bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of hypersensitivity reactions to oxaliplatin with cumulative dose of oxaliplatin.
Authors: Saito M. , Yoshino T. , Kawamoto Y. , Bando H. , Arimura Y. , Fuse N. , Tahara M. , Doi T. , Ohtsu A.
Published: February 2017

584

Background: The incidence of hypersensitivity reactions (HSRs) to oxaliplatin (L-OHP) in colorectal cancer patients (CRC) receiving the 5-fluorouracil/leucovorin plus L-OHP (FOLFOX) regimen is reported to be 10 to 17%. There are several reports of clinical features of HSRs to L-OHP, but the relationship between HSRs and the cumulative dose of L-OHP has not been clarified.

Methods: From August 2005 to July 2009, a total of 54 CRC patients who developed HSRs during treatment with mFOLFOX6 or mFOLFOX6 plus bevacizumab regimen as first-line treatment, were reviewed retrospectively. Within this patient group, sixteen patients had an L-OHP-free interval of at least three months or more. We investigated the clinical features of HSRs associated with L-OHP in our institution, and evaluated the degree to which its occurrence is dependent upon the cumulative dose of L-OHP in patients who had an interruption of L-OHP.

Results: Within the sample of 54 patients, HSRs occurred after a median treatment course number of 8 (range 2-19), and the median cumulative dose of L-OHP being 700 mg/m2 (range 170-1615). In these subjects, grade1/2/3 HSRs developed in 33/20/1 patients, respectively. Re-challenge of L-OHP combined with prophylactic agents was performed in 42 patients (78%). There were 16 patients who had an L-OHP- free interval, in whom the major reason for L-OHP withdrawal was neurotoxicity, with reintroduction because of tumor progression or recurrence. Of these 16 patients, 10 developed the first HSRs after reintroduction of L-OHP. Among these 10 patients, grade1/2/3 HSRs developed in 6/3/1 patients, respectively, and occurred at a median course number of 2.5 following re-infusion of L-OHP, or 12 treatments after the initial infusion. The median cumulative dose of L-OHP at HSRs in this patient group was 213 mg/m2 after the re-introduced infusion, and a total of 1088 mg/m2 since initial onset of treatment.

Conclusions: Our results suggest that the development of HSRs during L-OHP treatment depends on the cumulative dose from the initial administration even in patients who experienced an L-OHP-free interval.

No significant financial relationships to disclose.
Ultraradical surgery and heated intraperitoneal chemotherapy (HIPEC) as multimodal treatment of advanced colorectal cancer.
Authors: Nikolic S. , Zegarac M. , Inic M. , Martinovic A.
Published: February 2017

585

Background: Examin does agressive surgical treatment in combination with HIPEC (oxaliplatin) could increase median survial in patients with advanced stage of colorectal cancer.

Methods: Ultraradical surgery and HIPEC was applied in patients who were initialy with peritoneal carcinomatosis or infiltration in around organs. We evaluated the patients during the period 2000-2010 in this retrospective study.

Results: During 2000 and 2010 we peformed 132 ultraradical surgical procedure. All patients were treated with HIPEC (40C) using oxaliplatin (410mg/m2) in 3l of perfusat during 90 minutes. The average duration of the procedure was 5h 57 minutes.The follow up period was 72 months. 120 had Ro and 12 had R1 resection. One year survival rate was 81.25% and three year survival rate was 56.25%, six year survival rate is 40.6%.

Conclusions: Ultraradical surgery combined with HIPEC prolongs patient's survival and is considered to be a safe procedure if performed by the experience team of oncological surgeons.

No significant financial relationships to disclose.
Vitamin K1 cream in the management of skin rash during anti-EGFR monoclonal antibody (mAb) treatment in patients with metastatic cancer: First analysis of an observational Italian study.
Authors: Pinto C. , Barone C. , Martoni A. , Di Tullio P. , Orlandi A. , Di Fabio F. , Cassano A. , Rojas Llimpe F. L. , Amoroso A. , Pini S.
Published: February 2017

594

Background: Cutaneous toxicity, and especially skin rash, is a predictable side- effect of anti-EGFR mAb therapy. Preclinical studies have shown that vitamin K1 reactivated EGFR-mediated signal transduction after inhibition via EGFR receptor antagonists. The aim of this study was to evaluate the impact of vitamin K1 cream in skin rash management.

Methods: In two Italian Oncology Centers sequential pts at the first therapy with cetuximab/panitumumab for metastatic cancer were treated with vitamin K1 cream at the first onset of grade ≥2 skin rash. Topical treatment with vitamin K1 (phytomenadione 0.1%) cream twice/die was administered continuously until the end of anti-EGFR treatment. Skin toxicity, according to NCI-CTC v3.0 grading system, was clinically evaluated every week and in a standardized way, taking pictures of 5 different body areas. Treatment benefit was evaluated according to symptom reduction and compliance to therapy.

Results: From February to September 2010, 33 pts, 22M (66.6%) and 11F (33.4%), median age 63 years (range 27-79), were evaluated. The primary tumor site was 3 (9.1%) esophagus/stomach, 28 (84.8%) colon-rectum, 2 (6.1%) head-neck. Eighteen (54.5%) pts were treated as first-line and 15 (45.5%) were pretreated. The regimen contained cetuximab in 26 (78.7%) pts and panitumumab in 7 (21.3%). The combination regimens were platinum compounds-based in 23 (69.6%) pts, and irinotecan-based in 6 (18.2%); panitumumab was administered in monotherapy in 4 (12.2%) pts. The median time of vitamin K1 cream treatment was 24 weeks (range 6-28); the oral tetracyclines therapy was associated in 13 (39.4%) pts. The decrease in skin rash to grade 1-0 was observed in 12 (36.4%) pts, and 13 (39.4%) pts showed unchanged grade 2. The increase to grade 3 in skin rash was observed in 8 (24.2%) pts. Good skin rash symptom control was obtained in 69.2% of pts. Cetuximab/panitumumab dose reduction and treatment delays was required in 9 (27.3%) pts.

Conclusions: These preliminary results suggest a favorable impact of vitamin K1 cream in skin rash management, which should be considered in a future clinical trial.

No significant financial relationships to disclose.
The PARSC trial: A prospective study for the assessment of recurrence risk in stage II colon cancer (CC) patients using ColoPrint.
Authors: Salazar R. , Rosenberg R. , Lutke Holzik M. , Marshall J. , Van Der Hoeven J. J. , Glimelius B. , Bibeau F. , Stork-Sloots L. , Bender R. A. , Tabernero J.
Published: February 2017

602

Background: Clinical trials have not yet shown convincingly if adjuvant chemotherapy is justified for stage II CC patients of whom 25% are at risk of recurrence. An 18-gene expression profile, ColoPrint, has been developed for identifying CC cancer patients more likely to develop recurrent disease and who would be candidates for adjuvant chemotherapy. The gene signature has been validated in independent cohorts of 206 CC patients and in in-silico datasets (Salazar et al, JCO in press). The profile classified 63.2% of the stage II patients (n=134) as low risk. The HR for relapse free survival (RFS) was 3.34 (p=0.017) with a 5-year RFS rate of 90.9% (95%CI, 84.0 -97.8%) for low risk patients and 73.9% (95%CI, 59.2-88.6%) for high risk patients. Moreover, the profile stratified patients independent of ASCO clinical risk factors.

Methods: A prospective trial, PARSC (Prospective Study for the Assessment of Recurrence Risk in Stage II CC Patients Using ColoPrint) has been initiated. The main objectives are: (1) determine risk assessment by ColoPrint profile versus clinical parameters based on local protocol and ASCO high-risk recommendations in stage II patients; (2) establish proportion of ′good prognosis′ and ′poor prognosis profile′ in various countries; and (3) validate the power of risk assessment and compare performance of ColoPrint and clinical risk assessment in estimating 3 year relapse rate. Inclusion criteria: age ≥ 18 years, adenocarcinoma of the colon, stage II,no neoadjuvant systemic therapy, no synchronous tumors, fresh tumor sample, and written informed consent. The treatment of the patient is at the discretion of the physician.

Results: The trial started in Sept. 2008 with currently 26 participating sites in 11 countries. So far, 223 stage II patients have been enrolled of whom 183 are eligible. 11 patients were rejected because of prior malignancies; 24 patients were rejected based on low tumor content of the sample (< 30% tumor cells), 3 patients had rectal cancer and 2 synchronous tumor.

Conclusions: The aim is to enroll 600 stage II patients to differentiate between 3 year relapse- free survival predicted by ColoPrint versus clinical factors.

[Table: see text]
Concurrent chemoradiotherapy with cetuximab plus twice-weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal squamous cell carcinoma.
Authors: Lin C. , Hsu C. , Cheng J. C. , Yen C. , Shiah H. , Lee J. , Wang H. , Yeh K. , Cheng A. , Lee Y.
Published: February 2017

79

Background: We investigated the efficacy and safety of adding cetuximab into twice-weekly paclitaxel/cisplatin-based concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Methods: Patients with operable ESCC (T3N0-1M0 or T1-3N1M0 or M1a) were treated with paclitaxel (35 mg/m2 1 h on days 1 and 4/week), cisplatin (15 mg/m2 1 h on days 2 and 5/week), cetuximab (400 mg/m2 2 h on day -5, then 250 mg/m2 2 h on day 3/week) and radiotherapy (2 Gy on days 1-5/week). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated for all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a radiation dose of 60-66 Gy.

Results: Sixty-two patients with ESCC were enrolled, and the majority had T3N1M0 or M1a tumors by endoscopic ultrasonographic staging (94%). All patients received CCRT to 40 Gy. Forty-three patients underwent surgery, and 17 patients continued definitive CCRT to 60-66 Gy. Of the scheduled doses of paclitaxel, cisplatin, and cetuximab, 80%, 79%, and 99% were given, respectively. The intent-to-treat pathological complete response rate was 24% (15/62) (95% confidence interval: 13-35%). At the median follow-up of 13.3 months, the one-year progression-free and overall survivals were 76% and 63%, respectively. The most common grade 3/4 toxic effects were leukopenia (51%), neutropenia (15%), esophagitis (19%), and infection (12%). Grade 1, 2, and 3 skin rash occurred in 59%, 36%, and 2% of patients, respectively. Grade 1, 2, 3, and 4 hypomagnesemia occurred in 14%, 5%, 0%, and 5% of patients, respectively.

Conclusions: Adding cetuximab to twice-weekly paclitaxel/cisplatin-based CCRT prior to esophagectomy is an active and tolerable treatment for locally advanced ESCC.

No significant financial relationships to disclose.
Phase II study of everolimus in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum.
Authors: Yoon D. , Ryu M. , Park Y. , Lee H. , Lee C. , Lee J. , Ryoo B. , Chang H. , Kim T. , Kang Y.
Published: February 2017

93

Background: To evaluate feasibility with activity and toxicities of everolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), in patients with advanced gastric cancer (AGC) who failed chemotherapy including both fluoropyrimidine and platinum (FP).

Methods: Fifty-four patients were enrolled between Jul 2008 and Feb 2010. Everolimus, 10 mg daily, was given until disease progression or unacceptable toxicity. Primary objective was to determine 4-month progression-free survival (PFS) and secondary objectives were to investigate response rate, toxicity and overall survival OS rate. Pre- (n = 28) and on-treatment (n = 19) tumor biopsies were evaluated for phosphorylated (p) mTOR, pS6 kinase1, pS6 and eukaryotic initiation factor 4E binding protein 1 expression.

Results: A total of 180 cycles of everolimus were administered with a median of 2 (range, 1-20) cycles in each patient. Two patients (3.7%) achieved confirmed partial response and 19 patients (35.2%) showed stable disease, resulting in a disease control rate of 38.9%. At a median follow-up duration of 8.7 months in surviving patients (range, 3.0–19.4 months), a 4-month PFS rate was 18.4% with a median PFS of 1.7 months (95% CI, 1.5-2.2 months) and a median OS time was 8.3 months (95% CI, 4.5-12.1 months). Peritoneal metastasis (Hazard ratio [HR], 3.97; 95% CI, 1.54-10.23; p = 0.010) and low expression level of pS6Ser240/4 at baseline (HR, 7.64; 95% CI, 2.591-22.51; p = 0.001) were significantly associated with shorter PFS time. Treatment was in general well tolerated. Toxicities of grade 3/4 included anemia (9.4%), thrombocytopenia (9.4%), hepatic dysfunction (11.3%) and pulmonary toxicities (one interstitial pneumonitis and a diffuse alveolar hemorrhage [DAH] case). The DAH and cardiopulmonary dysfunction in another case resulted in treatment-related mortalities.

Conclusions: Everolimus monotherapy showed modest activity against AGC refractory to FP. pS6Ser240/4 might be a potential biomarker for the clinical activity of everolimus. The toxicity profile was generally mild. However, careful monitoring for treatment-related pulmonary complication seems to be required.

[Table: see text]
A meta-analysis comparing positive surgical margin and complication rates of 110,016 patients undergoing open retropubic, laparoscopic, and robotic-assisted radical prostatectomy.
Authors: Sooriakumaran P. , Bloch D. , Hebert A. , Seshadri-Kreaden U. , Wiklund P. , Tewari A.
Published: February 2017

103

Background: There is no clear evidence to support one form of surgical approach over another with regards radical prostatectomy. The aim of this study was to analyze the literature available between 2002 and 2008 and compare positive surgical margin and complication rates for open retropubic, laparoscopic, and robotic radical prostatectomy.

Methods: A total of 110,016 patients formed the basis of this meta-analysis, representing the largest compilation of radical prostatectomy patients in the literature. Summary data were abstracted on year of publication, pre-operative patient characteristics, positive surgical margins, estimated blood loss, blood transfusions, conversions, length of hospital stay, and total intra- and peri-operative complications, with a further 21 individual perioperative complications selected a priori for abstraction and analysis.

Results: The open and laparoscopic surgical groups had similar overall positive surgical margin rates, with the robotic group having lower rates. Both minimally invasive approaches showed significantly lower estimated blood loss and rate of blood transfusions, and a shorter length of hospital stay when compared to an open approach. A further decrease in these parameters was seen when robotic assistance was used. Total complication rates were highest for the open approach, intermediate for the laparoscopic cohort, and lowest for the robotic group. For the individual complication analysis, the rates for death, readmission, reoperation, ureteral, bladder, and rectal injury, ileus, pneumonia, fistula, and wound infection showed significant differences between groups.

Conclusions: Robotic assisted laparoscopic radical prostatectomy has overall lower perioperative morbidity and improved early oncologic outcomes compared to conventional laparoscopic or open approaches. Further studies comparing longer term oncologic and functional outcomes, as well as cost-benefit comparisons are needed before making recommendations for or against a specific type of surgery.

[Table: see text]
A review of radical prostatectomy outcomes in active surveillance patients—The Sunnybrook experience.
Authors: Jethava V. , Vesprini D. , Loblaw D. A. , Mamedov A. , Nam R. , Klotz L.
Published: February 2017

104

Background: Prostate cancer is the most prevalent non-cutaneous cancer among North American men. Approximately 50% of these are favorable risk cancers; the NCCN guideline recommends active surveillance for these patients. Patients are generally followed by serial PSAs, DREs and/or TRUS-guided biopsies with triggers identified for each test. Consequently, about 30% of these cancers will be reclassified to a higher risk and require definitive treatment. Cases treated with radical prostatectomy (rP) give important insights into the biology of these cancers.

Methods: The ASURE database of active surveillance patients was used to identify cases; a retrospective chart review was completed. The following variables were extracted: primary reason for rP; % biochemical failure; % of patients requiring salvage radiation or hormone therapy; Gleason score (GS), tumor size staging and nodal status in the rP specimen; cause and rate of mortality; proportion of patients treated for PSA-doubling times less then 3 years presenting with a GS greater than 7. Descriptive statistics were used to summarize the results.

Results: Of 566 patients in the ASURE database, the charts of 26 patients having an rP were extracted. The primary cause for an rP was a PSA-doubling times less than 3 years (57% of patients) followed by a biopsy indicating a GS of 4+3 or greater (19%). 7% of patients (2/26) were not reclassified but preferred to be treated with rP. 4 patients had biochemical failure (15%) all 4 had salvage therapy. There was 1 cause-specific death. 85% of rP specimens had GS 7, while the remaining had GS 6. Half of these GS 7 individuals had PSA doubling times of less than 3 years.

Conclusions: Radical prostatectomy appears to be an effective deferred treatment for patients who are reclassified on active surveillance as evidenced by low prostate-cancer mortality, low rates of biochemical failure acceptable use of salvage therapy. Of interest is that the majority patients with PSAdt < 3 y have Gleason 7 disease on specimen.

No significant financial relationships to disclose.
Pathologic outcomes in patients with clinically low-risk prostate cancer deemed eligible for active surveillance.
Authors: Srivastava A. , Grover S. , Sooriakumaran P. , Rajan S. , El-Douaihy Y. , Tewari A.
Published: February 2017

110

Background: Active surveillance (AS) is becoming increasingly popular as a treatment option for men with clinically localized low-risk prostate cancer. Gleason score ≤ 6 and clinical stage ≤ T2a are selection criteria for AS. However, Gleason upgrading or upstaging from the diagnostic biopsy to the surgical specimen is not uncommon. We thus sought to identify risk factors that could more accurately predict Gleason upgrading and/or upstaging in AS-eligible men.

Methods: 786 patients from our prospective database of 2,412 men who underwent robotic-assisted radical prostatectomy by a single surgeon from January 2005 to August 2010 would have fulfilled standard AS criteria (Gleason sum ≤ 6, clinical stage ≤T2a disease, PSA <10ng/ml, <3 positive cores and ≤50% cancer present in a single core). This formed the basis of our study cohort. Clinicopathologic parameters, including number of cores at initial biopsy, biopsy cancer volume, preoperative PSA, number of cancer-positive cores, body mass index, and prostate volume were recorded prospectively. Data were evaluated using chi- square and multivariate logistic regression analyses. Receiver operator characteristic curves (ROC) were constructed to determine the optimal cutoff values.

Results: 320 of 786 AS-eligible patients (40.7%) had Gleason upgrading at final pathology following radical prostatectomy. Upstaging was present in 591 patients (75.1%). 626 patients (79.6%) had Gleason upgrading and/or upstaging. On univariate analysis, BMI, PSA density, preoperative PSA, lower prostate volume and maximum percentage of cancer in biopsy cores were predictors of Gleason upgrading and/or upstaging. On multivariate analysis, all variables, except for BMI and PSA density, lost statistical significance. PSA density > 0.1 ng/ml/cm3 and BMI >29 kg/m2 are the optimal cutoff values based on ROC analysis.

Conclusions: PSA density and BMI are significant predictors of Gleason upgrading and/or upstaging, and should be incorporated into contemporary selection criteria for AS protocols.

No significant financial relationships to disclose.
Robotic-assisted radical prostatectomy in a system of universal health care with limited access to high-tech resources.
Authors: Autran Gomez A. , Alzaharani A. , Williams A. , Chin J.
Published: February 2017

116

Background: The goal of radical prostatectomy (RP) is to minimize the positive surgical margin (PSM) rate. Robotic- assisted radical prostatectomy (RALP) has the theoretical advantages of enhanced ability to identify surgical dissection planes to improve surgical outcome but is associated with a learning curve. The objective is to review the PSM rate and intra- and postoperative complications (Clavien grading) correlating with possible risk factors in a low-density RALP by a high-volume, open RP surgeon working in the Canadian Healthcare System.

Methods: The data of 56 RALP from April 2004 to Dec 2009 by one surgeon contemporaneously performed 830 RP. PSM was analyzed and correlated with clinical variables. Univariable and multivariable analyses were used.

Results: PSM 19 (34%) cases. At univariable analysis, no association was observed between PSM and age BMI, PSA, number positive cores, % positive cores, Gleason biopsy and clinical stage. Pathological Gleason (p=0.012), pathological stage (p= 0.003) and % tumor in surgical specimen (p=<0.001) were associated with increased risk of PSM. At multivariable the % tumor in surgical specimen (p<0.001) were only independent predictive factor for PSM. According to localization of PSM Apical 9 (48%), PLR 4 (21%), PLL 4 (21%) and bladder neck 1 (5%). Mean follow-up 23 months. In PSM, 12 (63%) showed an undetectable PSA (≤0.01ng/mL) at 3 months. Using Clavien grading, 9 surgical complication in 9(16%) patients: 6 (grade 1–2) and 3 (grade 3–4). 4 patients with PSM had complications, 2 (grade1-2) and 2 (grade 3–4). At multivariable analyses, BMI (p=0.008) was the only predictive factor for occurrence of complications.

Conclusions: The pathological stage and tumor (%) in the surgical specimen were independent predictive factor for PMS. Applying the Clavien grading, most of the patients presented minor complications. The Canadian Universal Healthcare system with limited access to high-tech resources may not be ideal for introducing an expensive new surgical technique, especially for an ubiquitous procedure such as RP. However, results of our low-density series or sporadic cases were not inferior to reported initial experience series of RALP in the literature.

No significant financial relationships to disclose.
Association between radiographic response and overall survival in men with metastatic castration-resistant prostate cancer receiving chemotherapy.
Authors: Sonpavde G. , Pond G. R. , Berry W. R. , De Wit R. , Eisenberger M. A. , Tannock I. , Armstrong A. J.
Published: February 2017

118

Background: In men with metastatic castration resistant prostate cancer (CRPC),the association of measurable tumor responses with overall survival (OS) is unknown. We retrospectively evaluated the TAX327 phase III trial to study this relationship.

Methods: Eligible patients for this analysis included those with WHO-defined measurable metastatic disease randomized to receive either docetaxel or mitoxantrone. OS was estimated using the Kaplan-Meier method and the prognostic relationship of WHO-defined radiologic response with OS was performed using Cox proportional hazards regression. Landmark analyses evaluated survival from baseline and 2, 3, 4 and 6 months after baseline.

Results: Four hundred and twelve patients enrolled on the TAX327 trial had measurable tumors. Thirty-seven patients exhibited a complete or partial objective response (CR/PR, 9.0%), 116 had stable disease (SD, 28.2%), 99 had progressive disease (PD,24%) and 160 (38.8%) did not have a post-baseline objective assessment. Partial responders demonstrated longer median OS (29.0 months) than patients with SD (22.1 months), or those with PD (10.8 months) or those who were not assessed (12.7 months). These results remained after landmark analysis. We found a significant association between ≥30% PSA declines and radiologic response, with ≥30% PSA declines occurring in all patients with CR/PR, 79.8% of patients with SD and 34.4% with PD. Radiologic response remained a significant but modest post-treatment prognostic factor for OS after adjusting for treatment, pain-response and ≥30% PSA-decline (p=0.009).

Conclusions: In men with metastatic CRPC and measurable disease receiving chemotherapy, objective tumor response was prognostic for OS, and appears to complement PSA assessment.

[Table: see text]
Phase I trial of anti-PSMA designer T cells in advanced prostate cancer.
Authors: Junghans R. P. , Rathore R. , Ma Q. , Davies R. , Bais A. , Gomes E. , Beaudoin E. , Davol P. , Abedi M. , Cohen S.
Published: February 2017

130

Background: We created chimeric immunoglobulin-T cell receptors (IgTCR) specific for prostate specific membrane antigen (PSMA). When expressed in patient T cells, these “designer T cells” (dTc) specifically kill prostate cancer cells in vitro and in vivo in animal models, with 5/9 (55%) of xenografted mice experiencing complete remissions (Ma et al. Prostate 2004:61:12–25). A phase I clinical trial was approved by the FDA.

Methods: Patient T cells are retrovirally transduced and expanded ex vivo to span dose levels of 10^9 to 10^11 T cells. Patients undergo prior non-myeloablative (NMA) conditioning to create “hematologic space” into which designer T cells are infused for stable engraftment and prolonged in vivo efficacy. Patients are co-administered continuous infusion IL2. Outcomes include Phase Ia goals of safety and Phase Ib goals of establishing an optimal biologic dose in terms of designer T cell engraftment.

Results: Five patients have been treated, three at 10^9 and two at 10^10 cell dose levels. Excellent T cell modifications of 30%-60% were obtained. After NMA conditioning, T cells were infused. Stable engraftments of 1%-20% post-recovery at one month after T cell infusion, thus affirming one of the study end-points. Patients experienced neutropenic fever after conditioning, but no designer T cell-related toxicities. Two patients had partial responses with PSA reductions of 50 and 70% in the two months following treatment with projected benefits of 4 months gain of time to return to starting PSA levels. Results will be updated at the conference.

Conclusions: A new approach to adoptive immune therapy in metastatic prostate cancer has been devised with encouraging early results. Patients are being actively recruited. This clinical trial received partial funding from the US Army/DOD. Preclinical work was supported by the Prostate Cancer Foundation.

No significant financial relationships to disclose.
Results of a phase I/II clinical trial of BPX-101, a novel drug-activated dendritic cell (DC) vaccine for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sonpavde G. , McMannis J. D. , Bai Y. , Seethammagari M. , Bull J. M. , Hawkins V. , Dancsak T. , Lapteva N. , Spencer D. M. , Slawin K. M.
Published: February 2017

132

Background: We report results of a phase I/II clinical trial of BPX-101, a drug- activated autologous DC vaccine targeting PSMA.

Methods: Men with progressive mCRPC following up to one prior chemotherapy regimen were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and CD40 activating agent AP1903. BPX-101 was administered intradermally every 2 weeks for 6 doses, during the induction phase, and for nonprogressing patients, every 8 weeks for up to 5 doses during the maintenance phase. AP1903 (0.4 mg/kg) was infused 24 hours after each BPX-101 dose. Radiologic evaluation was performed every 12 weeks.

Results: Planned enrollment of 12 subjects has been completed, including 3 each at 4 × 106 and 12.5 × 106 cells/dose, and 6 at 25 × 106 cells/dose. All vaccine products were releasable. Median Halabi- predicted survival was 13.8 months. Two subjects went off protocol prior to the end of induction due to progression, 8 reached end of induction, and 2 are nearing completion of induction. Toxicities (e.g. injection site reactions) were generally mild. One high dose subject experienced a single acute cytokine reaction during infusion of AP1903 at the second vaccination, but continued induction without further drug-related adverse events. Notably, one post- docetaxel subject in the low dose cohort achieved a RECIST PR, and one chemo-naive subject in the mid-dose cohort with extensive visceral, nodal, and bone metastases experienced a RECIST CR with docetaxel-based chemotherapy after induction and maintains an undetectable ultrasensitive PSA (0.009 ng/mL) 10 months after enrollment. A third subject, in the high-dose cohort, experienced near complete elimination of multiple lung metastases with otherwise stable disease by the end of induction. Robust immune responses were seen in all three.

Conclusions: BPX-101 can be reliably manufactured and safely administered, followed by AP1903, at doses of at least 25 × 106 cells. Contrary to the observation that cancer vaccine therapy improves survival without short-term response, BPX-101-treated patients have experienced measurable disease responses, including near elimination of poor-risk visceral disease.

[Table: see text]
Effect of G-CSF prophylaxis on the occurrence of neutropenia in men receiving cabazitaxel plus prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the TROPIC study.
Authors: Ozguroglu M. , Oudard S. , Sartor A. O. , Hansen S. , Machiels J. H. , Shen L. , De Bono J. S. ,   for the TROPIC Investigators
Published: February 2017

144^

Background: The phase III TROPIC study showed that cabazitaxel plus prednisone (CbzP) improves survival compared with mitoxantrone plus prednisone (MP) in men with mCRPC who progressed after docetaxel-based therapy (HR 0.70; p<0.001; Lancet 2010;376:1147). In this study, a higher percentage of men in the CbzP group had grade ≥3 neutropenia (81.7% versus 58.0%). We analyzed the effect of G-CSF use on the occurrence of grade ≥3 neutropenia.

Methods: 755 men with mCRPC who progressed during or after a docetaxel-containing regimen were randomized to receive 10 mg of oral prednisone daily and either 12 mg/m2 of mitoxantrone or 25 mg/m2 of cabazitaxel every 3 weeks. Primary prophylaxis with G-CSF was not permitted at cycle 1, but was allowed after the first occurrence of neutropenia either lasting ≥7 days or complicated by fever >38.5°C, or fever >38.1°C for three observations during a 24- hour period, or infection. We analyzed the effect of G-CSF use on the occurrence of neutropenia in cycles 2–10. G-CSF use was defined as either prophylactic (administered within 3 days of chemotherapy dose) or therapeutic (administered more than 3 days after chemotherapy dose).

Results: A total of3246 cycles (1881 CbzP; 1365 MP) were administered from cycle 2 onward. No G-CSF was used in 2,322 cycles (1144 CbzP; 1178 MP) and the percentage of these cycles with grade ≥3 neutropenia was similar between the groups (44.6% CbzP; 38.4% MP). G-CSF was used in more cycles in the CbzP group as prophylaxis (588 CbzP; 118 MP; chi-square P<0.0001) and therapeutically (149 CbzP; 69 MP; P=0.0013). The percentage of CbzP cycles with grade ≥3 neutropenia was lower when G-CSF was used early as prophylaxis versus using it later as a therapeutic modality (24.7% versus 57.7%; P<0.0001). A reduction in grade ≥3 neutropenia favoring prophylactic versus therapeutic G-CSF was also observed in the MP group (9.3% versus 33.3%; P<0.0001).

Conclusions: The appropriate and timely use of G-CSF as prophylaxis reduces the occurrence of neutropenia in men receiving CbzP for mCRPC. Adherence to current guidelines on the use of G-CSF is recommended to manage this predictable side effect.

[Table: see text]
PSA doubling time (PSADT) and serum testosterone (T) during intermittent androgen deprivation (IAD) in patients with biochemically relapsed prostate cancer (BRCP; M0): Potential predictive implications.
Authors: Keizman D. , Huang P. , Antonarakis E. S. , Sinibaldi V. J. , Carducci M. A. , Denmeade S. R. , Eisenberger M. A.
Published: February 2017

150

Background: The systemic management of patients with BRPC remains controversial. IAD is commonly employed. Aims: To evaluate the PSA dynamics and serum T in pts with BRPC treated with IAD until the development of PSA refractoriness or clinical evidence of metastatic disease.

Methods: Data were retrospectively analyzed in all pts with BRCP treated with GnRH at PSA thresholds according to pre-treatment PSADT (10-15ng/mL, 15-20, and 20-30 for PSADT ≤3 mos, 3-9 mos, and ≥ 9 ms, respectively) and continued until PSA nadir. Antiandrogen (AA) was added for PSA > 1.0 ng/mL after 3 mos). Follow-up (FU) consisted of PSA and T q3 mos. Cycles were repeated at the above preselected PSA thresholds and continued until lack of PSA response. Scans were obtained prior to cycles and at the time of CRPC state. Mixed effects model was used to study PSADT change over cycles. Multivariate cox regression model was used to identify prognostic variables.

Results: From 1995-2010, with a mean FU of 71 mos (range 22-183 months), 96 pts received a mean of 2.8 cycles (range 1-9) of IAD; 58 (60%) remain on treatment and 38 (40%) were switched to continuous ADT due to PSA refractoriness (n=11) or positive scans (n=27). PSADT at the first off treatment (tx) interval (mean 3.1, 0.59-30.5 range, median 2.3) was significantly shorter than the baseline (p<0.0001; mean 9.7, range 0.27-53.9, median 7.34) but remained relatively stable (p=0.29) in subsequent cycles. PSADT adjusted for T recovery (≥3 ms after T recovery to ≥ 150 ng/dL) was significantly longer (p=0.006) than that based only on all PSA determinations (mean 5.4, range 1.31-30.5, median 3.7 versus mean 3.1, range 0.59-30.5, median 2.3). Significant factors associated with probability of PSA refractoriness were pre-IAD PSADT (≥ 6 vs <6 ms), first off tx interval PSADT (≥3 ms vs <3m), the use of AA during first tx cycle, and PSA nadir during the first tx interval (<0.1 vs ≥0.1 ng/mL).

Conclusions: Our data suggest that PSADT becomes shorter after the initial cycle of IAD and correlate with T recovery. PSA dynamics and need for AA to enhance PSA nadir are associated with PSA refractoriness in pts BRPC treated with IAD.

No significant financial relationships to disclose.
On-target activity of neoadjuvant cixutumumab and combined androgen deprivation therapy for high-risk prostate cancer: A phase II trial.
Authors: Dean J. P. , Montgomery R. B. , Wan J. , Cohen P. , Haugk K. , Corman J. M. , Ellis W. J. , Dalkin B. L. , Ludwig D. L. , Plymate S. R.
Published: February 2017

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Background: IMC-A12 (cixutumumab) is a fully human monoclonal antibody which targets the insulin-like growth factor receptor 1. Preclinical data suggests that the combination of androgen deprivation and IMC-A12 is much more effective than either treatment alone. This clinical trial tests the effectiveness of the combined treatment in a neoadjuvant fashion before radical prostatectomy. We have assayed serum samples from the first 18 patients to identify signs of on-target activity in this setting.

Methods: Eligible men with high risk localized prostate cancer are defined by one of the following: Gleason score ≥ 8, PSA ≥ 20, Clinical Stage T2c-T3, or a risk for relapse exceeding 50% as defined by the Kattan nomogram. Men are treated for 3 months with goserelin, bicalutamide, and biweekly IMC-A12 infusions (10 mg/kg). The primary objective of the trial is to determine the rate of pathological complete response with an accrual goal of 28 men. Using samples from the first 18 patients on study, serum protein markers were assayed by ELISA and serum PSA and glucose levels were determined by clinical laboratory analysis.

Results: Significant increases in c-peptide (1.7-fold, p<0.01), IGF-I (4.1-fold, p<0.01), IGF-II (1.32-fold, p<0.001), IGFBP-3 (1.9-fold, p<0.01), growth hormone (8-fold, p<0.01) were noted after initiation of ADT+IMC-A12, compared to pre-treatment levels. Non-significant increases of insulin (1.9-fold), IGFBP-1 (2-fold), and glucose (1.24-fold) levels were seen. Stratification of patients by nadir PSA levels correlated with residual tumor volume, likelihood of positive surgical margins and likelihood of lymph node metastases. Interestingly, patients with lower nadir PSA levels had smaller increases in c-peptide (50%, p<0.01), insulin (66%, p<0.02) and blood sugar (21%, P<0.01) compared to the patients with higher nadir PSA levels.

Conclusions: Combined with ADT in the neoadjuvant setting, IMC-A12 effectively targets the IGF-1R axis in prostate cancer patients. Metabolic differences between patients may alter the efficacy of IMC-A12 in this setting.

[Table: see text]
Maintenance of the suppressed level of serum testosterone by administration of three-monthly formulations of luteinizing hormone-releasing hormone agonists at six-month intervals in Japanese patients with prostate cancer: A prospective study.
Authors: Fujii Y. , Yoshida S. , Yokoyama M. , Iimura Y. , Numao N. , Saito K. , Koga F. , Masuda H. , Kawakami S. , Kihara K.
Published: February 2017

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Background: Treatment with an LH-RH agonist is a standard alternative to surgical castration for prostate cancer patients. The serum testosterone level is kept at castrate levels continuously during LH-RH agonist therapy in almost all patients (Fujii Y, BJU Int 2008). LH- RH agonists, however, are more expensive than surgical castration, with drugs costing between US $300 and $500 per month in Japan. Recent studies suggest that 3-monthly formulations of LH-RH agonists suppress the serum testosterone levels far longer than the 3-month dosing interval.

Methods: A total of 43 Japanese patients with prostate cancer who were treated with 3-monthly LH-RH agonists (23 with 11.25mg leuprolide, and 20 with 10.8 mg goserelin) for one year or longer and whose testosterone levels were kept at castrate level (defined as < 50 ng/dL) were entered into this prospective, longitudinal study. After entry, the 43 men received the same 3-monthly LH-RH agonists at 6-month intervals, and had serum LH and testosterone tests performed at 3-month intervals. Bicalutamide was combined with the LH-RH agonists in 12 of the patients.

Results: At entry, median patient age was 74 years (range 59 to 89), median duration of LH-RH agonists treatment was 26 months (12 to 125), and median LH and testosterone levels were <10 ng/dL (<10 to 60) and 5 ng/dL (<5 to 18), respectively. The 43 patients received a total of 162 administrations (median 5, range 1 to 6) of the LH-RH agonists at 6-month intervals, and had a total 335 hormonal tests (median 10, range 2 to12) performed during the median followup period of 30 months. Serum LH and testosterone levels were kept suppressed during the treatment. Of the 43 patients, two had serum testosterone just above the castrate level (54 and 56 ng/dL) once each among their 12 and 8 hormonal assays, respectively.

Conclusions: Administration of 3-monthly LH-RH agonists, either leuprolide or goserelin, at 6-month intervals could maintain the castrate level of serum testosterone at least in Japanese prostate cancer patients who have received LH-RH agonists treatment for one year or longer.

No significant financial relationships to disclose.
Evaluation of oral cyclophosphamide activity by CTC enumeration in patients with docetaxel-refractory castration-resistant metastatic prostate cancer: Potential utility in primary refractory disease.
Authors: Goodman O. B. , Symanowski J. T. , Fink L. M. , Vogelzang N. J.
Published: February 2017

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Background: Recent data suggest that circulating tumor cell (CTC) enumeration is a surrogate predictive endpoint for survival in metastatic castration-resistant prostate cancer (mCRPC). Data supporting the notion of changing therapy from docetaxel based on CTC numbers is limited in PC, due to a limited experience with second-line systemic therapies following docetaxel failure.

Methods: Peripheral blood from patients receiving cyclophosphamide following progression on docetaxel was analyzed by CellSearch Methodology (Veridex, LLC; Warren NJ) enumerate CTC. Circulating tumor cells were enumerated prior to and at least three weeks following the initiation of cyclophosphamide. Patients were categorized as responsive, defined as a follow up CTC of <5 cells or a greater than a 90% decline in counts between CTC determinations, or refractory (all others). Cyclophosphamide responsiveness was then correlated with docetaxel responsiveness using a Fisher-exact test.

Results: Twenty two patients received oral cyclophosphamide therapy (50-150 mg/day). Of these, twelve (55%) were clinically primary docetaxel refractory, assessed by either clinical or PSAWG2 criteria while on docetaxel, and ten (45%) were initially responsive but subsequently progressed on docetaxel. Of the twelve patients who were primarily refractory to docetaxel, seven (58%) exhibited a cyclophosphamide response. In the majority of these cases, this response was durable with a complete disappearance of CTC. Conversely, only one patient (10%) who initially responded to docetaxel was sensitive to cyclophosphamide (P=0.031).

Conclusions: Using a CTC endpoint cyclophosphamide appears to be active in patients initially refractory to docetaxel, but not those who initially responded. These data support the further evaluation of the potential for selective clinical utility of cyclophosphamide as second-line chemotherapy.

[Table: see text]
A phase I study of TRC105 (anti-CD105 monoclonal antibody) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Adelberg D. , Apolo A. B. , Madan R. A. , Gulley J. L. , Pierpoint A. , Kohler D. R. , Trepel J. B. , Steinberg S. M. , Figg W. D. , Dahut W. L.
Published: February 2017

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Background: TRC105 is a human/murine chimeric IgG1 monoclonal antibody to CD105 (endoglin) that inhibits angiogenesis and tumor growth through inhibition of endothelial cell (EC) proliferation, antibody-dependent cellular cytotoxicity and induction of apoptosis. CD105 is highly expressed on proliferating vascular ECs. Preclinical and clinical evidence demonstrates an important role for angiogenesis in mCRPC biology.

Methods: The primary objective is to evaluate safety and identify the maximum tolerable dose of TRC105. Secondary objectives include the assessment of TRC105 pharmacokinetics, PSA response rate and overall response rate (ORR). Eligibility requires ECOG performance status (PS) ≤ 2 and progressive mCRPC. Three cohorts of 3-6 patients receive TRC105 at doses of 1, 3 or 10 mg/kg IV over 1–4 hours every 2 weeks of a 4 week cycle. Premedications are dexamethasone, acetaminophen, famotidine, and diphenhydramine. PSA is evaluated prior to each treatment and response is assessed every 2 cycles with imaging studies.

Results: Eight patients are enrolled in cohorts 1–3. Median age is 65 (range 47–84), ECOG PS 1 (1–2), Gleason score 8 (6–10), on–study PSA 201 (0.10 – 3,373), and number of prior therapies after gonadotropin-releasing hormone agonist or anti-androgen therapy 2.5 (0–6). Median time on study is 14 weeks (7–16). Dose-limiting toxicity was not observed. Grade 1 to 2 infusion reactions occurred in 4 patients. PSA declines were seen in both patients in cohort 3 (26% and 51% from baseline); each had progressed on docetaxel and at least one second-line agent. Five of 6 evaluable patients with measurable soft tissue disease achieved stable disease (2 in cohort 1, 2 in cohort 2 and 1 in cohort 3); the latter 3 patients in cohorts 2 and 3 remain on study.

Conclusions: TRC105 is tolerated at doses up to 10 mg/kg every 2 weeks with early evidence of clinical activity in patients with mCRPC. Accrual is ongoing to evaluate higher doses and more frequent dosing.

No significant financial relationships to disclose.
Obese men, higher PSA nadir values after radical prostatectomy (RP), and higher biochemical recurrence (BCR) rates: Results from the SEARCH database.
Authors: Ho T. S. , Aronson W. J. , Terris M. K. , Presti J. C. , Kane C. J. , Amling C. L. , Freedland S. J.
Published: February 2017

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Background: Obesity is associated with risk of BCR after RP. It has been suggested this may be due to poor surgical technique and greater risk of positive margins. We examined whether obesity predicted the risk of a detectable PSA nadir after RP (as a measure of residual PSA-producing tissue left behind) and if this accounted for the greater risk of BCR in obese men in the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

Methods: We identified 1,011 men treated with RP from 2001 to 2010 in SEARCH who had known data for pre-operative BMI and ultrasensitive PSA nadir within 6 months after RP. The association between BMI (<25, 25-29.9, and >30 kg/m2) and PSA nadir (0, 0.01-0.09, 0.10-0.19, and >0.2) was tested using chi-squared and linear regression adjusting for clinical and pathological characteristics. A proportional hazards model was used to test the association between BMI and BCR adjusted for clinical and pathological characteristics and with and without PSA nadir.

Results: Higher BMI was associated with higher PSA nadir (chi-squared, p=0.03). On multivariate analysis, obesity (p<0.001) was associated with higher PSA nadir. Among men with a PSA nadir <0.2 ng/ml (i.e. those who did not recur based upon PSA nadir alone), obesity was associated with BCR when not adjusted for PSA nadir (HR 1.85, 95% CI 1.19-2.89, p=0.007). Adjusting for PSA nadir attenuated, but did not eliminate this association (HR 1.65, 95% CI 1.05-2.59, p=0.03). Even among men with an undetectable PSA nadir, obesity remained significantly associated with BCR (HR 3.45, 95% CI 1.41-8.47, p=0.007). Interestingly, among men with a detectable PSA nadir, but <0.2 ng/ml, obesity did not predict BCR with (HR 1.21, 95% CI 0.71-2.07, p=0.49) or without adjustment for PSA nadir (HR 1.41, 95% CI =0.82-2.41, p=0.22).

Conclusions: Obese men are more likely to have a higher PSA nadir suggesting technical issues confound an ideal operation in obese men. However, the increased PSA nadir does not completely explain the higher PSA recurrence rates. These data further support the idea that obesity is biologically associated with prostate cancer progression.

No significant financial relationships to disclose.