bluuebunny/crossref_metadata_2025 huggingface dataset:
Combination of cetuximab and chemotherapy in the first-line treatment of metastatic colorectal cancer: Slovakian experience.
Authors: Salek T. , Sebo E. , Mazalova D. , Chovanec J. , Stresko M. , Thomkova A. , Andrasina I. , Barilla R. , Hlavata Z. , Mego M.
Published: February 2017

622

Background: Cetuximab is an EGFR-targeting IgG1 monoclonal antibody that is active against EGFR-expressing Kras wild type metastatic colorectal cancer (mCRC) in monotherapy or in combination with chemotherapy. Here, we report efficacy and safety of combination of cetuximab and chemotherapy in patients (pts) with mCRC treated in major cancer centers in Slovakia from 01/2009 to 07/2010.

Methods: Forty consecutive pts (28F/12M) with EGFR expressing Kras wild type mCRC (14 pts-rectal cancer, 26 pts-colon cancer) treated with irinotecan-based (29 pts-73%) and oxaliplatin-based (11 pts-27%) chemotherapy were evaluated. Median age was 59 years (44-77).17 pts were pretreated with adjuvant therapy. No of metastatic sites: 1 mts -22 pts (55%), 2 mts-13 pts (32.5%), 3 mts -5pts (12.5%). Median CEA level before therapy 13.5 (1-1,800).

Results: 10 pts achieved complete remission (25%), 21 pts partial remission (52.5%), 8pts disease stabilization, 1pt disease progression. Median progression-free survival (mPFS) was 16 months, 1 year survival 65%-95% CI (50-80), median follow-up was 13 months (range 4-20m). The main Gr 3-4 toxicity was skin rash 2pts (5%) and diarrhea 2 pts (5%). Any grade toxicity: rash 32 pts (80%), diarhea 8pts (20%), neuropathy 8pts (20%), weakness 3pts (7.5%), neutropenia 2pts (5%), trombocytopenia 2pts (5%).

Conclusions: Our experience confirms the efficacy and acceptable safety profile of combination chemotherapy and cetuximab in first line mCRC patients.

No significant financial relationships to disclose.
Early outcome of a phase II study of yttrium-90 radioactive resin microspheres in the treatment of colorectal adenocarcinoma metastatic to the liver after failure of first-line combination chemotherapy (inSIRT Trial).
Authors: Roeland E. , Shimabukuro K. A. , Fanta P. T. , Rose S. C. , Reid T. R.
Published: February 2017

626

Background: Liver metastases develop in at least half of the cases of colorectal cancer (CRC) and the liver is often either the dominant or the only site of metastases. It is estimated that up to 90% of patients with metastatic CRC die as a consequences of their hepatic metastases and resultant liver failure. We are evaluating the aggressive management of liver metastases through the incorporation of Yttrium-90 radioactive microspheres after evidence of progressive disease following a first-line FOLFOX based regimen with or without bevacizumab. Optimal timing for microsphere treatment relative to chemotherapy has not yet clearly been established. In this abstract, we present preliminary data of a phase II study evaluating tumor and biochemical response rates.

Methods: Patients with disease progression despite first-line FOLFOX based therapy with or without bevacizumab are eligible for the inSIRT trial. Interventional radiology and nuclear medicine assess the liver lesions and the patient receives selective internal radiation therapy (SIRT) microspheres therapy. Bilobar hepatic disease requires a second treatment. 4-6 weeks after the final microspheres therapy, patients proceed to second-line chemotherapy with FOLFIRI.

Results: To date, 3 metastatic CRC patients have been treated on this protocol and a total of 5 patients enrolled. No significant adverse events have been noted. Preliminary results for 3 patients show stable disease after failure of first-line combination chemotherapy up to 160 days after treatment.

No significant financial relationships to disclose.
Clinical significance of genetic variations in the PI3K/PTEN/AKT/mTOR pathway in Korean patients with colorectal cancer.
Authors: Lee S. J. , Kim J. G. , Chae Y. S. , Kang B. W. , Jeon S. W. , Park J. S. , Park J. Y. , Choi G. S. , Lee Y. J.
Published: February 2017

628

Background: Signaling through the PI3K/PTEN/AKT/mTOR pathway is responsible for balancing cell survival and apoptosis. Accordingly, the present study analyzed 14 SNPs of the PI3K/PTEN/AKT/mTOR pathway genes and their impact on the prognosis for patients with colorectal cancer.

Methods: Four hundred and forty-four consecutive patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and 14 polymorphisms of the PI3K/PTEN/AKT/mTOR pathway genes determined using a real-time PCR genotyping assay.

Results: Pathologic stages after surgery were as follows: stage 0/I (n=85, 19.1%), stage II (n=149, 33.6%), stage III (n=147, 33.1%), and stage IV (n=63, 14.2%). Univariate and multivariate survival analysis including stage, age, site of disease, adjuvant chemotherapy, and CEA level showed that these polymorphisms were not associated with progression-free or overall survival. For the clinicopathologic parameters, CEA level and TNM stage were significant prognostic factors in a Cox model for survival.

Conclusions: None of the 14 SNPs of the PI3K/PTEN/AKT/mTOR pathway genes investigated in this study was found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer.

No significant financial relationships to disclose.
The role of the KRAS G13D mutation in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus cetuximab.
Authors: Tejpar S. , Bokemeyer C. , Celik I. , Schlichting M. , Van Cutsem E.
Published: February 2017

630

Background: The CRYSTAL and OPUS studies showed that adding cetuximab (cet) to first-line chemotherapy (CT) significantly improved clinical benefit in patients (pts) with KRAS wild-type (wt) mCRC. Pts with KRAS codon 12 or 13 mutations are excluded from cet treatment. Studies suggest that not all KRAS mutations are equivalent in their biologic effects. Occasional responses and prolonged disease stabilization have been recorded following cet treatment of tumors with mainly KRAS codon 13 mutations. We investigated the influence of the most common KRAS codon 13 mutation (G13D) on clinical outcome compared with pts with other KRAS mutations or wt tumors in the CRYSTAL and OPUS trials.

Methods: KRAS mutations were detected in tumor DNA from archival material using a PCR clamping and melting curve technique. Treatment arms were compared by KRAS mutation status for progression-free (PFS) and overall survival (OS).

Results: In the CRYSTAL study of 1,063 evaluable pts 63% were KRAS wt, 6% were G13D mutant (mt) and 32% had other mutations. In the OPUS study of 315 evaluable pts, 57% were KRAS wt, 7% were G13D mt, and 36% had other mutations. Compared with KRAS wt pts those with G13D mutations did not benefit from the addition of cet to CT (Table). Data of comparisons of the G13D mutation with other KRAS mutations in these studies will be presented.

Conclusions: Patients with KRAS G13D mt tumors did not appear to benefit from the addition of cet to first-line CT for mCRC. This analysis confirms the current practice of KRAS mutation testing as the standard diagnostic tool for determining first-line treatment of mCRC pts.

[Table: see text]

[Table: see text]
Long-term outcome of almost 3,000 patients with carcinoma of the esophagus: Evaluation of the new UICC/AJCC staging system.
Authors: Gertler R. , Schuster T. , Feith M.
Published: February 2017

64

Background: In the new 7th edition of the TNM classification for cancers of the esophagus, the UICC stage groups are still based on the anatomic extent of the tumor alone. In contrast, the AJCC prognostic groupings is the first staging system for esophageal cancer to add histologic tumor type, tumor site and grade.

Methods: Data of a single center cohort of 2,920 patients operated for cancers of the esophagus were analyzed. Statistical methods to evaluate survival of the patients and the prognostic performance of the new staging systems included Kaplan-Meier analyzes and time dependent ROC-analysis.

Results: UICC stage, R-status, histologic tumor type and age were identified as independent prognostic factors for cancers of the esophagus. Grade and tumor site, additional parameters in the new AJCC prognostic groupings, were not significantly correlated with survival. Patients with esophageal adenocarcinoma had a significantly better long-term prognosis after resection than patients with squamous cell carcinoma (p < 0.0001). The new number-dependent N- classification proved superior to the former site-dependent classification with significantly decreasing prognosis with increasing number of lymph node metastases (p < 0.001). The new subclassification of T1 tumors also revealed significant differences in prognosis between pT1a and pT1b patients (p < 0.001). However, the multiple new UICC and AJCC subgroupings did not prove distinctive for survival between stages IIA and IIB, IIIA and IIIB, and between IIIC and IV.

Conclusions: The new 7th edition of the TNM classification improved the predictive ability for cancers of the esophagus, however, stage groups could be condensed to a clinically relevant number. Differences in patient characteristics, pathogenesis and especially survival clearly identify adenocarcinomas and squamous cell carcinoma of the esophagus as two separate tumor entities requiring differentiated therapeutic concepts.

No significant financial relationships to disclose.
Evaluation of the seventh TNM classification system in patients with esophageal cancer receiving chemoradiotherapy.
Authors: Nomura M. , Kodaira T. , Mizota A. , Kondoh C. , Shitara K. , Yokota T. , Takahari D. , Ura T. , Hatooka S. , Muro K.
Published: February 2017

83

Background: The new 7th edition of the TNM classification system is based on pathologic data of esophageal cancer underwent surgery alone. No report is available on the prognostic evaluation of the new staging system in patients treated with chemoradiotherapy (CRT). The objective of this study was to evaluate the prognostic impact of the 7th edition of the TNM staging system in esophageal cancer patients treated with CRT.

Methods: A retrospective review was performed of 301 consecutive patients who met the following inclusion criteria: (1) squamous cell carcinoma of thoracic esophagus; (2) total radiation dose ≥ 50 Gy; (3) concomitant chemotherapy consisting of 5-fluolouracil and platinum; (4) no previous thoracic radiotherapy or surgery. We compared the prognostic impact of the 6th and 7th editions of the TNM staging systems. Also, we compared the prognostic impact of stage group and prognostic group, which was newly defined in the 7th edition. Survival analysis was performed by using log-rank and Cox regression testing.

Results: Patients with stage I/II/III/IV were 52/42/54/153 and 57/46/128/70 according to 6th and 7th edition, respectively. Eighty-four patients were shifted to a lower stage in 7th edition compared with 6th edition, and most of these were from stage IV to III (n = 74). There were significant differences among stages I to III (p < 0.01, respectively) according to each edition. However, 7th edition poorly distinguishes between stages III and IV (p = 0.43). The survival curve of stage IV (lymph) almost completely overlapped with stage III (p = 0.69), although there were significant differences between stages IV (lymph) and IV (organ) (p = 0.04). Among the factors included in prognostic group in 7th edition, the histological grade and cancer site had no significant influence on patient survival, and T factor was only independent prognostic factors in multivariate analysis (p < 0.01).

Conclusions: Our study suggested several pitfalls in 7th TNM classification as prognostic factor in patients who received CRT.

No significant financial relationships to disclose.
Phase II study of weekly low-dose everolimus plus weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil and leucovorin for first-line treatment in patients with advanced gastric cancers.
Authors: Yeh K. , Shen Y. , Li C. , Yen C. , Hsu C. , Lin Z. , Chen L. , Su W. , Chao Y. , Cheng A.
Published: February 2017

86

Background: Cisplatin-HDFL, consisting of weekly 24-hour infusions of cisplatin and high-dose 5-fluorouracil (5-FU) and leucovorin (LV), is an effective and low-toxicity regimen for patients with advanced gastric cancer (GC) in Taiwan (J Clin Oncol. 1994;12(4):875; J Clin Oncol. 2006;24(18S):A14063). Everolimus (RAD001), a derivative of rapamycin, is an orally bioavailable mTOR inhibitor. We have demonstrated that low-dose everolimus (0.5-5.0 nM) sensitizes cytotoxic effects of cisplatin and 5-FU in GC cells (Proc Am Assoc Cancer Res. 2007;48:A4043).

Methods: Patients who had pathologically confirmed chemonaive advanced GC, at least 1 measurable lesion, a fasting serum triglyceride level > 70 mg/dl, ECOG PS 0-2, and adequate organ functions were treated with everolimus 10 mg po on days 1, 8, and 15 concurrently with the initiation of chemotherapy; cisplatin 35 mg/m2 iv 24h infusion on days 1 and 8; 5-FU 2,000 mg/m2 and LV 300 mg/m2 (HDFL) iv 24h infusion on days 1, 8, and 15, in a every 28-day cycle. Response assessment was performed every 2 cycles. The primary endpoint was confirmed objective response rate (RR) by RECIST.

Results: Between March 2008 and July 2010, 24 patients (M:11, F:13) with a median age of 53 (range: 33-69) were evaluable for response. The overall RR was 50% (95% CI: 29-71%) with 12 partial responders. Among a total of 162 cycles (median: 7, range: 1-13) given, grade (Gr) 3/4 toxicities included neutropenia (4.3%), infection (2.5%), nausea (3.1%) and vomiting (3.1%). Gr 1/2 nausea, vomiting, stomatitis, and diarrhea developed in 19.2%, 15.4%, 14.8%, and 5.5% of cycles, respectively. Skin rash and hand-foot syndrome were mild. One patient developed reversible HDFL-related hyperammonemic encephalopathy. Median progression-free survival was 8.4 months (range: 1.3-15.4+) and median overall survival was 14.8 months (range: 4.0-21.6+).

Conclusions: Weekly low-dose everolimus plus weekly cisplatin-HDFL is an effective first-line regimen for patients with advanced GC. Addition of weekly low-dose everolimus to infusional cisplatin-HDFL did not add gastrointestinal toxicities.

No significant financial relationships to disclose.
A phase II, open-label, multicenter, prospective study of paclitaxel plus capecitabine with subsequent capecitabine maintenance therapy as first-line treatment for metastatic or recurrent gastric cancer.
Authors: Shen L. , Gong J. , Zhang X. , Hu B. , Zhang F. , Zhang J. , Xu N. , Fan Q. , Bai Y. , Jiao S.
Published: February 2017

98

Background: Paclitaxel has been shown to be effective in AGC. We assess the efficacy and safety of PX-X therapy as first-line treatment for metastatic or recurrent GC in a phase II, multicenter, prospective study.

Methods: Patients with previously untreated gastric adenocarcinoma, signed informed consent, target lesion(s), KPS ≥ 70 and adequate organ functions are eligible. Paclitaxel was given as 80 mg/m2 by 3-hour infusion day 1,8, capecitabine 1,000 mg/m2, BID, D1-14, Q3W. Cycles were repeated until progression or maximum 6 or AEs. Then the patients without progression began the second stage treatment as X with same dose/schedule until progression or AEs. PFS, RR, DCR, OS and AEs are the end points evaluated in this study.

Results: From 12/2006 to 4/2010, 195 patients (ITT) were enrolled in 21 centers, 1 patient was withdraw due to allergy to paclitaxel, 194 cases were PP. After median follow up of 16.2 months, 16 cases lost. In ITT, 119 pts progressed, 104 pts died. Mean cycles the patients completed was 5. CR and PR were achieved in 1.0% (2 pts) and 32.3% (63 pts) of pts (RR 33.3%), 75 pts had SD (38.5%), 25 pts (12.8%) progressed. PFS of ITT is 208 d (95% CI: 169.1-246.8) and estimated OS is 456 d (95%CI: 286.9-624.2). 45 pts continued to X after PX with good tolerance, median cycles accepted was 4, and OS was longer than 590 d. 23 patients accepted surgery after chemotherapy; the survival data have not been reached. After disease progression, 61 cases accepted second-line treatment, including oxaplatin/irinotecan-based chemotherapy, target therapy, and local therapy. AEs were mild and the grade 3/4 toxicities were leucopenia (13.8%), alopecia(13.3%), neutropenia (8.2%), fatigue (6.7%), nausea/vomiting (5.1%), HFS (5.1%), diarrhea(3.6%), neurotoxicity (3.1%), hepatic dysfuction (2.6%), and anaphylactic shock (0.5%). No treatment- related deaths were recorded in all patients.

Conclusions: PX-X as first-line treatment was promising in advanced gastric cancer. Further evaluation of this combination therapy is being carried on phase III clinical trial of ML22697.

No significant financial relationships to disclose.
PSA response and early PSA progression evaluated in patients randomized in a phase III trial comparing androgen-deprivation therapy (ADT) plus docetaxel versus ADT alone in hormone-naive metastatic prostate cancer (GETUG-AFU 15/0403).
Authors: Gravis G. , Fizazi K. , Joly F. , Oudard S. , Priou F. , Latorzeff I. , Delva R. , Esterni B. , Habibian M. , Soulie M.
Published: February 2017

10

Background: Androgen deprivation therapy (ADT) is the standard treatment of hormone naïve metastatic prostate cancer (HNMPC). We initiated a phase III multicentre trial comparing ADT with or without docetaxel (D) in HNMPC (GETUG 15) and the primary endpoint is overall survival. PSA progression defined as an increase of 25% over baseline or nadirin the first 7 months was recently shown to be a strong predictor of death in HNMPC (Hussain M et al J Clin Oncol 27: 2009).

Methods: Patients (pts) with HNMPC were randomly assigned to either arm A (ADT plus D: 75mg/m2 q3w, 9 cycles) or arm B (ADT). From 10/2004 to 12/2008, 385 pts were accrued. The median baseline PSA values were 29.4 ng/mL (0.05-2,170) in arm A and 25.3 ng/mL (0.1-11,900) in arm B. Data on PSA response are available in 171/192 pts (arm A) pts and 181/193 pts (arm B) at 3 months and 156 pts (arm A) and 148 pts (arm B) at 6 months.

Results: A PSA response (> 30%) was achieved at 3 months in 93.6% (arm A) and 85.1% (arm B; p=0.02). A PSA response (> 50%) was achieved at 3 months in 90.6% (arm A) versus 80.1% (arm B; p=0.01). When assessed at 6 months, a PSA response (> 30%) was obtained in 94.9% (arm A) versus 86.5% (arm B; p=0.02). A PSA response (> 50%) was achieved in 94.9% (arm A) versus 85.8% (arm B; p=0.01) A PSA progression (25% increase) was observed in 1.3% in arm A and 10.1% in arm B (p=0.002).

Conclusions: The addition of 3-weekly docetaxel to ADT significantly improves PSA response and significantly reduces PSA progression at 6 months in patients with HNMPC.

No significant financial relationships to disclose.
Intensity-modulated radiation therapy (IMRT) for prostate cancer: Toxicity and biochemical control in 183 Chinese patients from a single institution in Hong Kong.
Authors: Poon D. M.
Published: February 2017

101

Background: To report the biochemical outcome and the acute and late toxicities in 183 Chinese patients with clinically localized prostate cancer treated with IMRT.

Methods: Between May 2001 and November 2009, 183 patients with clinically localized prostate cancer were treated with IMRT at the Prince of Wales Hospital. Median follow-up was 44 months (range 8.5 to 112 months).Treatment was planned using an inverse-planning approach, and the beams were delivered by dynamic multileaf collimation. Four-field box technique was used for pelvic irradiation (pelvic RT) if indicated in phase I and IMRT was used for prostate boost in phase II. The median age of the patients was 71.4 (range 45 to 82). According to the NCCN risk classification, 18 (9.8%), 47 (25.7%) and 118 (64.5%) patients belong to favorable, intermediate, and unfavorable risk group respectively. The median prescription dose of the planning target volume of the prostate gland (PTV-G) is 72Gy (range from 66 to 76Gy). 77 patients (42.1%) received pelvic RT. 129 patients (70%) received neoadjuvant hormone and 106 patients (57.9%) received adjuvant hormone. Acute and late toxicities were scored according to the Common Terminology Criteria for Adverse Events Version 4.02. Biochemical failure was defined according to the Houston definition (absolute PSA nadir plus 2ng/ml dated at the call).

Results: The 5-year actuarial biochemical-failure free survival for patients in favorable, intermediate and unfavorable risk groups were 95%, 80%, and 83% respectively. 3 patients (1.6%) experienced grade 3 acute gastrointestinal (GI) toxicity. There were no grade 3 acute genitourinary (GU) toxicity. There was no grade 4 acute GI or GU toxicity. 14 patients (7.7%) developed grade 2 late GI toxicity and 8 patients (4.4%) developed grade 3 late GI toxicity. 5 patients (2.7%) developed grade 2 late GU toxicity and 5 patients (2.7%) developed grade 3 late GU toxicity. There was no grade 4 late GI or GU toxicity.

Conclusions: These data demonstrate that IMRT for prostate cancer is feasible and safe in Chinese population. The early biochemical outcome is encouraging and the grade 3 late GI and GU complications were below 5%.

No significant financial relationships to disclose.
High-grade prostate cancer with favorable results in the modern era.
Authors: Ramahi E. , Swanson G. P. , Du F. , Basler J.
Published: February 2017

107

Background: Historically, patients with high-grade prostate cancer have the worst outcomes. With the advent of prostate- specific antigen (PSA) screening, diagnosing prostate cancer no longer depends on palpation of a bulky mass on digital rectal exam and prostate cancers are found at an earlier stage. Our aim is to determine the outcome of a modern cohort of high grade patients with the available treatment options.

Methods: We reviewed the STVHS Tumor Registry and identified those patients diagnosed with prostate cancer between 2002 and 2008 capturing those patients with Gleason score >7 on biopsy. Details including all recorded PSA values, biopsy and surgical pathology results, primary, neoadjuvant and adjuvant treatment, as well as response to treatment were recorded and analyzed using Kaplan-Meier estimates, log-rank test, and multivariate analysis using Cox proportional hazards models.

Results: We identified 297 patients with Gleason 8–10 cancer with a median follow up of 35 months. Initial treatment was surgery in 136, radiation in 52, and androgen ablation in 110; one patient has both surgery and androgen ablation. Five and 10 year biochemical-free survival (BFS), metastasis-free survival, and overall survival are shown in the Table . Overall, 5 year biochemical failure-free survival was 50% and metastasis free survival was 89%, resulting in an overall survival of 77%.

Conclusions: Historically, patients with a Gleason score of 8–10 have done very poorly. However, in the modern era, regardless of the initial treatment, the outcome is not as dire. Possible reasons are less bulky tumors or other facets of stage migration. While there is room for improvement, we should not have a nihilistic impression of how these patients will respond to treatment.

[Table: see text]

No significant financial relationships to disclose.
Long-term results of salvage cryotherapy for prostate cancer.
Authors: Williams A. , Martinez C. , Chalasani V. , Lu C. , Ng C. , Pautler S. E. , Chin J.
Published: February 2017

108

Background: The optimum treatment of Prostate cancer recurrence following external bean radiation therapy (EBRT) remains a controversial topic. The primary problem with comparing salvage techniques following EBRT is the lack of long term data. We reviewed the long- term overall survival, disease-specific survival and disease free survival of patients who have undergone salvage cryotherapy to the prostate gland.

Methods: A retrospective analysis was performed on all patients undergoing salvage cryotherapy for locally recurrent prostate cancer after EBRT by a single surgeon at a single institution from 1995-2004. Patients preoperative, perioperative and postoperative data was reviewed and recorded. Should a patient no longer be followed by the urology service the Patients and the patient's primary care physician or urologist were contacted. Mortality data, PSA results, bone scan results and any details of hormone therapy were recorded for this study.

Results: 187 patients were included in the current study from which 176 patients had records available for follow up giving a follow up rate of 94%. Mean follow up was 7.46 years (1-14 years). 52 patients were followed for greater than 10 years. Average time to prostate cancer recurrence in patients who developed recurred was 2.3 years and average time to hormone therapy in these patients was 2.8 years. Overall survival at 10 years was high at 87%. Risk factors for recurrence of tumour identified were presalvage PSA, preradiation and presalvage gleason score. Preradiation gleason score had little impact on survival. PSA nadir of >1.0ng/mL was highly predictive of early recurrence. Disease-free survival rates of between 39 and 64% depending on risk factors.

Conclusions: Cryotherapy has a definite role in the management of prostate cancer, representing a minimally invasive salvage treatment with acceptable 10 year disease free survival (DFS) of upwards of 39% and specific groups attaining 10 year DFS of 64%. Presalvage PSA and Gleason score are the best predictors of disease recurrence, whilst preradiation gleason score did not correlate with risk of disease recurrence. A PSA Nadir greater than 1 ng/mL indicates a poor prognosis in which early ADT should be strongly considered.

No significant financial relationships to disclose.
A novel repeat biopsy nomogram based on three-dimensional extended biopsy.
Authors: Sakura M. , Kawakami S. , Ishioka J. , Fujii Y. , Numao N. , Saito K. , Koga F. , Masuda H. , Fukui I. , Kihara K.
Published: February 2017

111

Background: There is no perfect cohort in which nomograms are developed because no biopsy method can detect all cancers. To minimize this inherent verification bias, having a cohort with fewer false negative cases is advantageous. Based on a cohort examined with three-dimensional (3D) extended biopsy protocol, we developed a novel nomogram for diagnosis of prostate cancer on repeat biopsy.

Methods: Of 4,074 consecutive male patients undergoing prostate biopsy at our institutions between 2000 and 2009, 775 men with at least one previous negative biopsy underwent repeat biopsy with 3D protocol. Men with previous atypical glands or atypical small acinar proliferation and/or without available prostate-specific antigen (PSA) kinetics information were excluded. The remaining 515 men constituted the study cohort. We developed a logistic regression-based nomogram with 70% of the cohort selected randomly; we validated it with the remaining 30%. Predictive accuracy and performance characteristics were assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots, respectively. The threshold probability was evaluated with decision curve analysis.

Results: We developed a novel repeat biopsy nomogram incorporating age, free to total PSA ratio, prostate volume, history of previous extended biopsy, and PSA doubling time. Validation confirmed predictive accuracy with an AUC value of 0.791. Calibration plots showed good agreement. The decision curve of the nomogram was superior to the decision curve of biopsying all men in a range of threshold probability over 0.15. At the threshold of 0.2, the number of unnecessary biopsies could be reduced by 10 per 100, without missing PCa.

Conclusions: We developed a novel repeat biopsy nomogram based on a cohort examined with 3D extended biopsy. This repeat biopsy nomogram is clinically beneficial, saving a substantial number of unnecessary biopsies.

No significant financial relationships to disclose.
Validation of the AJCC staging system (7th edition) in Asian patients with localized prostate cancer undergoing radical radiotherapy.
Authors: Wong M. , Yip C. , Hou X. , Tan P. , Huang H. , Chowbay B. , Lau W. , Tan T. , Tan M. , Wong F.
Published: February 2017

112

Background: The epidemiology of prostate cancer (PCa) varies widely internationally. Although prostate cancer is usually regarded as uncommon in Asia, dramatic rises in recent years have resulted in it being ranking third by incidence in Singapore. Conventional prognostic parameters derived from Western populations have been integrated into systems such as the new AJCC seventh edition staging system, the validity of which is unclear in Asia. We thus sought to validate its performance, alongside other prognostic factors in a large Asian series of radiotherapy patients.

Methods: A retrospective review of 404 consecutive Singaporean patients receiving radical radiotherapy between 1997 and 2005 at the National Cancer Centre was performed. The primary outcome was biochemical relapse free survival (BRFS), defined by the Phoenix criteria. Prognostic risk groups were defined using AJCC seventh edition. Univariate analysis (UVA) and multivariate analysis (MVA) was performed for other putative risk factors: age, race, Gleason score, prognostic risk grouping, tumour classification, radiation delivery technique, radiotherapy dose, hormonal therapy (HT) and initial PSA.

Results: Median age was 69; median BRFS was 55 months with 71 biochemical relapses. 4 risk factors showed univariate association with BRFS: AJCC risk groups (p=0.038), T-stage (p=0.018), RT dose (p=0.025) and initial PSA value (p=0.013) with AJCC risk groups and initial PSA value remaining significant after MVA ( Table ). Harrell's c-index for AJCC risk grouping was 0.56, with no significant difference seen in outcomes between AJCC risk group II and III.

Conclusions: Our results validate the new AJCC seventh edition prostate cancer prognostic risk grouping in an Asian radiotherapy population for the first time; the actual association however is relatively weak possibly due to differences in biology, screening or epidemiology.

[Table: see text]

No significant financial relationships to disclose.
Does increasing number of core biopsies change the results of needle biospy in prostate cancer?
Authors: Farhat M. H. , Dabaja A. , Agarwal P.
Published: February 2017

113

Background: The superiority of extended sampling of the prostate compared to standard sextant biopsy in predicting the final Gleason score has been controversial. In the literature, sextant biopsies have a match rate between 28–68% and an upgrading rate of 25–57%. Consequently, multiple studies recommend that extended biopsies should be the standard of care. This study examines the effect of greater core biopsy number on upgrading GS and predicting surgical pathology.

Methods: Prostate biopsies of 984 patients who underwent RP between 2001 and 2008 were retrospectively reviewed. The GS of the biopsies was compared to the pathological specimens using the Chi-square test. Further adjusted comparison was performed using logistic regression. A clinical significant upgrade was defined as increase of the total GS or the primary GS.

Results: The majority of the upgrading occurred in biopsy Gleason 3+3 and 3+4 cases. Upgrading was seen in 35.1% of patients with 6 cores or less, 34.5% with 7–12 cores, and 45.5% with 13+ cores (p=0.061). Number of cores, BMI, or prostate size did not affect upgrading, while perineural invasion, cancer volume on a biopsy, and D'Amico risk criteria increased the likelihood of upgrading.

Conclusions: The extended core biopsy does not seem to correlate with higher gleason score or to better predict the final pathologic gleason score compared to standard sextant biopsies in prostate cancer. D'Amico risk factors, perineural invasion, and cancer volume can be viewed as risk factors for upgrading especially in GS 3+3.

No significant financial relationships to disclose.
Nomograms to predict 3-year biochemical recurrence after robotic-assisted laparoscopic radical prostatectomy based on preoperative and perioperative variables of 774 patients.
Authors: Sooriakumaran P. , John M. , Srivastava A. , El-Douaihy Y. , Grover S. , Bhagat D. , Rajan S. , Leung R. , Tewari A.
Published: February 2017

115

Background: Predictors of biochemical recurrence after robotic-assisted laparoscopic radical prostatectomy (RALP) are not well reported in the literature. We wanted to investigate preoperative predictors as well as the influence of nerve sparing and positive surgical margin status on 3-year biochemical recurrence.

Methods: 774 patients with at least 3 year follow up had undergone RALP by a single surgeon at our institution. Biochemcial recurrence was defined as a postoperative PSA >0.2 ng/ml. Multivariable logistic regression models were used to develop the biochemical recurrence predictive nomograms: nomogram 1- age, BMI, PSA density, clinical stage, biopsy Gleason, percent positive cores, perineural invasion; nomogram 2- age, BMI, PSA density, clinical stage, biopsy Gleason, percent positive cores, perineural invasion, nerve sparing, positive surgical margins (none, unifocal, or multifocal). The predictive accuracy of the models was assessed in terms of discrimination and calibration.

Results: Both nomograms discriminated well between patients that recurred and those that did not (bootstrap corrected c-indices of 0.766 and 0.806 for nomograms 1 and 2 respectively). Nomogram 1 was well calibrated, but nomogram 2 over- predicted the probability of biochemical recurrence in patients at >30% risk.

Conclusions: Our nomogram based on age, BMI, PSA density, clinical stage, biopsy Gleason, percent positive cores, and perineural invasion on preoperative biopsy has a good predictive ability to differentiate between RALP-treated patients that biochemically recur by 3 years from those that do not. Adding nerve sparing and surgical margin status further improved discriminatory ability but at the expense of over-prediction for patients at high risk. These nomograms may be used to guide the use of nerve sparing and the management of positive margins in men undergoing RALP for clinically localized prostate cancer.

No significant financial relationships to disclose.
Phase III study of the efficacy and safety of zibotentan (ZD4054) in patients with bone metastatic castration-resistant prostate cancer (CRPC).
Authors: Nelson J. B. , Fizazi K. , Miller K. , Higano C. S. , Moul J. W. , Morris T. , McIntosh S. , Pemberton K. , Gleave M. E.
Published: February 2017

117

Background: Endothelin-1 and the endothelin A (ETA) receptor have been implicated in prostate cancer progression in bone. Zibotentan, a specific ETA receptor antagonist, had a promising signal for prolonged overall survival (OS) in a phase II study of patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain. The aim of this phase III study was to confirm the efficacy and safety of zibotentan in a similar but larger population.

Methods: Patients with CRPC and bone metastases were randomized 1:1 to zibotentan 10 mg/day po or placebo, plus standard of care including chemotherapy. The primary endpoint was OS. Secondary endpoints included times to pain progression, chemotherapy use, new bone metastases, and safety. Efficacy endpoints were analyzed using a log-rank test. At least 263 deaths were required for formal analysis. If the true hazard ratio (HR) for zibotentan versus placebo was 0.67, the analysis would have 90% power to demonstrate a statistically significant effect in OS at the 5% level.

Results: A total of 594 patients were randomized (299 to zibotentan; 295 to placebo). Baseline group demographics were similar. Mean age was ∼71 yrs, and 64% were Caucasian. Although median OS was longer in zibotentan-treated patients than those receiving placebo (median 24.5 vs 22.5 months), the difference did not reach significance (HR [95.2% confidence interval]; 0.87 [0.69–1.10]: P=0.240). No significant differences were observed for any secondary endpoints. The most commonly reported AEs in the zibotentan group, peripheral edema and headache, were consistent with the pharmacologic action of zibotentan as a vasodilator. Cardiac failure events, actively solicited following a phase II signal, were higher in the zibotentan group (any grade, 5.7%; Common Terminology Criteria for Adverse Events [CTCAE] grade ≥3, 3.0%) than placebo (any grade, 1.7%; CTCAE grade ≥3, 1.0%), but were manageable and reversible.

Conclusions: In this placebo-controlled phase III trial treatment with zibotentan 10 mg/day did not lead to a significant improvement in OS in patients with CRPC and bone metastases. Zibotentan had an acceptable safety profile.

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Correlation of 11c-choline PET-CT with time to treatment and disease-specific survival in men with recurrent prostate cancer after radical prostatectomy.
Authors: Breeuwsma A. J. , Pruim J. , Leliveld A. M. , Dierckx R. A. , de Jong I. J.
Published: February 2017

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Background: Restaging with PET-CT in biochemical recurrent prostate cancer after prostatectomy shows a higher frequency of (false) negative cases compared to restaging after EBRT. It is uncertain if this reflects low volume of disease and/or low grade as biopsies fail to prove recurrent cancer in 50% of cases. We followed the clinical course of men with recurrent prostate cancer (PCa) after radical prostatectomy and investigated treatment and survival. PET-CT data were correlated with clinical data, PSA kinetics and disease specific and overall survival. We also studied relative survival comparing an age matched group from the Central Dutch Statistical Office (CBS).

Methods: 64 patients underwent 11C-Choline PET-CT on PSA relapse. All patients were initially treated with radical prostectomy and reached PSA nadir of <0.1ng/mL. Recurrent disease was defined as PSA <0.4ng/mL after nadir. Patients were either treated with watchful waiting, adjuvant radiotherapy and/ or androgen deprivation therapy based on individual assesments by the treating urologists. Chi-square, log-rank and Mann-Whitney-U tests were used to study this population

Results: The 64 patients had median PSA of 1.4ng/mL. Median follow-up period of patients was 50 (6–124) months. Ten patients died during the course of follow-up of which 5 due to metastasized PCa. No significant differences were seen in age, time to recurrence, total PSA at recurrence and PET-CT results. Patients with abnormal PET had higher PSAVel (median 3.09 ng/mL/yr vs 10.17, p= 0.002) and and shorter PSADT (med 4.83 mo vs 0.53, p= 0.016). Median time to treatment was significantly lower in the PET-CT negative group. Age of patients at death from the whole group did not differ from the age of death in an age matched group. Disease specific survival was significantly higher in the PET-CT negative group (p0.05).

Conclusions: A negative 11C-Choline PET-CT correlated with a higher disease specific survival and a lower treatment rate. Overall survival of the group was equal to the age matched cohort.

No significant financial relationships to disclose.
Phase II study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue disease.
Authors: Smith D. C. , Smith M. R. , Small E. J. , Sweeney C. , Kurzrock R. , Gordon M. S. , Vogelzang N. J. , Scheffold C. , Ballinger M. D. , Hussain M.
Published: February 2017

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Background: XL184 is an oral, potent inhibitor of MET and VEGFR2. MET pathway activation promotes tumor growth, invasion and metastasis. Overexpression of MET and/or its ligand HGF are associated with prostate cancer metastasis. In preclinical studies, androgen ablation upregulates MET signaling. Preliminary data from the open label Lead-in Stage of an ongoing adaptive design phase II randomized discontinuation trial are presented.

Methods: Eligible pts had CRPC, measurable disease with or without bone metastasis, and disease progression on ≤1 prior non-hormonal systemic treatment. XL184 was administered orally for 12 weeks (wks). Tumor (RECIST) and bone scan response (complete or partial resolution) were assessed every 6 wks. Primary endpoint is objective response rate at wk 12. Pts with SD at wk 12 will enter a placebo-controlled randomized phase.

Results: As of 10/4/10, 72 pts have been enrolled. Median time on study was 50 days (range, 6+-350+ days). Median age was 69 yrs; 45% of pts were docetaxel-pretreated. All pts had measurable disease, including 69% with visceral metastases. To date, there are 24 response evaluable pts, defined as enrolled ≥12 wks prior to data cutoff. 5/24 (21%) pts had a partial response (≥30% reduction) in measurable disease with 3 responses confirmed at 12 wks and 2 unconfirmed responses ongoing. 6/24 (25%) had PSA declines of ≥50%. 13 of 15 (87%) pts with known bone metastases had either complete or partial resolution of lesions on bone scan. Bone scan responses were associated with investigator-reported improvement in bone pain in 11/15 (73%) with pain at baseline. Effects on osteoclast and osteoblast activity were observed: plasma C-telopeptide declined ≥50% in 8/12 (66%) pts and serum total alkaline phosphatase (tALP) declined ≥50% in 5/8 (63%) pts with bone metastases and baseline elevated tALP. The most common AEs ≥Grade 3 severity (related) were fatigue (10%), diarrhea (3%) and elevated AST (3%).

Conclusions: XL184 results in tumor responses, partial or complete resolution of lesions on bone scan, and symptom relief in pts with metastatic CRPC, including those pretreated with docetaxel. XL184 also decreased biomarkers of both osteoblast and osteoclast activity.

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Antitumor activity of MDV3100 in pre- and post-docetaxel advanced prostate cancer: Long-term follow-up of a phase I/II study.
Authors: Higano C. S. , Beer T. M. , Taplin M. , Efstathiou E. , Anand A. , Hirmand M. , Fleisher M. , Scher H. I. ,   Prostate Cancer Clinical Trials Consortium
Published: February 2017

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Background: MDV3100 is a novel androgen receptor (AR) antagonist selected for potent AR activity and devoid of partial agonist effects. A preliminary report of the phase I/II study described anti-tumor activity and adverse events (Scher HI et al. Lancet. 2010;375:1437). This abstract provides long-term follow-up on time to PSA and radiographic progression in this trial.

Methods: Patients (pts) with progressive castration resistant prostate cancer (CRPC) were enrolled in sequential cohorts of 3-6 pts at MDV3100 doses of 30, 60, 150, 240, 360, 480 and 600 mg/day. Once the tolerability of a dose was established, enrollment was expanded at doses ≥60 mg/day to include approximately 12 chemotherapy naïve (naïve) pts and 12 pts previously treated with docetaxel (post-chemo) per cohort.

Results: 140 pts were enrolled of which 18 (13%) pts continue on active treatment (16 naive and 2 post-chemo). The median time on treatment is 51 weeks for naïve and 17 weeks for post-chemo groups. Median time on treatment for the 18 patients still on study is 131 weeks. The median time to PSA progression, defined per-protocol as a ≥25% increase in PSA from baseline, was not met for naïve and was 33 weeks for post-chemo groups. Median time to PSA progression by Prostate Cancer Clinical Trials Working Group 2 criteria was 41 weeks for naïve and 20 weeks for post-chemo groups. Median time to radiographic progression was 56 weeks for naive and 24 weeks for post-chemo groups. Circulating tumor cell counts available for 128 of 140 pts showed 91% (70/77) with favorable pre-treatment counts (<5 cells/7.5 mL blood) remaining favorable post-treatment, while 49% (25/51) converted from unfavorable pre-treatment to favorable post-treatment.

Conclusions: MDV3100 demonstrates durable anti-tumor activity in pts with CRPC both before and after chemotherapy. Based on these promising results MDV3100 is currently being evaluated in two global phase III studies in pts with metastatic CRPC, the AFFIRM study in pts previously treated with docetaxel and the PREVAIL study in chemotherapy-naïve pts who have progressed on androgen deprivation therapy.

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Subsequent treatment with APC8015F and its effect on survival in the control arm of phase III sipuleucel-t studies.
Authors: George D. J. , Nabhan C. , Gomella L. G. , Whitmore J. B. , Frohlich M. W.
Published: February 2017

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Background: Sipuleucel-T is an autologous cellular immunotherapy approved for metastatic castrate resistant prostate cancer.

Methods: After disease progression, subjects in the control arms of 3 randomized controlled sipuleucel-T trials were offered 3 infusions of APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control generation.

Results: Of 249 control subjects, 165 (66.3%) received APC8015F; the median time from randomization to first infusion was 5.2 months (range 1.8 to 33.1), median time from objective disease progression to first APC8015F infusion was 2.2 months (range 0.5 to 14.6), and 145 subjects (87.9%) received all 3 infusions. The frequency of infusional toxicities was increased following APC8015F relative to control infusion, but was slightly lower than following sipuleucel-T. APC8015F-treated subjects (n=155) had improved post-progression survival relative to untreated controls (n=61) (HR=0.52 [95%CI 0.37, 0.73] p=0.0001, log rank test, unadjusted Cox regression); however, APC8015F-treated subjects had more favorable prognostic features than untreated controls. A Cox regression analysis adjusting for baseline PSA and LDH demonstrated that APC8015F therapy remained a predictor of survival in control subjects (HR=0.56 [95%CI 0.40, 0.80]; p=0.001). A Cox regression model adjusting for age, PSA, LDH and post-randomization docetaxel use (yes/no), also showed a significant effect for salvage treatment among control subjects (HR=0.55 [95%CI 0.39, 0.78] p<0.001). Examination of APC8015F product characteristics demonstrated that cumulative CD54 upregulation was associated with survival following first infusion in subjects who progressed and received APC8015F (p=0.03), consistent with previous reports of correlations between sipuleucel-T product parameters and overall survival.

Conclusions: Although confounded with measured and unmeasured factors influencing outcome, these analyses suggest that post-progression treatment with APC8015F may have extended the survival of subjects in the control arms of these studies.

[Table: see text]