bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of IL-6, IL-8, bFGF, PDGF-BB, and VEGF-A as prognostic and predictive biomarkers for anti-VEGF in metastatic colorectal cancer (mCRC).
Authors: Price Timothy Jay , Townsend Amanda Rose , Bruhn Maressa , Lee Chee , Wrin Joe , Shivasami Aravind , Arentz Georgia , Tebbutt Niall C. , Cunningham David , Hardingham Jenny ,   Australasian Gastrointestinal Trials Group
Published: February 2017

502

Background: There remains a need for predictive biomarkers in mCRC to better identify patients who clinically benefit from anti-VEGF therapy, in particular bevacizumab (BEV). The AGITG MAX trial compared capecitabine (C) with capecitabine (+/- mitomycin C (M)) and BEV and PFS was superior in the CB+/-M arm. Here we have taken a panel of pro-angiogenic proteins to assess whether there is a signal for a predictive factor for bevacizumab outcome in the MAX trial tissue population (TTP). Methods: Protein was isolated from FFPE tumour tissue and assayed using custom Bio-plex arrays to assess the expression levels of candidate tumour biomarkers IL-6, IL-8, bFGF, PDGF-BB and VEGF-A. As there are no accepted cutoff points for these analytes we chose the medians of distribution of each of these biomarkers as cutoff points for dichotomization into “high” v “low”. We then correlated levels of the biomarkers with objective response rate, disease-free and overall survival. Results: Total protein was isolated from FFPE tumour sections from 41.5% of patients (n=196) recruited into the MAX clinical trial and assayed for the proteins using a multiplex platform. Patients were generally balanced, tumour tissue population v intention to treat. Median follow up time is 30.2 mths. For patients receiving BEV there was no relationship between the level of IL-6, IL-8, bFGF, PDGF-BB and VEGF-A and PFS and OS. In patients treated with BEV/C vs. C alone, low tumor VEGF-A was predictive of better ORR as compared to those with a high level (ORR 53% vs 38%, p = 0.03). Multivariate analyses showed low VEGF-A expression level was a significant prognostic factor for longer progression free survival (median PFS 9.3 months low VEGF-A v 7.2 months high VEGF-A, multivariate adjusted HR 1.55 (95% CI 1.12-2.13), p = 0.008). Conclusions: We have shown that the chosen panel of pro-angiogenic proteins was not predictive for PFS or OS outcomes when B is added to C in mCRC. However low VEGF-A level did predict for higher ORR and was an independent prognostic marker for PFS in this cohort.
Association of PTEN protein loss with upgrading of prostate cancer from biopsy to radical prostatectomy.
Authors: Carvalho Filipe LF , Lotan Tamara L , Peskoe Sarah B. , Hicks Jessica , Good Jennifer , Fedor Helen L. , Humphreys Elizabeth B , Han Misop , Platz Elizabeth , Squire Jeremy , DeMarzo Angelo , Berman David M.
Published: February 2017

127

Background: Active surveillance is increasingly recommended for men with low-risk Gleason Score 3+3=6 (GS 6) prostate cancer. Yet, approximately one-third of patients with GS 6 cancer on biopsy are upgraded to higher GS at radical prostatectomy (RP). Previous studies have shown that clinical-pathologic parameters (age, prostate-specific antigen [PSA], prostate volume, extent of disease) are weak predictors of GS6 tumor upgrade. Our goal was to investigate the utility of PTEN as a molecular marker to predict upgrading in GS 6 biopsies. Methods: In a retrospective case-control study, 71 patients with GS 6 tumors on needle biopsy that were upgraded to GS 7 or higher cancer at RP (cases) were compared to 103 patients whose GS 6 tumors on needle biopsy were not upgraded at RP (controls). The most extensively involved needle core biopsy from each case was immunostained and scored for PTEN protein loss using a previously validated immunohistochemical (IHC) assay and binary scoring system. Confirmatory fluorescence in situ hybridization (FISH) was used to assess for PTEN gene deletion in biopsies with PTEN protein loss. The correlation of upgrading with PTEN loss and with clinical-pathologic variables was assessed by logistic regression. Results: Patients with upgraded cancers were older than controls (61.8 vs. 59.3 years), had higher mean pre-operative PSA levels (6.53 vs. 5.26 ng/mL), and a higher fraction of biopsy cores involved by tumor (0.42 vs, 0.36). However, of all pathologic variables, PTEN protein loss by IHC was most predictive of upgrading. Overall, PTEN protein loss was found in 18.3% (13 out of 71) of upgraded cases compared to 6.8% (7 out of 103) of controls (p=0.02). In the cases with PTEN protein loss, FISH confirmed homozygous PTEN deletion in 90% (9 out of 10) of upgraded tumors compared to 67% (4 out of 6) of interpretable not upgraded controls. On multivariate analyses, even after adjusting for age, preoperative PSA, clinical stage and race, GS 6 tumors with PTEN protein loss on biopsy were significantly more likely to be upgraded at RP compared to those without PTEN loss with odds ratio (OR) = 3.04 (1.08-8.55; p=0.035). Conclusions: In prostate needle biopsies, PTEN IHC may help distinguish men with low risk cancer from men with intermediate or higher risk cancers.
Feasibility of docetaxel-prednisone (DP) in frail elderly (age 75 and older) patients with castration-resistant metastatic prostate cancer (CRMPC): GERICO10-GETUG P03 trial led by Unicancer.
Authors: Mourey Loic , Gravis Gwenaelle , Sevin Emmanuel , Priou Frank , Bompas Emmanuelle , Sarda Corinne , Houede Nadine , Carola Elisabeth , Abadie Lacourtoisie Sophie , Latorzeff Igor , Orsini Christine , Filleron Thomas
Published: February 2017

152

Background: Chemotherapy with docetaxel-prednisone (DP) is one of the standard treatment of castration-resistant metastatic prostate cancer (CRMPC). However little is known about feasibility of DP in frail elderly patients seen in daily practice. Methods: Randomized phase II study evaluating prospectively the feasibility of DP administered either q3w (Arm A: 60 mg/m² cycle one then 70 mg/m²) or weekly (Arm B: 35 mg/m² D1 D8 q3w) in patients age 75 or older, assessed through comprehensive geriatric assessment (CGA) and classified according to the International Society of Geriatric Oncology (SIOG) as vulnerable (SIOG group 2) or frail (SIOG group 3). Failure was defined as: (1) stop or delay of chemotherapy more than 2 weeks, (2) need for dose reduction more than 25%, (3) febrile neutropenia or NCI CTC grade 3 non-haematological toxicity (excluding alopecia), and (4) decrease of activities of daily living (ADL) scoring two or more points. The study was based on a Simon’s optimum two-stage design for each group (α = 5%, 1-β = 90 %, p0 = 0.70 and p1 = 0.90). An interim analysis was planned after enrolment of 15 patients per arm, with continuation of the program if at least 12 patients met the feasibility criteria. Results: From December 2010 to August 2012, 21 centers have included 66 CRMPC patients, 45 and 21 in SIOG groups 2 and 3 respectively, based on investigators evaluation. The planned interim analysis primary endpoint is based on group allocation by a steering committee (per-protocol [PP] population). The enrolment in group 3 was prematurely closed on October 2012 after inclusion of 19 PP patients (Arm A/B, n=9/10) on recommendation of a safety committee due to an excess of toxic deaths. In this group, only four patients completed six cycles of DP in each arm. In group 2, the planned interim analysis was performed after inclusion of 30 PP patients (Arm A/B n=15/15): 11 and 10 patients in Arm A and B did not meet the predefined criteria for feasibility (73.3%; 95%CI=[44.9; 92.2] and 66.6%; 95%CI=[38.4; 88.2], respectively, and only nine and seven respectively completed six cycles of DP. Conclusions: Chemotherapy with DP given q3w or weekly is not feasible in CRMPC patients age 75 and older classified in SIOG group 2 and 3, according to our study criteria. Patients age 75 and older shouldn’t be offered DP without a CGA. Clinical trial information: NCT01254513.
Treatment patterns in patients with recurrent high-risk bladder cancer.
Authors: Ballon-Landa Eric Christian , Chamie Karim , Bassett Jeffrey C. , Daskivich Timothy J. , Lai Julie , Hanley Janet , Konety Badrinath R. , Litwin Mark S. , Saigal Christopher ,   The Urologic Diseases in America Project
Published: February 2017

303

Background: Patients with high-risk bladder cancer are apt to develop multiple recurrences. Since the association of recurrences with aggressive treatment in individuals with recurrent high-grade disease has not been quantified, we sought to determine whether increasing number of recurrences correlates with higher treatment rates. Methods: Using linked SEER-Medicare data, we identified subjects with recurrent high-grade, non-muscle-invasive disease diagnosed in 1992–2002 and followed until 2007. Using propensity score and competing-risks regression analyses, we quantified the incidence of radical cystectomy, radiotherapy, and systemic chemotherapy after each recurrence. We further restricted our analyses of treatment in auspicious environments, defined as those patients most suited for aggressive intervention: age <70, Charlson 0, and undifferentiated T1 tumors treated at academic cancer centers. Results: Of 4,521 subjects, (59.6%) 2,694 recurred more than once within two years of diagnosis. Compared with patients who only had one recurrence, those with ≥4 recurrences were less likely to undergo radical cystectomy (9.7% vs 12.1%, p value=0.03), but more likely to undergo radiotherapy (18.0% vs 12.1%, p value<0.01) and systemic chemotherapy (6.7% vs 4.2%, p value<0.01). For patients with ≥4 recurrences, only 25% were treated with curative intent, while 43% were similarly treated in auspicious environments. Conclusions: Only 25% of patients with high-risk bladder cancer who recur ≥4 times undergo treatment for curative intent. Increasing recurrences do not appear to alter the treatment course, as patients and their doctors may be unable or unwilling to proceed with aggressive treatment despite mounting risk of disease progression. [Table: see text]
A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).
Authors: Apolo Andrea Borghese , Parnes Howard L. , Madan Ravi Amrit , Gulley James L. , Wright John Joseph , Hoffman-Censits Jean H. , Dawson Nancy Ann , Trepel Jane B. , Khadar Kattie , Schlom Jeffrey , Merino Maria , Raffeld Mark , Steinberg Seth M. , Choyke Peter L. , Lindenberg Maria Liza , Folio Les , Agarwal Piyush K. , Figg William Douglas , Bottaro Donald P. , Dahut William L.
Published: February 2017

307

Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after >12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.
Results of a randomized controlled study of personalized care plans in breast cancer survivors from a single institution.
Authors: Haq Rashida , Brezden-Masley Christine , Lee Ronita , Richter Suzanne , George Ralph L. , Simpson Jory , Rackal Julia , Leung Fok Han , Jovicic Aleksandra , Kong Amy , Li Benjamin , Gulasingam Pauline , Jainudeen Tara
Published: February 2017

109

Background: In 2006, Institute of Medicine recommended care plans for coordination of care of cancer survivors. Our pilot study of multifaceted care plans met information and communication needs of breast cancer (BC) survivors and their primary care providers (PCP). In this study, a Personalized Multifaceted Care Plan (PMCP) was developed, implemented and evaluated. Methods: This was a randomized study with mixed methods design. Upon REB approval, 78 women diagnosed with invasive BC for adjuvant treatments were recruited from the breast clinic from June 2013 to March 2015. After informed consent, participants were randomized to the control or the intervention group and stratified to chemotherapy (CT) vs. endocrine therapy (ET). The intervention group received a PMCP (paper based treatment and care plans (TP & CP) with information on breast pathology, treatment sequence, supportive care and follow-up guidelines with access to a website). CT arm patients received a TP at the start of therapy and a CP at completion. ET patients received the CP upfront. Quantitative outcomes were assessed by 3 standardized questionnaires at baseline and following treatment. Within-group baseline and post-intervention scores were compared using paired t-tests. The post-intervention control group and intervention group’s scores were compared using unpaired t-tests. In the intervention group, qualitative analysis was done through focus groups of BC survivors & PCP interviews. Results: Baseline scores in the mean intervention and control groups were similar. In the CT arm of the intervention group, post-intervention scores on Communication and Efficacy Scale showed statistically significant increase (p < 0.05, 95% CI). Results in the control group and in the intervention group of patients on ET were not significantly different. Focus group participants commented that the PMCP helped them feel ‘educated’ and engaged in their cancer treatment and their PCPs found the PMCP contained useful, concise medical summaries. Conclusions: Upfront PMCP improves self-efficacy scores in patients on CT. Qualitative analysis substantiates the benefits of PMCP. PMCP should be standard of care in BC survivors receiving CT.
End-of-life cancer care: Health service delivery in the last 12 months of life in Calgary, Alberta, Canada.
Authors: Kerba Marc , Sinnarajah Ayn , Rose M Sarah , Nicholson Lynn , Wheler Barbara , Enns Bert ,   The Calgary Zone Palliative Care Collaborative
Published: February 2017

171

Background: In Calgary, Alberta, the Calgary Zone Palliative Care Collaborative (CZPCC) undertook a study to examine the current state of cancer and palliative services and to recommend steps to address gaps in service delivery. We hypothesized that early access to palliative care services would reduce utilization of active cancer treatments and services for individuals nearing the end of life. Our study objectives were to determine the utilization and timing of acute, palliative and oncology-related services in Calgary. Methods: This retrospective study examined cancer registry and administrative data for patients > 18 years, who died in 2012. Measures of aggressive end of life care (EOL) were also collected. A combination of descriptive statistics, tests of association and multivariate regression analysis were conducted. Results: N = 1909 died of cancer in 2012: median age 73 years (IQR: 62-82 years) and median disease duration 364 days (IQR: 92-1114 days). 40.6% of patients received systemic treatment in last 12 months of life. 29.9% received radiotherapy and 13.0% received psychosocial/spiritual care. Palliative care contact was 80.7%, inclusive of 20.6% who had an intensive palliative care unit admission. 5.2% had EOL chemotherapy and 3.8% received EOL radiotherapy. Up to 10.4% of patients had one or more hospital admission. There was no significant effect of age on those who received aggressive EOL care. Men had an increased probability to receive aggressive EOL care (p = 0.015). Tumor group was also associated with receiving aggressive EOL (p < 0.001), with the highest utilization in Head and Neck and hematological malignancies. In patients with a disease duration of > 4 months those who received palliative care at least 2-3 months prior to death were less likely to receive aggressive EOL care (P < 0.001). Patients whose disease duration was < 1 month were less likely to receive aggressive EOL care if they received palliative care services (p = 0.02). Conclusions: The provision of palliative care services at the end of life is most needed among men and certain tumor groups who are the highest users of aggressive EOL care.
Determination factors of patients' decision between surgery and chemoradiotherapy for stage I esophageal carcinoma: From the results of JCOG0502—A comparative study of the two modalities.
Authors: Kato Ken , Igaki Hiroyasu , Ito Yoshinori , Nozaki Isao , Daiko Hiroyuki , Yano Masahiko , Udagawa Harushi , Nakagawa Satoru , Takagi Masakazu , Okabe Hiroshi , Abe Tetsuya , Okuno Tatsuya , Hihara Jun , Toh Yasushi , Akutsu Yasunori , Shibuya Yuichi , Mizusawa Junki , Nakamura Kenichi , Fukuda Haruhiko , Kitagawa Yuko ,   Japan Esophageal Oncology Group of Japan Clinical Oncology Group (JCOG)
Published: February 2017

114

Background: Surgery is the standard of care for stage I esophageal squamous cell carcinoma. However, definitive chemoradiothearpy (CRT) is optional treatment which can preserve organ function with cure. The aim of this study was to investigate what factors have influence patients(pts)’ decision on the treatment, surgery or CRT. Methods: JCOG0502 is a randomized controlled trial comparing surgery to CRT. Sufficient information about both treatments was provided for pts before enrollment. Pts who declined to participate in randomized part can choose a preferred treatment and join a non-randomized part of JCOG0502. Between Dec 2006 and Feb 2013, 379 pts were enrolled to JCOG0502 from 37 institutions of Japan Clinical Oncology Group. Among those, 368 pts who enrolled to non-randomized part were analyzed. Clinical baseline data, social data and doctor’s preference which was not mandatory informed to patients were collected on the case report forms and compared between surgery arm and CRT arm. Preference of doctors for each pt was divided into three categories, A: “surgery is preferred”, B: “either is adequate” and C: “CRT is preferred”. This trial was registered as UMIN000000551. Logistic regression were performed to evaluate the influence of each factors. Results: Of the 368 pts, 209 pts chose surgery with their own intention, while 159 pts chose CRT. There were no differences on baseline clinical characteristics between two groups except median age (Surgery: CRT = 62:65 years). Multivariate logistic regression analyses showed that >=65 years (vs<65) (OR 2.04, p=0.006), male (vs female) (OR 2.10, p=0.043), multi-focal primary (vs single) (OR 2.76, p=0.013), status of patient’s children (vs presence of children) (absence of children: OR 2.27, p=0.034) (unknown: OR 4.422, p=0.13), and B or C category of preference of the doctor (vs A) (B:OR 11.67, p<0.001)(C:HR 29.64, p<0.001) were associated with selection of CRT. Conclusions: Older age, male, multifocal primary, absence of children and doctor’s preference are independent factor to choose CRT. Doctor’s preference to each pt was the strongest factor on decision making of patients.
Prognostic factors in locally advanced, unresectable esophageal cancer patients treated with chemoradiotherapy (exploratory analysis of JCOG0303).
Authors: Okuno Tatsuya , Mizusawa Junki , Kato Ken , Shinoda Masayuki , Katayama Hiroshi , Igaki Hiroyasu , Tsubosa Yasuhiro , Kojima Takashi , Okabe Hiroshi , Kimura Yusuke , Kawano Tatsuyuki , Kosugi Shinichi , Toh Yasushi , Kato Hoichi , Nakamura Kenichi , Fukuda Haruhiko , Ishikura Satoshi , Ando Nobutoshi , Kitagawa Yuko ,   Japan Esophageal Oncology Group of Japan Clinical Oncology Group (JCOG)
Published: February 2017

150

Background: The prognosis of patients (pts) with locally advanced esophageal squamous cell carcinoma (LAESCC) is generally dismal. Definitive chemoradiotherapy (CRT) with cisplatin plus 5-fluorouracil (CF-RT) is the standard treatments especially for the pts with unresectable LAESCC. The aim of this study is to investigate the possible prognostic factors and predictive accuracy of the Glasgow Prognostic Score (GPS) in the pts with unresectable LAESCC treated with CRT. Methods: 142 patients were enrolled to JCOG0303, and assigned to standard CF-RT group and low-dose CF-RT group. 131 pts with sufficient data were used for this analysis. Cox regression model was used for an analysis of prognostic factors of the pts with unresectable LAESCC treated with CF-RT. GPS was classified by baseline CRP and serum albumin. Pts with a CRP ≤ 1.0 mg/dL and albumin ≥ 3.5 g/dL were allocated to GPS0 group. If only CRP was increased or albumin decreased,pts were allocated to the GPS1 and pts in whom CRP was > 1.0 mg/dL and albumin level < 3.5 g/dL were classified as GPS2. Results: The pts background was as follows: median age (range), 62 (37-75), male / female, 119/12; ECOG PS 0/1/2, 64/65/2; clinical stage (UICC 6th) IIB/III/IVA/IVB, 3/75/22/31. As a result of multivariable analysis including all variables, the factors which became statistically significant were shown in the table. In several sensitivity multivariate analyses, only esophageal stenosis was indicated as a common poor prognostic factor. In addition, overall survival tended to decrease according to GPS subgroups (median survival time(m): GPS0/GPS1/GPS2 16.1/14.9/8.7). Conclusions: Presence of stenosis was thought to be one of the candidates for stratification factor in randomized trial for unresectable LAESCC pts. Furthermore, GPS represents a prognostic fator in LAESCC pts treated with CRT. Clinical trial information: 000000861. [Table: see text]
Baseline demographics of the randomized, placebo-controlled, double-blind, phase III RADIANT-4 study of everolimus in nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NET).
Authors: Yao James C. , Buzzoni Roberto , Carnaghi Carlo , Fazio Nicola , Singh Simron , Wolin Edward M. , Tomasek Jiri , Raderer Markus , Lahner Harald , Lam Du Hung , Cauwel Helene , Valle Juan W. , Delle Fave Gianfranco , Van Cutsem Eric , Strosberg Jonathan R. , Tesselaar Margot Et , Shimada Yasuhiro , Oh Do-Youn , Kulke Matthew , Pavel Marianne E. ,   The RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial (RADIANT-4) Study Group
Published: February 2017

276

Background: NET are malignant tumors arising from neuroendocrine cells throughout the body. Everolimus (EVE), a mammalian target of rapamycin inhibitor, is approved for the treatment of advanced, well-differentiated pancreatic NET. There is an unmet medical need in GI and lung NET; targeted therapies, such as everolimus, are of particular interest. Methods: Patients with advanced nonfunctional NET of GI or lung origin with progressive disease (PD) within the past 6 months were randomized (2:1) to EVE 10 mg/d or placebo, both with best supportive care. Concomitant use of somatostatin analogue (SSA) was not allowed during the study, except for control of emergent carcinoid symptoms not manageable by standard therapy. Patients were stratified based on tumor sites, prior SSA exposure, and WHO performance status (PS) at baseline. Primary endpoint was progression-free survival (PFS) as assessed by central radiology review using modified RECIST 1.0 criteria. Primary analysis is planned after ~176 PFS events. Crossover to open label EVE after progression would not be allowed prior to the primary analysis. Overall survival was the key secondary endpoint. Results: Recruitment is completed. Of 388 patients screened, 302 were randomized (planned, 285). Median age was 63 years, 53% were females, and majority of them (76.2%) were white. The most common tumor sites were lung (29.8%), ileum (23.5%), and rectum (13.2%). WHO PS was 0 in 219 (72.5%) patients and 1 in 82 (27.2%) patients; 52% had received SSA prior to study entry. As of Sep 16, 2013, 173 (57.3%) patients remain on treatment, 127 (42.1%) discontinued treatment and 2 (0.7%) were not treated. PD (24.2%) and adverse events (10.6%) were the most common reasons for treatment discontinuation. Results of primary analysis are expected by early 2015. Conclusions: RADIANT-4 is the first phase III study to assess the efficacy and safety of EVE in patients with nonfunctional NET of GI or lung origin. Non-crossover design and prospective stratification of the population based on known prognostic factors should minimize confounding in the estimation of the treatment effect. Clinical trial information: NCT01524783.
A multicenter randomized, open-label, proof-of-concept, phase II trial comparing gemcitabine with and without IMM-101 in advanced pancreatic cancer.
Authors: Dalgleish Angus George ,   The IMAGE I Trial Investigators
Published: February 2017

336

Background: Immunotherapy is becoming established as an effective way of treating cancer. Immodulon Therapeutics is developing IMM-101, a heat-killed whole cell preparation of Mycobacterium obuense (NCTC 13365), which modulates systemic immune responses, as an adjunctive immunotherapy for pancreatic cancer. Methods: Patients with advanced pancreatic cancer and a WHO score of 0-2 were assigned randomly to receive IMM-101 (0.1 mL intradermal injection of 10 mg/mL) plus Gemcitabine (Gem) (1000 mg/m2for 3 consecutive weeks out of 4) or Gem alone. Per protocol, this could be continued to a 12-cycle maximum. The primary efficacy endpoint was overall survival (OS). Safety, tolerability and progression free survival (PFS) were also assessed. Results: A total of 110 patients were randomized, 75 to receive IMM-101 plus Gem and 35 Gem alone (ITT population). The PP population consisted of 63 and 35 patients, respectively. Conclusions were similar; here we report results of the PP analysis. Median OS was increased significantly by 29% to 7.2 months in the IMM-101 plus Gem group compared to 5.6 months in the Gem group (p=0.022; HR 0.60, 95% CI 0.38-0.94). Median PFS was increased significantly by 83% to 4.4 months in the IMM-101 plus Gem group compared to 2.4 months in the Gem group (p=0.003; HR 0.51, 95% CI 0.32-0.81). In the pre-defined sub-group of patients with metastatic disease (n=82), median OS was increased significantly by 70% to 7.5 months in the IMM-101 plus Gem group (n=54) compared to 4.4 months in the Gem group (n=28) (p=0.002; HR 0.46, 95% CI 0.28-0.76). A highly significant 91% increase in median PFS from 2.3 months in the Gem group to 4.4 months in the IMM-101 plus Gem group was observed (p<0.001; HR 0.40, 95% CI 0.24-0.66). IMM-101 was well tolerated. The only adverse events of NCI CTC ≥Grade 3 occurring more frequently in the IMM-101 group (absolute difference in frequency between the groups >5%) were asthenia 10.8% and abdominal pain 8.1% (both 2.9% in the Gem group). Conclusion: Clinically meaningful increases in OS and PFS were demonstrated with IMM-101. No additional burden of adverse events above those relating to chemotherapy or the underlying disease was observed. Clinical trial information: NCT01303172.
Quality-adjusted survival in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) receiving first-line therapy with panitumumab plus FOLFOX versus FOLFOX alone in the PRIME trial.
Authors: Wang Jianmin , Dong Jun , Johnson Patrick , Maglinte Gregory A. , Rong Alan , Barber Beth L. , Douillard Jean-Yves
Published: February 2017

537

Background: The pivotal phase III PRIME trial demonstrated that, compared with FOLFOX alone, panitumumab plus FOLFOX prolongs overall survival and progression-free survival in patients with RASWT mCRC without having a detrimental effect on overall quality of life. The objective of this analysis was to use the quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method to compare quality-adjusted survival between the treatment arms of PRIME. Methods: Patients with RASWT mCRC from each treatment arm of PRIME were included in this analysis, and the area under the survival curve (AUSC) was estimated using the nonparametric Kaplan-Meier method (48 months follow-up). The AUSC was partitioned into three health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST, i.e., PFS minus TOX), and relapse (REL, i.e., OS minus PFS). The durations of the health states were then adjusted using utility weights derived from patient-reported EuroQoL 5 measures. The null hypothesis of no difference between treatment arms was tested based on the normal approximation, with standard errors calculated by the bootstrap method. In the primary analysis, TOX consisted of grade 3 and 4 adverse events. A sensitivity analysis, with grade 2, 3, and 4 adverse events classified as TOX, was performed. Results: Of 1,183 patients with mCRC who were randomized, 512 patients had RAS WT tumors (panitumumab plus FOLFOX, n=259; FOLFOX alone, n=253) and were included in this analysis. Patients receiving panitumumab plus FOLFOX had a significantly longer Q-TWiST (20.5 months) than patients receiving FOLFOX alone (18.2 months) resulting in 2.3 ± 1.0 (SE) additional quality-adjusted months (p<0.03). The sensitivity analysis yielded similar results, indicating that the analysis was robust. Conclusions: This Q-TWiST analysis showed that in a previously untreated RAS WT mCRC population, patients treated with panitumumab plus FOLFOX had a significantly improved duration of quality-adjusted survival compared with patients treated with FOLFOX alone. Clinical trial information: NCT00364013.
Next-generation sequencing (NGS) in metastatic gastrointestinal cancer (mGIC) patients: Translation from sequence data into clinical practice.
Authors: Moreira Raphael Brandao , Alessandretti Matheus Bongers , Abrahao Carina Mina , Lino Aline Da Rocha , Sousa Tarcia Tarciane Soares de , Amarante Marcus Paulo Fernandes , Gomes Jessica Ribeiro , Martins Junior Rodnei Merlrina , Carvalho Rafael Ferreira de , Kawamura Haddad Carolina , Schutz Fabio Augusto Barros , Peixoto Renata D'Alpino , Cruz Marcelo Rocha , Maluf Fernando C. , Buzaid Antonio C. ,   COAEM
Published: February 2017

72

Background: A considerable number of patients with mGIC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mGIC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 236 genes and selective intronic sequencing from 19 genes for refractory mGIC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 32 patients were tested. Primary tumors consisted of colorectal adenocarcinoma (37,5%), pancreatic adenocarcinoma (31,2%), gastric adenocarcinoma (12,5%), cholangiocarcinoma (12,5%) and hepatocellular carcinoma (6%). Most patients (87,5%) were found to harbor potentially actionable genetic alterations involving mitogen-activated protein kinase (93,7%), phosphatidylinositol 3-kinase-AKT (18,7%), p53 (50%) and cell-cycle regulation (9%) pathways. Of the 6 patients who received the suggested targeted therapy, 4 achieved an objective response. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced gastrointestinal cancer patients. The assay provided clinical benefit in 12% of the patients.
Risk of cardiovascular events with degarelix versus leuprolide after biochemical relapse of prostate cancer: Exploratory analysis of a randomized controlled trial.
Authors: Higano Celestia S. , Crawford E. David , Shore Neal D. , Bosnyak Zsolt , Malmberg Anders , Neijber Anders , Klotz Laurence
Published: February 2017

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Background: Androgen deprivation therapy (ADT) has been associated with increased cardiovascular (CV) risk in men. A pooled analysis of phase 3 trials comparing LHRH agonists with degarelix in PCa patients indicated a lower risk of CV events or death in those treated with degarelix. We now report the incidence of non-fatal CV events in men with PCa and pre-existing CV disease (CVD) treated with degarelix or leuprolide in the CS37 trial. Methods: CS37 was a prospective, randomized trial comparing intermittent (n=175) and continuous (n=50) degarelix with continuous leuprolide (n=178) in patients with biochemical relapse of PCa in the United States. CV events were retrospectively analyzed up to Month 12 (intermittent arm events censored at Month 7). Cox regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: 143 men (35%) had pre-existing CVD at baseline; 88 treated with degarelix and 55 treated with leuprolide. For degarelix and leuprolide treatment arms, median age (range) was 75 (51–88) and 73 (53–89) years and median BMI (range) 28.0 (17.7–40.7) and 30.1 (23.5–48.3) kg/m2, respectively. A slightly higher proportion of men treated with leuprolide than degarelix had a Gleason score of 7–10 (35 [64%] vs 46 [52%]) and slightly more men treated with degarelix vs leuprolide had hypertension (31 [35%] vs 15 [27%]), diabetes (70 [80%] vs 39 [71%]) and used statin medication (67 [76%] vs 36 [65%]) at baseline. The proportion of men who smoked or had hypercholesterolemia at baseline was similar between treatment arms. During the observation period, a subsequent CV event occurred in 3 (3.4%) men treated with degarelix and 8 (14.5%) treated with leuprolide (HR=0.22; 95% CI 0.05–1.03, p=0.054). Conclusions: Retrospective analysis of men with pre−existing CVD in CS37 identified a lower risk for subsequent CV events in men treated with degarelix vs leuprolide. The difference in CV event risk was seen within 12 months of treatment initiation. Our analysis adds to previous data on CV risk with ADT and supports consideration of CV risk factors when choosing a drug for androgen deprivation.
Weekly cabazitaxel in "unfit" metastatic castration-resistant prostate cancer patients (mCRPC) progressing after docetaxel (D) treatment: Preliminary results of CABASEM-SOGUG phase II trial.
Authors: Fernandez Calvo Ovidio , Fernandez Parra Eva , Perez-Valderrama Begoña , Mellado Begoña , Ochoa de Olza Maria , Castellano Daniel E. , Domenech Montserrat , Hernando Polo Susana , Anido Urbano , Arranz Arija Jose Angel , Caballero Cristina , Juan M Jose , Duran Ignacio , Campayo Marc , Serrano Monica , Climent Miguel Angel ,   SOGUG: Spanish Oncology Genitourinary Group
Published: February 2017

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Background: Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement after D in metastatic castration-resistant prostate cancer (mCRPC) in a three-weekly schedule. Its main toxicity is hematological, especially in unfit patients. We aimed to evaluate efficacy and safety of weekly C/prednisone (P) schedule in "unfit" mCRPC previously treated with D. Methods: Unfit pts defined as ECOG 2, dose reduction due to febrile neutropenia during D treatment or radiation therapy affecting more than 25% of bone marrow reserve, with mCRPC progressing after D treatment with adequate bone marrow, liver and kidney functions were included. C 10 mg/m2 was administered on days 1, 8, 15 and 22 of 5-week cycles with P (5 mg b.i.d.). Radiological and PSA response were evaluated according to the PCWG2 (Scher H, 2008) criteria and toxicity according NCI-CTC AE. Results: To date 70 pts have been enrolled and data are available for 66. Median age was 73 y (range 54-84), 67% pts had ECOG 2, 87% had bone, 14% liver and 11% lung metastases. Half of pts had Gleason >7. Treatment: 271 cycles (median: 3; range: 1-12); 1002 weekly infusions (median 11; range 1-48). Median dose intensity was 93%. Eighteen of 55 pts (32.7%) achieve ≥50% PSA response and 5 (9.1%) ≥80% PSA response. Radiological response was evaluable in 56 pts. PR was observed in 4 pt (7.1%) and SD in 29 pts (51.8%). Median PFS was 3.9 months. Median OS was 14.2 months. Most frequent toxicities of all grades as % of pts were: anemia (71.2%), asthenia (43.9%), thrombocytopenia (15.1%), leukopenia (24.2%), diarrhea (27.3%), nauseas (18.2%), neutropenia (12.1%), peripheral neuropathy (7.6%), and anorexia (18.2%). Grade 3-4: thrombocytopenia (4.5%), anemia (6%), neutropenia (3.0%), asthenia (10.6%), diarrhea (1.5%), anorexia (1.5%), No grade IV diarrhea nor febrile neutropenia were observed. Conclusions: Weekly cabazitaxel (10 mg/m2) plus prednisone administered to unfit pts seems a highly effective treatment and safe, with no grade 4 neutropenia, diarrhea or febrile neutropenia reported. Clinical trial information: NCT01518283.
Evaluation of basal and luminal subtypes of urothelial carcinoma in African American and non-African American patients.
Authors: Kardos Jordan , Melquist Jonathan J , Chism David D. , Choi Woonyoung , Cockerill Katherine , Paluri Ravi Kumar , Moses Kelvin A , Sonpavde Guru , McConkey David James , Kim William Y. , Dinney Colin P. N. , Milowsky Matthew I.
Published: February 2017

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Background: African American (AA) patients with urothelial carcinoma (UC) have been known to have a worse prognosis even when corrected for variables such as tumor stage and grade. Analysis of gene expression of several malignancies has resulted in the discovery of molecular subtypes with well-defined intrinsic biology. Recent studies in high grade (HG), muscle-invasive UC have led to the identification of two intrinsic, molecular subsets termed “luminal” and “basal” with characteristics of stages of urothelial differentiation, and that remarkably reflect the luminal and basal-like molecular subtypes of breast cancer. Patients with basal-like UC have a significantly worse overall survival. Methods: A total of 215 HG muscle-invasive UC tumors from the MDACC (n=75) and TCGA (n=140) were used to make intrinsic subtype calls using gene expression profiling (MDACC: DASL [cDNA-mediated Annealing, Selection, extension, and Ligation] and TCGA: RNA seq). Basal and luminal subtype calls were derived using previously published subtype classifiers (Damrauer et. al. PNAS, 2014 and Choi et. al. Cancer Cell, 2014). Patients were classified into AA and non-AA (white, Hispanic, or Asian) based upon self-reported race. Results: In total there were 16 and 199 tumors from AA and non-AA patients respectively. In non-AA patients, the proportion of tumors that were classified as basal and luminal were approximately equal (93 and 106 respectively), while in AA patients, there was enrichment of basal tumors (12 basal and 4 luminal) (p=0.03735, Fisher’s exact test). Conclusions: AA patients are enriched in the basal molecular subtype of UC. Similar findings have been previously documented in AA women with breast cancer. The enrichment of basal UC in AAs suggests that a biological explanation may in part underlie the poor outcomes seen in AA patients. Future studies will explore the prognostic and predictive implications of basal subtype in AA patients with UC.
Charting DNA methylation of long non-coding RNA in clear-cell renal cell carcinoma.
Authors: Malouf Gabriel , Zhang Jianping , Tannir Nizar M. , Thompson Erika , Spano Jean-Philippe , Khayat David , Su Xiaoping
Published: February 2017

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Background: Long non-coding RNAs (lncRNA) play a key role in regulating cell physiology through different mechanisms including the recruitment of histone-modifying enzymes. Recently, lncRNA classification of clear-cell renal cell carcinomas (cc-RCC) established four subtypes with different clinico-pathological features. However, the interplay between those lncRNA and DNA methylation patterns remains unknown. Methods: We performed a genomic analysis of GENCODE lncRNAs in cc-RCC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 471 primary tumors. Furthermore, we reannotated data of DNA methylation combining 27K (n=173) and 450K (n=298) Infinium arrays. We described global correlations between lncRNA expression and DNA methylation and established lncRNA methylation subtypes based on distinct signatures. In addition, we identified lncRNA regulated by DNA methylation and associated with poor outcome. Results: We identified 2,138 lncRNAs which contain promoters located in CpG islands (CGI). Out of those, 59 (2.8%) lncRNAs showed DNA methylation in both normal and cancer as compared to 1,487 (69.5%) lncRNA which were unmethylated in both of them. Importantly, 592 (27.7%) lncRNAs gained DNA methylation in ccRCC and this was associated with the repression of the expression of 70 of them. Unsupervised clustering of lncRNA using the most variable DNA methylation probes revealed three robust subtypes associated with distinct outcome. Finally, by integrating cancer subtypes data with clinical information, we identified several lncRNAs which promoter methylation was associated with patient outcome. Conclusions: Our study represents the first integrative analysis of lncRNA and DNA methylation in ccRCC and provides new insights in the role of epigenetic alterations in kidney cancer. Furthermore, we identified a subset of lncRNA regulated epigenetically which may represent potential therapeutic targets.
Is RCC truly radioresistant? Local control rates of metastatic renal cell carcinoma (RCC) to the lung using stereotactic radiotherapy (SBRT).
Authors: Altoos Basel M , Amini Arya , Bourlon Maria Teresa , Fisher Christine M. , Bedrick Edward , Flaig Thomas W. , Lam Elaine Tat , Kessler Elizabeth Riley , Kavanagh Brian D. , Karam Sana D
Published: February 2017

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Background: The use of radiation therapy (RT) for renal cell carcinoma (RCC) is controversial because RCC has traditionally been considered to be “radioresistant”. Based on this concern, current studies have suggested the need for higher doses with conventional fractionation (CF) or the use of SBRT with RCC. The purpose of this study is to determine the efficacy of these modalities by comparing the radiographic and symptomatic local control (LC) rates in patients with metastatic RCC to the lung. Methods: We retrospectively analyzed the radiographic and symptomatic RT response in 27 consecutive RCC patients with 37 RCC lung lesions treated between 2005 to 2014. Twenty-six (70.2%) were treated with SBRT and eleven (29.8%) with CF. Only 9 patients (33.3%) had symptoms prior to RT. Median SBRT dose and fraction was 50 Gy (range 25-60) and 3 (range 1-6) versus CF 30 Gy (range 20-55) and 10 (range 5-22) respectively. Toxicity was evaluated by CTCAE 4.0. Results: Median follow up was 16 months (range 1-102). Rates of radiographic local control with SBRT and CF were 92.3% vs. 55.4% respectively (p=0.0016). Under univariate analysis, predictors for radiographic LR were gross tumor volume (GTV) > 20 cc (p < 0.0001), planned tumor volume (PTV) of > 100 cc (p < 0.0001), and biologic effective dose (BED) < 70 Gy (p=0.0001). Subanalysis of CF demonstrated that a BED < 54 Gy was also a strong predictor for LR (p=0.0012). Under multivariate analysis, PTV was a strong predictor for radiographic LR (odds ratio [OR] = 42.2, p=0.0492). For the 9 symptomatic patients, 3 of 4 (75%) patients in the CF arm and 4 of 5 (80%) in the SBRT arm experienced partial or complete symptomatic relief. The median time to relief of symptoms in the SBRT and CF arms were 0.5 and 2 months, respectively. All patients receiving CF had symptomatic LR compared to none in the SBRT arm (p=0.0124). One patient in the SBRT arm had grade 2 hiccups and one with grade 2 pneumonitis in the CF arm. There were no other grade 2 toxicities or higher. Conclusions: SBRT demonstrated an encouraging local control rate and was capable of safely providing symptomatic relief to patients. The traditional view of radioresistance in RCC may not apply in the era of SBRT.
Place of short-term androgen deprivation therapy in intermediate-risk prostate cancer treated with radiotherapy: A phase III trial.
Authors: Nabid Abdenour , Carrier Nathalie , Vigneault Eric , Souhami Luis , Lemaire Céline , Brassard Marc-André , Bahoric Boris , Archambault Robert , Vincent François , Nguyen-Huynh Thu-Van
Published: February 2017

5

Background: The place of short term androgen deprivation therapy (STADT) in combination with radiation therapy (RT) for patients with intermediate risk prostate cancer (IRPC) remains controversial. The purpose of this prospective, randomized trial was to compare outcomes between patients with IRPC treated with different doses of RT with or without STADT, (PCS III trial, Clinical Trials.gov, NCT00223145). Methods: From December 2000 to September 2010, 600 patients with IRPC were randomized to 6 months of STADT and two levels of prostate RT doses of 70 (arm 1) or 76 Gy (arm 2) versus prostate dose-escalated RT alone at 76 Gy (arm 3). STADT consisted of bicalutamide and gosereline for six months. RT (2 Gy per fraction) started four months after the beginning of STADT. Biochemical failure and disease-free survival (DFS) were primary end-points, with overall survival (OS) as secondary endpoint. DFS and OS rates were estimated with Kaplan-Meier and compared with log rank test and Cox regression. Results: Patient’s characteristics were well balanced among the 3 arms (median age 71 years, median PSA 10 ng/ml, median Gleason score 7). At a median follow-up of 75.4 months, biochemical failure occurred in 84 (14%) patients (arms 1 to 3: 12.5%, 8.0%, 21.5%) with statistical difference between arm 1 and 3 (p = 0.023) and arm 2 and 3 (p < 0.001). There was no significant difference between arm 1 and 2. A total of 113 (19%) patients had died with only 6 deaths (1%) attributed to prostate cancer. The 5-/10-year DFS rates were 93%, 97.5% and 86%, and 77%, 90% and 64.5%, respectively. Significant differences in DFS between the treatment arms were observed at 5 years but at 10 years it was observed only between arm 1 and 3 (p=0.01) and arm 2 and 3 (p<0.001). The 5-/10-year OS rates were 91%, 95% and 93%, and 64%, 70% and 78%, respectively. There was no statistical difference in OS between arms at 5 and 10 years. Conclusions: In patients with IRPC, the use of STADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved OS. Source of Funding: AstraZeneca Pharmaceuticals Grant. Clinical trial information: NCT00223145.