3 on prostate needle biopsy often have their tumors downgraded at radical prostatectomy. The presence of these preoperative biopsy parameters could affect pretreatment counseling and impact patient management.

Meta- and pooled analysis of GSTP1 polymorphism and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A --> 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.

Phase II trial of capecitabine and weekly docetaxel for metastatic castrate resistant prostate cancer.

PURPOSE: Synergy is observed with the combination of capecitabine and docetaxel due to docetaxel mediated up-regulation of thymidine phosphorylase. A phase II trial was performed with the combination for metastatic, castrate resistant prostate cancer. MATERIALS AND METHODS: Eligible patients had metastatic, castrate resistant prostate cancer, no prior chemotherapy for metastatic disease and normal organ function. Docetaxel (36 mg/m(2) per week intravenously) on days 1, 8 and 15, and capecitabine (1,250 mg/m(2) per day in 2 divided doses) on days 5 to 18 were administered in 28-day cycles. The response was assessed every 2 cycles. Biomarker correlative studies were performed on blood dihydropyrimidine dehydrogenase, and the thymidine phosphorylase-to-dihydropyrimidine dehydrogenase and thymidine synthase-to-dihydropyrimidine dehydrogenase ratios in available prostate tumor tissue. RESULTS: A total of 30 patients with a median age of 69 years were enrolled in the study. We noted bone pain in 21 patients (70%), Gleason score 8 or higher in 18 (60%), measurable disease progression in 9, bone scan progression in 18 and prostate specific antigen progression in 22. Grade 3 or 4 neutropenia was seen in 3 patients and grade 3 hand-foot syndrome was found in 2. No treatment related deaths occurred. A prostate specific antigen response of 50% or greater decrease was observed in 22 patients (73%), of whom 9 (30%) had 90% or greater decrease. A partial response was noted in 5 of 9 patients (56%) with measurable disease. Median time to progression was 6.7 months (90% CI 4.2-7.7) and median overall survival was 22.0 months (90% CI 18.4-25.3). CONCLUSIONS: The combination was well tolerated and it demonstrated favorable response rates with durable remission and survival outcomes.

The use of 3'-deoxy-3'-18F-fluorothymidine (FLT) PET in the assessment of long-term survival in breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. METHODS: This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into "responder" and "non-responder" groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. RESULTS: 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them "responders". The remaining nine patients were "non-responders" to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. CONCLUSION: Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer.

PURPOSE: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured. RESULTS: Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range, -85 to -5%, n = 11) and -41% (range, -60 to -25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. CONCLUSIONS: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Retrospective review of cancer patients > or =80 years old treated with chemotherapy at a comprehensive cancer center.

CONTEXT: The percentage of cancer patients > or =80 years old is expected to increase in the next few years. However data on the use of chemotherapy in these patients are limited. OBJECTIVE: We conducted a retrospective review to define the profile of patients > or =80 years old who received chemotherapy at our center and assess their survival. DESIGN, SETTING AND PARTICIPANTS: Patients > or =80 years treated with chemotherapy between 1 January 2000 and 31 December 2004 were included in this analysis. RESULTS: Of the 4689 patients treated with chemotherapy over the 5-year period, 133 patients (3%) were > or =80 years old. The median age was 83 years. 61% were females and 39% were males. 16% had hematologic tumors and 84% had solid tumors. Gynecological (32%) and aerodigestive cancers (27%) were the most common sites and lung cancer (22%) was the most common cancer. During the first regimen, 512 cycles of chemotherapy were delivered with a median of 3 cycles (range: 1-24 cycles). 49% received single and 51% multidrug regimens. Carboplatin was the most common single agent and carboplatin and paclitaxel was the most common combination among solid tumor patients. 19% of solid tumor patients received radiation with chemotherapy. The 1-year survival among hematologic cancer and solid tumor patients was 65% and 48%, respectively. Stage of disease was the only statistically significant factor predicting survival. CONCLUSIONS: In cancer patients > or =80 years old selected for chemotherapy, both single and multi-agent therapy appeared to be feasible.

Topotecan weekly bolus chemotherapy for relapsed platinum-sensitive ovarian and peritoneal cancers.

OBJECTIVE: Topotecan at a dose of 1.5 mg/m(2) on days 1 to 5 of a 21-day cycle is an approved therapy for recurrent ovarian cancer. However, heavily pretreated patients may be predisposed to hematologic adverse events. This prospective study, therefore, investigates the safety and efficacy of an alternate weekly schedule of topotecan in patients with recurrent ovarian or peritoneal cancer. METHODS: Patients with potentially platinum-sensitive recurrent ovarian or peritoneal cancer were treated with 4.0 mg/m(2) weekly topotecan as tolerated until disease progression. Antitumor response and safety were assessed. Dose reductions, delays, or omissions were implemented for grades 3-4 adverse events. RESULTS: Of the 41 enrolled patients (median age, 62 years; range, 42 to 82 years), 39 patients had ovarian cancer, and 2 patients had peritoneal cancer. The median platinum-free interval was 11.7 months. A median of 9 topotecan cycles (range, 1 to 45 doses) was administered. Weekly topotecan was well tolerated: 7 (17%) patients had grades 3-4 neutropenia, and 9 (22%) had grades 3-4 fatigue. No grade 4 thrombocytopenia or anemia was reported. Of 38 response-evaluable patients, 1 (3%) had a complete response, 8 (21%) had a partial response, 16 (42%) had stable disease, and 13 (34%) had progressive disease. CONCLUSIONS: Weekly topotecan was well tolerated in patients with platinum-sensitive ovarian or peritoneal cancer at first relapse, with a hematologic profile that compared favorably with that of the 5-day topotecan regimen. Moreover, antitumor activity was similar to that reported for the 5-day regimen.

Overexpression of the Pluripotent Stem Cell Marker Podocalyxin in Prostate Cancer.

BACKGROUND/AIM: Podocalyxin, a member of the CD34 family of cell surface sialomucins, is overexpressed in human embryonal carcinoma cell lines, as well as in several cancer types, and is associated with poor prognosis. Podocalyxin variants are associated with an increased risk and aggressiveness of prostate cancer. Herein podocalyxin protein expression in prostate cancer was characterized. MATERIALS AND METHODS: Expression of podocalyxin as well as of TRA-1-60 and TRA-1-81 antigens was assessed immunohistochemically in 84 radical prostatectomy specimens and in adjacent normal tissues. RESULTS: Podocalyxin expression and H-scores were considerably higher in prostate tumors compared to normal tissues. High TRA-1-60 and TRA-1-81 staining was detected, however, in a much smaller percentage of prostate tumors, while their expression and H-scores were low in normal tissues. Similar trends for all three proteins were observed in prostatic intraepithelial neoplasia. CONCLUSION: Overexpression of podocalyxin in prostate cancer renders the protein a putative immunohistochemical marker of prostate cancer that may contribute to stratification of patients for optimal treatment.

Phase I Trial of the Combination of Docetaxel, Prednisone, and Pasireotide in Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Pasireotide (SOM230; Novartis Inc, Basel, Switzerland) is a multitargeted somatostatin receptor analogue likely to treat the neuroendocrine, and docetaxel resistant components within metastatic castrate-resistant prostate cancer (mCRPC). This phase I trial tested the combination of pasireotide, docetaxel, and prednisone in pretreated mCRPC. PATIENTS AND METHODS: Chemotherapy naive mCRPC patients received docetaxel 75 mg/m2 intravenously every 21 days and pasireotide intramuscularly every 28 days at escalating dose levels of 40, 60, and 80 mg. Maximum tolerated dose and recommended phase II dose (RP2D) were assessed. RESULTS: Eighteen patients were enrolled with a median age of 65 (range, 49-75) years, and pretherapy prostate-specific antigen of 259.9 ng/mL. The dose-limiting toxicities were Grade 4 hyperglycemia unresponsive to therapy and Grade 4 neutropenia lasting for > 7 days in 1 patient each occurring at the 80-mg dose level of pasireotide. The RP2D was determined at 60 mg every 28 days. Four patients at the 60 mg dose had Grade 3 or 4 hyperglycemia, which responded adequately to therapy. Median time to progression and survival were 7.2 and 18.3 months, respectively. Three of 6 patients with circulating tumor cells ≥5 converted to circulating tumor cells < 5 post therapy. The insulin like growth factor-1 levels revealed a median 51% decrease after therapy. The neuron-specific enolase and chromogranin did not show any marked change. CONCLUSION: The addition of pasireotide to docetaxel and prednisone is clinically feasible at a dose level of 60 mg every 28 days. The combination showed potential for clinical efficacy but needs to be compared with the standard docetaxel and prednisone regimen.