bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pond Gregory Russell , Berry William R. , Galsky Matt D. , Wood Brian A. , Leopold Lance Howard , Sonpavde Guru
Published: February 2017

51

Background: Data suggest docetaxel clearance is increased in castrate men. An association of docetaxel-induced grade ≥3 neutropenia with overall survival (OS) may provide a rationale for tailored dosing in mCRPC.

Methods: The association of cycle 1 neutropenia with OS was examined in a randomized phase II trial of 221 men with mCRPC receiving docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor), which performed weekly blood cell counts during the first cycle. Patients from both arms were combined as no outcome or neutropenia differences were observed. OS was calculated from randomization by the Kaplan-Meier method and Cox proportional hazards regression models were used to estimate the association with OS.

Results: The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for stratification factors (HR: 0.64, p= 0.048). Excluding men with delayed cycle 2 yielded a more significant association of grade 3-4 neutropenia on day 8 with survival (Table). Men with ≥grade 3 neutropenia and ≥30% PSA decline by day 90 had improved OS compared with men exhibiting neither (HR: 0.51, p=0.014).

Conclusions: In mCRPC receiving docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, suggesting its potential utility as a pharmacodynamic marker in this hypothesis-generating analysis. Since the association was stronger after excluding patients that experienced dose delays, grade 3 neutropenia may confer a more favorable therapeutic index than grade 4 neutropenia. The exploration of dose modulation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted.

[Table: see text]
Use of zoledronic acid therapy–associated severe hypophosphatemia to identify poor-prognosis patients with metastatic castration-resistant prostate cancer.
Authors: Warr Julia , Yam David , Goodall Shannon , VanDraanen Leah , Giotis Angie , Pasetka Mark , De Angelis Carlo , Emmenegger Urban
Published: February 2017

58

Background: Zoledronic acid (ZOL) therapy is associated with severe (i.e., grade 3/4 according to CTCAEv4.0) hypocalcemia and hypophosphatemia in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) to bone. However, as opposed to the distinct clinical picture of hypocalcemia, the symptoms of hypophosphatemia are less pathognomonic. Furthermore, the rate of hypophosphatemia is not regularly reported.

Methods: To characterize the rate and circumstances of severe hypophosphatemia in mCRPC patients undergoing ZOL therapy, we identified mCRPC patients receiving at least 3 doses of ZOL therapy at our Centre between 2004 and 03/2011. Patient demographics, disease and laboratory parameters were extracted by using the Oncology Symptom Control and Information Resource database, and by means of manual chart review.

Results: 11 of 112 patients (10%) developed grade 3/4 hypophosphatemia (nadir) after 241±223 days (mean±SD) following the first dose of ZOL. Only one patient presented with concomitant severe hypocalcemia. Interestingly, the hypophosphatemia nadir coincided with rising PSA readings in 9 out of 10 informative patients. Furthermore, ZOL-associated severe hypophosphatemia identified mCRPC patients with worse outcome (time from CRPC diagnosis to death 628±317 days, versus 901±526 days in CRPC patients without severe ZOL-associated hypophosphatemia, p < 0.028).

Conclusions: 10% of mCRPC patients undergoing ZOL therapy presented with grade 3/4 hypophosphatemia. While hypocalcemia usually occurs within the first 6 months of ZOL therapy, ZOL-associated severe hypophosphatemia is a relatively late event. It appears to occur at the time of disease progression and is associated with a poor outcome.
A phase I trial of AEZS-108 (AN-152) in castration- and taxane-resistant prostate cancer.
Authors: Liu Stephen V. , Schally Andrew V , Dorff Tanya B. , Tsao-Wei Denice D. , Groshen Susan G. , Xiong Shigang , Hawes Debra , Quinn David I. , Tai Yu-Chong , Block Norman L. , Engel Juergen , Pinski Jacek K.
Published: February 2017

60

Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH-R), which is highly expressed on prostate cancer cells. AEZS-108 (AN-152) is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of these receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide both enumeration of CTCs and LHRH-R expression on captured CTCs as well as results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs.

Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity for up to 6 cycles. The primary endpoint was safety.

Results: Enrollment began in November 2010 and completed in September 2011. Twelve patients were accrued onto 3 dose levels. No DLTs have been noted. At the time of submission, a decrease in PSA was noted in 5 of the 10 evaluable patients. The grade 3 or 4 toxicities were primarily hematologic. Final reports detailing toxicity, RECIST response and PSA response will be reported. All correlative studies will also be reported.

Conclusions: AEZS-108 is well tolerated and has demonstrated early signs of antitumor activity in men with CRPC. We will report the recommended dose for the planned phase II study.
Modeling fecal incontinence symptoms 6 years after high-dose radiation for prostate cancer: Clinical and dosimetric predictors.
Authors: Fellin Giovanni , Rancati Tiziana , Fiorino Claudio , Vavassori Vittorio , Cagna Emanuela , Mauro FloraAnna , Malinverni Giuseppe , Valdagni Riccardo
Published: February 2017

71

Background: To evaluate the incidence of late fecal incontinence (linc) after high-dose radiotherapy (RT) in prostate cancer patients (pts) accrued in AIROPROS 0102 trial (RT doses: 70-80Gy, 1.8-2Gy/fr) and to model the relationship between linc and clinical/dosimetric factors.

Methods: Self-reported questionnaires of 515 pts with a minimum follow up of 6 yrs were analyzed with respect to linc. G1 linc was scored if unintentional stool discharge was “sometimes” experienced, G2 linc if unintentional stool discharge was “often” experienced or if pts sporadically used sanitary pads; G3 if pts reported daily unintentional stool discharge or use of sanitary pad >2 times/week. Correlation between pre-treatment morbidities, hormonal therapy, drug prescription, presence of diabetes or hypertension, abdominal surgery prior to RT (SURG), presence of G2-G3 acute fecal incontinence (ACUINC), pelvic nodes and seminal vesicles irradiation, mean rectal dose, dose-volume histograms constraints (from V20Gy to V75Gy) and linc was investigated by uni- and multivariate (MVA) logistic analyses. 347/515 pts had at least 3 toxicity questionnaires in the first 36 mos after the end of RT. Correlation between the mean score of fecal incontinence in the first 36 mos and linc at 6 yrs was also investigated.

Results: 50/515 G1, 3/515 G2 and 3/515 G3 linc were reported. In MVA, V40Gy (continuous variable, p=0.09, OR=1.015), use of antihypertensives (protective factors, p=0.005, OR=0.38), SURG (p=0.004, OR=4.7), presence of haemorrhoids (p=0.008, OR=2.6) and ACUINC (p=0.007, OR=4.4) resulted to be correlated to linc. Based on MVA results, a nomogram was developed. Linc at 6 yrs was also correlated to the mean incontinence scores in the first 36 mos (p<0.0001): pts without linc at 6 yrs had a mean score of 0.1 during the first 36 mos, while pts with G1 and with G2-G3 linc at 6 yrs had a mean score of 0.5 and 0.78 during the first 36 mos, respectively.

Conclusions: Mean score for incontinence during the first 36 mos after RT can be used as a surrogate endpoint for late (>6yrs) fecal incontinence. Linc is correlated to clinical and dosimetric risk factors and individualised toxicity prediction can be performed through a nomogram.
Hormonal impact of salvage chemotherapy with carboplatin plus weekly docetaxel in patients with castration- and docetaxel-resistant prostate cancer (DRPC).
Authors: Reuter Christoph W. , Morgan Michael A. , Fenner Martin , Grünwald Viktor , Ganser Arnold
Published: February 2017

74

Background: Recent data suggest that carboplatin may be effective in combination with docetaxel in DRPC. Platinum(II)-complexes have been shown to interfere with testosterone biosynthesis by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3b-hydroxysteroid dehydrogenase (HSD3B1,2) and 17a hydroxylase/C17,20-lyase (CYP17A1).

Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Since February 2005, 68 consecutive DRPC pts were treated with at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n=42) and during DC treatment (n=36).

Results: Response of prostate-specific antigen (PSAR; ≥50% PSA) was observed in 32/68 (47.1%) patients. At the time of the current analysis the median follow-up time was 13.6 months and 43/68 patients had died. Median progression-free survival (PFS) for all patients was 7.5 months (CI 95% 5.4, 9.5) and median overall survival (OS) was 18.6 months (CI 95% 12.3, 24.9). In PSAR, PFS was 15.7 versus 4.8 months in PSANR (p<0.001; hazard ratio HR 0.19, CI 0.09, 0.39) and OS was 25.6 versus 8.1 months (p<0.001; HR 0.21 CI 0.10, 0.42). This regimen was reasonably well tolerated, with leukopenia/neutropenia as the most common reversible grade 3/4 toxicity (39.7/33.8%). Median free testosterone levels were 0.935 pg/ml before and 0.185 pg/ml during DC treatment (nadir; p<0.001). While free testosterone levels before DC treatment were associated with lower PSAR (HR 6.32 CI 1.60, 25,0; p=0.009), free testosterone nadir levels <0.18 pg/ml during DC treatment were associated with higher PFS (HR 0.126 CI 0.04, 0.46, p=0.002) and OS (HR 0.07 CI 0.008, 0.53; p=0.01).

Conclusions: These data suggest that DC may be an important second-line treatment option for DRPC patients by inhibiting the testosterone biosynthesis.
Truncation of BRAF and Raf1 in prostate cancer in China.
Authors: Lu Yong-Jie , Liu Xiaoyan , Mao Xueying , Hylands Lucy , Clark Jeremy , Cooper Colin , Ren Guoping
Published: February 2017

77

Background: Chromosome translocations and fusion genes have been identified as common events in carcinomas in recent years and TMPRSS2:ERG fusions have been found in about half of human prostate cancers. However, by genome-wide analysis of Chinese prostate cancer cases, we found that certain genomic alterations, commonly identified in prostate cancer samples from the Western countries, occurred at a very low frequency in China, including the fusion of TMPRSS2:ERG. In 2010, recurrent fusion genes involving the RAF family gene BRAF and Raf1 were identified (Palanisamy et al, Nature Med. 16:793). Although the frequency of fusions involving BRAF and Raf1 are at a much lower frequency than fusion of TMPRSS2:ERG, BRAF and Raf1 are drugable, making them potential therapeutic targets. As the TMPRSS2:ERG fusion is infrequent in Chinese prostate cancers, we investigated if fusions involving BRAF and Raf1 occur at a higher frequency in prostate cancer in China than in Western countries.

Methods: We used the fluorescence in situ hybridization signal split apart approach on prostate cancer samples made into tissue microarrays to detect the frequency of BRAF and Raf1 truncations. Three BAC probes on each side (5’ and 3’) of the two genes were labeled differentially using biotin and digoxigenin and subsequentially detected as red and green fluorescent signals, respectively.

Results: We found that BRAF was truncated in four (two split signals, one 5’ deletions and one 3’ deletions) of the 193 informative cases (2.07%) and RAFaf1 (two 5’ deletions and one split signals) was truncated in three of 201 informative cases (1.49%). Although in some cases, three or four copies of these genes were detected, extensive copy number gain caused by amplification was not detected.

Conclusions: These results indicate that truncations and potentially fusion of BRAF and Raf1 exist in Chinese prostate cancer, but at a similar low frequency as found in the Western samples (6/349 for BRAF and 4/450 for Raf1). Further studies are required to confirm the functional consequence of these truncations and to evaluate the therapeutic value of targeting these genes in this sub-group of prostate cancers.
C11-acetate PET for docetaxel prednisone (DP) response assessment in castrate-resistant prostate cancer (CRPC).
Authors: Sharma Nancy , Menda Yusuf , Boles-Ponto Laura , Vaena Daniel A.
Published: February 2017

83

Background: C11-acetate (acetate) positron-emission tomogram (PET) has shown promise in detection of metastasis in prostate cancer in recent studies. Our study tested the feasibility of acetate-PET to predict early response to DP in CRPC.

Methods: Men with metastatic CRPC for whom DP was indicated were enrolled in a prospective study of acetate-PET imaging and bone scans. Patients (pts) were imaged with both modalities at study entry and after 3 cycles of DP. DP was continued beyond cycle 3 until PCWG2-defined progression or toxicity. Treating physicians were blinded to acetate-PET results. No pts were on statins. The study was IRB-approved.

Results: 6 pts with documented bone metastases were imaged (5 both pre and post-therapy.) Pre-therapy acetate-PET identified osseous metastases in all 6 pts. Remarkably, in one pt with previous radiation therapy, pre-therapy acetate-PET was negative for disease in the radiated area whereas bone scan showed persistent activity. The median number of DP cycles was 7 (5-16). 4 pts had ≥ 50% PSA decline. The median time to progression (TTP) was 5 months (mo). Of the 4 pts with PSA response, 2 had response on acetate-PET with TTP 5 mo and 10 mo respectively. One pt had > 50% PSA response but progression after 3 cycles based on PET, and met PCWG2 criteria for progression at 3.5 mo. The 4th pt with PSA response had stable findings on post-therapy PET and had >10 mo TTP. The pt who had no PSA response had stable post-therapy PET and had 2 mo TTP. Bone scan was stable in 4 pts and showed progression in 1 pt.

Conclusions: Response or progression on acetate-PET can be seen after a few chemotherapy cycles for CRPC. This study supports the exploratory inclusion of acetate-PET in future therapeutic clinical trials, with the potential to enhance the early prediction of treatment outcome. Acetate-PET might also allow more precise identification of viable target lesions than bone scan.
Radiation Therapy Oncology Group (RTOG) 9413: Randomized trial comparing whole pelvic radiotherapy (WPRT) to prostate only (PORT) and neoadjuvant hormone therapy (NHT) to adjuvant hormone therapy (AHT).
Authors: Roach Mack , Yan Yan , Lawton Colleen Anne , Hsu I-Chow Joe , Lustig Robert A. , Jones Christopher U. , Rotman Marvin , Zeitzer Kenneth Lee , Werner-Wasik Maria , Kim Harold , Thomas Charles R. , Shipley William U. , Sandler Howard Mark
Published: February 2017

96

Background: RTOG 9413 demonstrated that NHT+WPRT improved progression-free survival (PFS) compared to NHT+PORT, WPRT+AHT and PORT+AHT. We update primary and secondary endpoints (SE): biochemical failure (BF), time to metastasis (Mets), prostate specific survival (PSS) and overall survival (OS).

Methods: RTOG 9413 opened on April 1, 1995, and closed on June 1, 1999, with 1275 eligible pts who were required to have a risk of lymph node (LN) involvement >15% but LN-positive pts were ineligible. They were stratified by T Stage, GS (<7 vs 7-10) and PSA (>30 vs < 30ng/ml) and randomized to PORT +/- WPRT to 70 Gy and NHT or AHT. Hormonal therapy (HT) consisted of flutamide, and leuprolide or goserelin, monthly x 4 mos, beginning 2 mos before RT and continued until RT is completed (NHT) or beginning at the completion of RT (AHT). For this analysis PFS was defined as the first occurrence of local/regional or LN progression, Mets, BF (PSA nadir+2ng/mL), or death from any cause. PSS is defined as a death due to prostate cancer, treatment toxicity or unknown causes with local progression, Mets or BF.

Results: For the entire cohort WPRT or NHT did not appear to improve any endpoint compared with PORT or AHT, (although there was a trend for improvement in regional failure for WPRT vs PORT, (p=0.07)). However, there were complex sequence/volume dependent interactions between HT and RT and statistically significant differences between the 4 arms in PFS (p=0.03). There was a trend for NHT+WPRT to improved PFS compared to NHT+PO (p=0.07) and WPRT+AHT (p=0.04). NHT+WPRT was associated with an increased risk of late GI toxicity, 5% compared to 0.6%, 2% and 2% for NHT+PORT, WPRT+AHT and PORT+AHT (p<0.001) but not in GU late toxicity.

Conclusions: The failure to improve SE or definitively impact PFS may reflect sample size, pt selection, and inadequate RT doses. RTOG 0924 will test the hypotheses that modern techniques and doses will improve OS without increasing late toxicity.
Relationship of time to testosterone (T) and PSA rises during the first “off treatment” interval (1OFF) of intermittent androgen deprivation (IAD) with time to castration resistance (CRPC) and prostate cancer mortality (PCM) in men with biochemical relapse (BR).
Authors: Yu Evan Y. , Kuo Kevin F , Hunter-Merrill Rachel , Gulati Roman , Hall Suzanne P , Gambol Teresa E , Etzioni Ruth D , Higano Celestia S.
Published: February 2017

99

Background: A recent phase III trial of intermittent vs. continuous AD supports IAD as standard of care for men treated with AD for BR. To identify potential factors during 1OFF prognostic for time to CRPC or PCM, relationships with times to T and PSA rises from our prospective trial of IAD in men with BR were analyzed.

Methods: 72 patients were treated with IAD, each cycle consisting of 9 months of leuprolide and flutamide followed by a variable “off treatment” interval. T and PSA were followed monthly; AD was resumed when PSA reached a pre-specified value. Cycles repeated until CRPC, defined as ≥2 PSA rises with T<50 ng/dL. We evaluated patients who completed 1OFF and reached T>50 with a Cox proportional hazards model, controlling for age at study entry, to quantify association of time to first T>50 with time from this point to CRPC or PCM. Similarly we quantified association of PSA rise during 1OFF and after first T>50 with these endpoints.

Results: A longer time to PSA rise during 1OFF or after T>50 was associated with longer time to CRPC, while longer time to first T>50 was marginally associated with shorter time to PCM. Specifically, a 30-day increase in time to PSA rise during 1OFF or after T>50 was associated with a 21% or 27% reduction in the risk of CRPC, while a 30-day increase in time to first T>50 was associated with a 39% increase in the risk of PCM.

Conclusions: That longer time to PSA rise during 1OFF was associated with longer time to CRPC is not surprising, but the association between longer time to first T>50 and time to PCM has not been reported. To validate these findings, an extended analysis is underway and will be presented.

[Table: see text]
Cosmetic outcome after intraoperative radiotherapy or external beam radiotherapy for early breast cancer: An objective assessment of patients from a randomized controlled trial.
Authors: Keshtgar Mohammed R. , Williams Norman R. , Corica Tammy , Bulsara Max , Saunders Christobel , Flyger Henrik , Bentzon Niels , Cardoso Jaime S. , Michalopoulos Nikolaus , Joseph David John ,   on behalf of the TARGIT Trialists' Group
Published: February 2017

59

Background: The international randomised contolled TARGeted Intraoperative radioTherapy (TARGIT) trial has demonstrated non-inferiority between the novel technique of TARGIT (intra-operative radiotherapy with Intrabeam) and conventional whole-breast external beam radiotherapy (EBRT) in women with early breast cancer, in terms of the primary outcome measure of risk of local relapse within the treated breast. With very low recurrence rates, cosmesis becomes an increasingly important outcome of breast conserving treatment with both surgery and radiotherapy. This study was performed to determine if the single high dose of TARGIT leads to impaired cosmesis. Methods: A validated, objective assessment tool for evaluation of cosmetic outcome was used. Frontal digital photographs were taken at baseline (before TARGIT or EBRT) and yearly thereafter for up to five years. The photographs were analysed by BCCT.core software which produces a composite score based on symmetry, colour and scar. Results: 342 patients were assessed, all over 50 years old with a median age at baseline of 64 years (IQR 59 to 68). The scores were dichotomised into Excellent and Good (EG), and Fair and Poor (FP). There were statistically significant increases in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group at year 1 (OR = 2.07, 95% CI 1.12 to 3.85, p = 0.021) and year 2 (OR = 2.11, 95% CI 1.0 to 4.45, p = 0.05). Conclusions: Following an objective assessment of aesthetic outcome in patients from a randomised setting, this study demonstrates that those treated with targeted intraoperative radiotherapy have a superior cosmetic result compared with those patients who received conventional whole-breast external beam radiotherapy.
Estimation of travel time and costs required for patients with cancer to receive outpatient treatment using electronic medical record data.
Authors: Isshiki Takahiro , Kimura Yuko , Takei Naoko , Hagino Noboru , Komatsu Tsunehiko
Published: February 2017

270

Background: Cancer creates a tremendous financial burden. Cancer-related costs are categorized into direct, indirect and psychosocial costs. Although there have been many reports on medical care costs, which are direct, those on other costs are extremely scarce. We estimated travel time and costs required for cancer patients to receive outpatient treatment. Methods: We studied 524 cancer patients given anti-cancer treatment between February 2009 and December 2012 at the Outpatient Chemotherapy Center of Teikyo University Chiba Medical Center. Address data were extracted from Data Warehouse electronic medical records, and travel distance and time required for outpatient treatment were calculated via MapInfo and ACT Distance Calculator Package. Transportation costs were estimated on the basis of ¥274 (= $3.00) per kilometer. Results: Average round-trip travel distances, times, and costs by cancer type are shown below. Average round-trip travel distance, time, and cost for all patients were 26.7 km, 72.5 minutes, and ¥7,303 ($79.99), respectively. Conclusions: Cancer patients incurred a travel cost of approximately ¥4,000 to ¥9,000 ($40.00 to $100.00) for each outpatient treatment. With population aging, seniors living alone and senior households are increasing, and outpatient visits are becoming a common burden. [Table: see text]
Association of 2-O, 3-O desulfated heparin (ODSH) plus combination gemcitabine (G)/nab-paclitaxel (A) with preliminary benefit in untreated metastatic pancreatic cancer.
Authors: Sigal Darren , Marcus Stephen G , Rosen Peter J. , Cohen Steven J. , Lee Peter , Nguyen Timmy , Gribbin Thomas Edward , Quintana Diez Pedro , Borad Mitesh J.
Published: February 2017

284

Background: ODSH, a low anticoagulant heparin derivative, interferes with several important pancreatic cancer cell survival pathways. A randomized phase II trial was initiated to determine if ODSH improves the activity of G/A, a promising pancreatic cancer investigational therapy. Preliminary data are presented here for the first 10 patients administered ODSH as part of an initial run-in phase prior to patient randomization. Methods: Patients with previously untreated, metastatic pancreatic cancer were treated with G (1,000 mg/m2) and A (125 mg/m2) plus ODSH (4 mg/kg bolus followed by a 48 hr. continuous IV infusion at a dose of 0.375 mg/kg/hr) on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity. Patients were required to have ECOG ≤ 1 and appropriate blood and liver function levels. The primary endpoint was progression-free survival (PFS). Results: 10 patients (median age, 66 years) were administered up to 5 cycles of G/A plus ODSH. Per RECIST criteria, a partial response (PR) was achieved in 5 patients (50%) and the median PFS will exceed 6 months. Disease control (PR or stable disease for > 16 weeks) occurred in all 10 patients. Of 9 patients with baseline elevated CA 19-9 levels, 8 had > 60% reduction. ODSH was well tolerated and unexpectedly appeared to preserve marrow function as no patients had grade 3/4 thrombocytopenia or grade 4 neutropenia during any of the cycles. Conclusions: Although G/A and FOLFIRINOX are important advances, additional progress is necessary for metastatic pancreatic cancer patients. ODSH may interfere with pancreatic cancer invasion, metastasis, and chemo-resistance by inhibiting P- and L-selectins, heparanase, and the HMGB1-RAGE axis, respectively, suggesting that ODSH may enhance chemotherapy activity. This preliminary analysis in a small number of patients is encouraging and consistent with a previous report for this regimen (Von Hoff, J Clin Oncol, 2011). ODSH has also been very well tolerated and early data suggests that it may preserve platelet and neutrophil levels. Further follow-up of the ongoing randomized phase II trial is warranted. Clinical trial information: NCT01461915.
FOLFERA: A randomized phase II study of irinotecan, 5-fluorouracil (5-FU), and folinic acid (FOLFIRI) with or without addition of the endothelin receptor antagonist (ETAR) zibotentan in patients with metastatic colorectal cancer after failure of oxaliplatin-containing chemotherapy.
Authors: Thomas Anne L. , Casbard Angela Claire ,   FOLFERA Trial Management Group
Published: February 2017

406

Background: Zibotentan (Z) is an oral specific ETAR antagonist. The ETAR is over expressed in colorectal cancer, and pre-clinically, antagonism of the ETAR has been shown to enhance cytotoxicity when combined with cytotoxics such as 5-FU. This multi-center, randomized, double-blind, placebo-controlled phase II study evaluated the safety and anti-tumor activity of irinotecan and 5-FU (as the FOLFIRI regimen) in combination with Z in advanced colorectal cancer. Methods: Patients (pts) with advanced colorectal cancer who had progressed after oxaliplatin-containing chemotherapy (FOLFOX) were randomized (1:1) to receive 10 mg O.D Z/placebo (continuous dosing) with standard dose FOLFIRI for a maximum of 12 cycles. Z /placebo could be continued until progression or unacceptable toxicity in those patients with a documented response. The primary objective was progression–free survival (PFS) with secondary endpoints of safety and blood and archival tumor samples collected for translational work including circulating tumour cell (CTC) analysis. This study was run as part of the AZ/NCRN alliance, endorsed by Cancer Research UK (CRUKE/09/023) and coordinated by the Wales Cancer Trials Unit, Cardiff University. Results: A total of 111 patients were recruited: 61% men, median age of 62 years. Z was well tolerated with G3/4 toxicity balanced between both groups (34/55 patients in Z and 38/56 in placebo group). The study was terminated before the planned number of pts (122) were recruited due to lack of efficacy of the drug in two other tumour types. Median PFS was 4.0 months in the Z group and 7.4 months in the placebo group (HR=1.86, 95% CI 1.20 to 2.87, p=0.005). The CTC analysis in relation to outcome in the placebo group will be presented. Conclusions: Zibotentan does not have anti-cancer activity in combination with FOLFIRI in patients with colorectal cancer treated with previous FOLFOX. Taken in consideration with the other trial data we do not recommend the further development of zibotentan in oncology. Clinical trial information: 73199181.
Final results of first European phase II trial of intravenous cetuximab (Cet) and hepatic artery infusion of irinotecan, 5-fluorouracil, and oxaliplatin in patients (pts) with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) after systemic treatment failure (OPTILIV, NCT00852228).
Authors: Levi Francis , Boige Valerie , Hebbar Mohamed , Smith Denis , Lepère Céline , Focan C. N. J. , Guimbaud Rosine , Carvalho Carlos , Tumolo Salvatore , Innominato Pasquale F. , Ajavon Yves , Truant Stephanie , Castaing Denis , De Baere Thierry , Kunstlinger Francis , Karaboué Abdoulaye , Bouchahda Mohamed , Rougier Philippe R , Adam Rene , Ducreux Michel ,   ARTBC International
Published: February 2017

466

Background: Multiple, large and bilateral LM-CRC can be downsized with chemotherapy (chemo) and resected with curative intent in ~15% pts (Adam et al. 2004). The complete resection rate (R0+R1) may be increased with Cet addition, triplet chemotherapy, chronomodulated delivery (Chrono) and hepatic artery infusion (HAI) (Bouchahda et al. 2009; Kemeny et al. 2009; Garufi et al. 2010; Goere et al. 2010). Purpose: To increase the R0+R1 rate from 15% to 30% in pts with unresectable KRAS wt LM-CRC despite failure of 1-3 prior chemo protocols. Methods: 64 pts received iv Cet (500 mg/m²) and Chrono (18 pts) or conventional (Conv, 46 pts) HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks multidisciplinary meetings. Results: There were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2). Liver lesions were bilateral in 50 pts (78.1%), with a median of 10 metastases (1-50) and largest diameter of 52 mm (15-172). Five courses (1-13) were given to 61 pts (3 never treated), as 3-4th line for 35 pts (54.6%). Grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (26%), fatigue (18%) and diarrhea (16%). Tumor response (RECIST) was achieved in 28 pts (2 CR, 26 PR), with an objective response rate of 46% [95%CL, 33-58]. Disease control rate was 95% [90-100]. The main endpoint was met, with R0-R1 resections in 19/61 pts, for an overall complete macroscopic resection rate of 28% [17-39]. R0+R1 resections were performed in 33.3% Chrono pts and 25.6% Conv pts, with worse initial prognosis for the Chrono pts (>6 segments involved, 50% vs 9%; > 9 metastases, 75% vs 27%). Median progression-free and overall survival were 8.7 months [6.9-10.5], and 25.7 months [14.2-37.2] respectively. Conclusions: The combination of intravenous Cet and triplet hepatic artery infusion safely doubled the expected rate of complete resections of LM-CRC, despite prior failure of systemic chemo. This most effective treatment option now deserves upfront testing. Clinical trial information: NCT00852228.
Dosimetric coverage of anal sphincter by 3D conformal fields in patients undergoing neoadjuvant chemoradiation for rectal cancer: An implication in the concept of sphincter-preserving radiation therapy.
Authors: Chen Yi-Jen , Chen Michelle B. , Liu Alan Jianan , Tsai Peter Tsung Wen , Liu An
Published: February 2017

558

Background: Functional impact related to dosimetric coverage of the anal sphincter in rectal cancer patients treated with neoadjuvant chemoradiation (NCRT) remains unknown. We evaluated the anatomic location of the anal sphincter to pelvic bony landmarks related to 3D conformal radiotherapy (3DRT) and studied the dosimetric coverage of the anal sphincter in patients undergoing NCRT for rectal cancer. Methods: Between June 2006 and March 2012, 64 patients with rectal cancer treated with NCRT were included. All patients were treated in prone position on a bellyboard by 3DRT with 3 or 4-field setup up to 5,040 (86%) or 5,400 (14%) cGy. The inferior borders of the RT fields used were the lower of either at 3-5 cm inferior to the lowest gross tumorous volume (GTV) or at the inferior border of the obturator foramina (IBOF). The anal sphincters were contoured retrospectively and dose distributions were determined using dose volume histograms. Results: The mean anal sphincter volume was 5.1 cm3 (range, 1.3 – 11.2 cm3). On average, the center of anal sphincter was 18.6 mm inferior to the IBOF. In 53 cases (82.8%), the anal sphincter was completely inferior to the IBOF. In the remaining 11 cases (17.2%), the anal sphincter was either overlapping the IBOF (10 cases; 15.6%), or completely superior to the IBOF (1 case; 1.7%). On average, the center of anal sphincter was 39 mm inferior to the lowest edge of GTV. In 19 cases (30%), the anal sphincter was completely outside of the inferior border of the RT fields. In another 10 cases (16%), the sphincter was more than 4 cm away from the GTV inferior border but was partially treated. The mean dose delivered to anal sphincter was 2795 cGy (range, 245–5441 cGy). Lower mean doses delivered to the anal sphincters were noted for larger distances from the center of the anal sphincter to the GTV. Conclusions: Minimizing dose delivered to anal sphincter is possible, especially for upper or mid rectal cancer. However, meticulous planning to define the inferior border of RT fields is necessary. Future studies will focus on the correlation between RT dose distribution to the anal sphincter and anal-rectal dysfunction.
Comparative effective analysis between enzalutamide and abiraterone in the treatment of metastatic castration-resistant prostate cancer.
Authors: Chopra Akhil , Haaland Benjamin , Lopes Gilberto
Published: February 2017

217

Background: Recently Abiraterone (A) and Enzalutamide (E), new drugs with different novel mechanisms of action, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) based on the COU-AA-301 and AFFIRM phase III trials, after docetaxel failure. The lack of direct comparative trials has introduced a new treatment dilemma for the practicing oncologist: is one drug more effective than the other? Methods: We performed an indirect comparative effectiveness analysis between E and A using the results of the AFFIRM and COU-AA-301 pivotal trials. Due to the lack of study-to-study replication of comparisons, these indirect comparisons are subject to the assumption that the relative effects of each drug relative to placebo are the same across studies. Results: 1) Overall survival (OS)- the respective hazard ratios (95% confidence intervals {CI}) in the AFFIRM and COU-AA-301 trials for OS for E vs. placebo and A vs. placebo were 0.63 (0.53-0.75) and 0.66 (0.56-0.79). The indirect estimate of the hazard ratio (HR) (95% CI; p-value) for E vs. A was 0.96 (0.75-1.22; 0.72) 2) Time to PSA progression- the respective HR(95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 0.25 (0.20-0.30) and 0.58 (0.46-0.73). The indirect estimate of the HR (95% CI; p-value) for E vs. A was 0.43 (0.32-0.58; 4.3 × 10-8). 3) Radiographic progression Free Survival (rPFS)- The respective HR (95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 0.40 (0.35-0.47) and 0.67 (0.59-0.78). The indirect estimate of the HR (95% CI; p-value) for E vs. A was 0.60 (0.49-0.74; 7.1 × 10-7). 4) PSA response- the respective odds ratios (95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 77.08 (34.02-174.70) and 5.49 (3.84-7.84). The indirect estimate of the odds ratio (95% CI; p-value) for E vs. A was 14.04 (5.75-34.28; 6.6 × 10-9). Conclusions: In this indirect comparative effectiveness analysis, E appears to be more effective than A in terms of time to PSA progression, rPFS and PSA response. OS was not different.
Phase I results from a study of lapatinib with gemcitabine and cisplatin (GC) in advanced/metastatic bladder cancer.
Authors: Daugaard Gedske , Sengeløv Lisa , Agerbaek Mads , Sternberg Cora N. , Van Herpen Carla , Collette Sandra , Marreaud Sandrine ,   European Organisation for Research and Treatment of Cancer
Published: February 2017

252

Background: Lapatinib (Tykerb, Tyverb) is a potent EGFR and ErbB2 inhibitor approved for the treatment of breast cancer. GC is a standard chemotherapy regimen for advanced/metastatic bladder cancer and there are preclinical and clinical data suggesting the role of EGFR and HER2 in urothelial carcinoma. This phase I study examined the safety of lapatinib in combination with GC in patients (pts) with bladder cancer. Methods: The primary phase I objective was to determine the maximum tolerated dose of lapatinib 750–1,250 mg that could be administered safely with GC in bladder cancer pts. A 3+3 dose escalation was used with lapatinib 750 mg, 1000 mg and then 1250 mg. Lapatinib was dosed daily and G (1000 mg/m² days 1, 8, 15) + C (70 mg/m² day 2) every 28 days. Results: 18 pts with median age 63 yrs (range 50-77) and ECOG PS 0/1 (66.7% with WHO-PS 0 and 33.3% with WHO-PS 1) were included. 3/6, 3/5 and 6/7 pts completed at least one cycle according to the protocol and received lapatinib 750 mg, 1000 mg and 1250 mg + GC, in cohorts 1, 2 and 3, respectively. No dose-limiting toxicities (DLTs) occurred in cohort 1 or 2 (3 pts each); in cohort 3 (2 x 3 pts), 1 of 6 pts had DLT (Gr4 related febrile neutropenia and renal failure). One discontinued due to pt decision after 1 cycle. Ten pts received 6 cycles and one 7 cycles. The response rate among the 11/12 eligible patients was 73% (1 CR, 7 PR, 3 SD and 1 not assessable). Further toxicity data together with responses in relation to EGFR and HER2 status will be presented. Conclusions: Within the limits of a phase I study, lapatinib 750–1,250 mg + GC appears safe and tolerable with considerable activity at the maximum planned dose in bladder cancer. Clinical trial information: NCT00623064.
Micropapillary bladder cancer: Stage at presentation and treatment outcome—Analysis of 121 patients from a cancer database.
Authors: Holyoak Joshua D. , Panfili Zachary , Kiran Ravi P. , Pokala Naveen
Published: February 2017

289

Background: The micropapillary variant of transitional cell cancer(MPTCC) is an aggressive pathological subtype of bladder cancer and radical cystectomy is recommended for patients with non−muscle invasive disease. This study compares the treatment patterns and survival outcome in 121 patients. Methods: Patients with MPTCC (code 8131) were identified from the Surveillance Epidemiology and End Results (SEER 17) database. Data was analyzed for demographics, stage, treatment, overall (OS) and cancer specific survival (CSS). Appropriate statistical tests were used. Results: 121 patients were identified (2001−08). Mean age was 73.3 years, 76.9% were male (76.9%, n=93), 82.7% were Caucasian. 40.5% (n=49) had non−muscle invasive (NMI) disease and 59.5% had muscle−invasive disease (MI) at diagnosis. The T stage was Ta or Tis (n=17), T1 (n=32), T2 (n=38) T3 (n=20) and T4 (n=14). 23 patients had node positive disease, the nodal status was not known in 4 patients. 10 patients had distant metastasis. Surgical procedures performed include, TURBT (n=83), Radical cystectomy (n=34), pelvic exenteration (n=1) and partial cystectomy (n=3). 8 patients received post−operative radiotherapy. The mean OS was 64.9, 42.9, 16.1 and 50.2 months and the mean CSS was 81.2, 56.3, 15.7 and 64.4 months for NMI, MI, distant and the whole group respectively. The 5−year OS was 40%, 54% and 34% and the 5 year CSS was 62%, 53% and 82% for the whole group, MI and NMI respectively. All patients with distant disease were dead by 28 months. On analysis of CSS by treatment type the 5−yr CSS for NMI was 81% (n=36) after TURBT and 100% (n=3) after Radical surgery. For MI disease the 3−yr CSS was 66% after TURBT (n=18) and the 5−yr CSS was 54% after radical surgery (n=29). On multivariate analysis, higher stage and age were associated with worse survival. TURBT was associated with better survival. Conclusions: MPTCC is a rare variant of TCC. 81% survival can be achieved with TURBT for non-muscle invasive MPTCC.
A phase I/II study of safety and efficacy of orteronel (TAK-700), an oral, investigational, nonsteroidal 17,20-lyase inhibitor, with docetaxel and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC): Updated phase II results.
Authors: Petrylak Daniel , Gandhi Jitendra G. , Clark William R. , Heath Elisabeth I. , Lin Jianqing , Oh William K. , Agus David B. , Carthon Bradley Curtis , Moran Susan , Kong Ning , Suri Ajit , Bargfrede Michael , Liu Glenn
Published: February 2017

59

Background: Orteronel is an investigational non-steroidal, selective inhibitor of 17,20-lyase, a key enzyme in the production of steroidal hormones. DP is currently an approved therapy in mCRPC; this phase 1/2 study examined orteronel + DP in men with mCRPC. Methods: Castrate men (testosterone [T] <50 ng/dL) with mCRPC, no prior chemotherapy and no ketoconazole/abiraterone received orteronel (400 mg BID) + D (75 mg/m2 q3w) + P (5 mg BID). The primary phase 2 objectives were tolerability, PK, serum PSA declines, and best PSA response. Secondary objectives included time to progression of PSA ± radiographic disease, response by RECIST 1.1. Results: At data cutoff (July 23, 2012), 24 men had been treated and 12 remained on study: median age was 66 yrs (n=24, range 53–87), ECOG PS 0/1 (88%/13%). At baseline, median PSA was 46 ng/mL (4.5–813) and T was 6.8 ng/dL (2.6–13.8). 9 men discontinued due to AEs (the most common was fatigue [13%]). All men reported at least 1 Gr ≥3 AE (23 were drug-related). Drug-related Gr ≥3 AEs ≥10% were neutropenia (38%); WBC decreased (25%); fatigue (21%); decreased neutrophil count (17%); blood alkaline phosphatase increased, and leukopenia (each 13%). The most common drug-related SAE was dehydration (13%). There were 2 on-study deaths, due to disease progression and respiratory distress, both considered unrelated to treatment. At 3 mo, PSA response was evaluable in 18 men; PSA30/50/90 rates were 83%/72%/28%. Best PSA decline (median) was -76% (n=23; -99 to +144%). Median T at 3 mo decreased to ≤0.2 ng/dL (0.3–10.6). Response was evaluable in 9 men; 5 achieved a PR; ORR was 56% (n=9; 80% CI: 30, 79). Median time to PSA progression was 6.1 mo (95% CI: 4.6, not reached); median time to radiologic progression was not reached. The Cmax of orteronel + DP was similar to that of DP alone with no evidence of DDI. Conclusions: Orteronel 400 mg BID + DP appears tolerable and shows androgen-lowering activity, and strong PSA and partial tumor response in mCRPC. There was no evidence of DDI between orteronel and DP. Updated data, including a detailed PK analysis, will be presented. Clinical trial information: NCT01084655.
Adjuvant gemcitabine plus docetaxel followed by 5FU chemoradiation for patients with resected pancreaticobiliary cancers: A single institution phase II study.
Authors: Cho May , Wang-Gillam Andrea , Gao Feng , Linehan David , Hawkins William G. , Suresh Rama , Fournier Chloe , Picus Joel , Tan Benjamin ,   GI02
Published: February 2017

325

Background: Adjuvant chemotherapy with Gemcitabine for six months has improved overall survival (OS) in resected pancreatic cancer compared to observation alone. The RTOG study showed adding gemcitabine to 5FU chemoradiation therapy showed improved OS in pancreatic head cancer patients. We evaluated the feasibility and safety of adjuvant gemcitabine plus docetaxel followed by radiation with 5FU after curative resection of pancreatic and biliary adenocarcinomas at our institution. Methods: Patients with resected pancreaticobiliary cancers were treated with 2 cycles of gemcitabine with docetaxel. Infusional 5FU at was given with 3-D conformal external beam radiation followed 4 weeks later by 2 more cycles of gemcitabine plus docetaxel. The primary objective was to evaluate the feasibility and safety of this regimen with the secondary aims to describe the toxicities, disease-free (DFS) and overall survival (OS) in these patients. Results: 50 patients were enrolled in the study. Median age was 59 with M;F ratio of 1:1.4 and 12% African-American. 30 patients had pancreatic cancer, 8 patients had ampullary cancer and 12 patients had gallbladder cancers. 30 patients completed all therapy. 4 patients withdrew the study due to non-medically related reasons. 7 patients had early disease recurrence. 6 patients withdrew consent due to side effects. 2 were taken off study after developing infection and 1 patient died of viral pneumonia leading into ARDS. Grade 3-4 Non-hematologic toxicities include diarrhea (12%), fatigue (4%), renal failure (2%), hepatic toxicity (4%). Grade 3-4 hematologic toxicities include neutropenia (30%), anemia (2%) and thrombocytopenia (10%). The median OS and DFS in pancreatic cancer is 17 and 9 months. The OS and DFS in ampullary cancer and gallbladder cancer is 27 and 14.4 months respectively. Conclusions: Adjuvant gemcitabine plus docetaxel followed by concurrent 5FU-CRT is feasible and tolerable. However, outcomes for pancreatic cancer patients appeared to be inferior compared to CONKO and RTOG studies. This regimen may be a reasonable adjuvant option for high risk biliary tract cancers. Clinical trial information: NCT00660699.