bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction treatment in first-line with chemotherapy + bevacizumab (bev) in metastatic colorectal cancer: Results from the gercor-DREAM phase III study.
Authors: Tournigand Christophe , Scheithauer Werner , Samson Benoit , Lledo Gérard , Viret Frédéric , Andre Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , Chibaudel Benoist , De Gramont Aimery
Published: February 2017

457

Background: the DREAM study compares a maintenance therapy with bevacizumab (bev) alone or with the erlotinib after a bev-based induction therapy with FOLFOX, or biweekly XELOX or FOLFIRI. Efficacy of the induction treatment is reported here. Methods: Patients (pts) with previously untreated metastatic colorectal cancer received one of the following regimen (investigator’s choice): mFOLFOX7-bev, biweekly mXELOX-bev or FOLFIRI-bev. Oxaliplatin was administered no more than 6 cycles. In the 1st cohort, pts received 3 months (m) of FOLFOX-bev or mXELOX-bev before randomization. In the 2nd cohort, pts received 3m of FOLFOX-bev or mXELOX-bev then 3 m of fluoropyrimidine-bev, or 6 m of FOLFIRI-bev before randomization. Pts with disease control were then randomized between bev alone or with erlotinib until progression. Results: FOLFOX-bev was administered in 424 pts, mXELOX-bev in 203 pts and FOLFIRI-bev in 67 pts. Pts characteristics for the whole population are: median age 63 yrs (26-80), male/female 59.8%/40.2%, synchronous mets/metachronous 82.6%/17.4%, PS 0/1/2 58%/39%/3%, LDH>UNL 53%, platelets >400000/mm3 27%. Patients received a median nb of 6 cycles of oxaliplatin for FOLFOX-bev and mXELOX-bev, and a median nb of 12 cycles of irinotecan with FOLFIRI-bev. Response rates are respectively 48%, 50% and 63%. Median PFS are respectively 8.61m, 8.97m and 9m. Severe toxicity profiles (grade 3-4) appear to be different according to the schedule : more neutropenia and diarrhea with FOLFIRI-bev, HFS and diarrhea with mXELOX-bev and neuropathy with FOLFOX-bev. Conclusions: Modified biweekly XELOX-bev provides similar efficacy results with FOLFOX-bev, and FOLFIRI-bev as induction therapy in first-line. Clinical trial information: NCT00265824.
Time course of regorafenib-associated adverse events in the phase III CORRECT study.
Authors: Grothey Axel , Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Cupit Lisa
Published: February 2017

467

Background: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Methods: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Results: The safety population comprised 753 patients (pts): REG n=500; placebo n=253. The mean treatment duration was 12.1 ± 9.7 weeks in the REG group and 7.8 ± 5.2 weeks in the placebo group. Treatment-emergent AEs occurred at any grade in 99.6% of REG pts and 96.8% of placebo pts, at grade 1/2 in 21.6% and 47.8%, respectively, at grade 3 in 56.0% and 26.5%, respectively, and at grade 4/5 in 22.0% and 22.5%, respectively. AEs occurring in ≥10% more REG than placebo pts were fatigue, hand–foot skin reaction (HFSR), anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, low platelet count. The most frequent AEs deemed to be regorafenib related were HFSR, fatigue, diarrhea, hypertension, and rash/desquamation. The frequency of these AEs over time is shown in the Table. The incidence of HFSR, fatigue, hypertension, and rash/desquamation peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles. The incidence of diarrhea remained relatively constant throughout treatment. AEs led to dose modification in 66.6% of pts in the REG group and 22.5% in the placebo group. Data on dose intensity across treatment cycles will be presented. Conclusions: In the CORRECT trial, the incidences of the most common AEs in the REG group peaked early during treatment. There appeared to be no evidence for cumulative toxicity of REG. Clinical trial information: NCT01103323. [Table: see text]
A phase II multicenter study of metastasectomy for intra- and extra-hepatic metastases from colorectal cancer.
Authors: Wei Alice Chia-chi , Coburn Natalie G. , Moulton Carol-anne , Cleary Sean P , Law Calvin , Greig Paul David , Gallinger Steven
Published: February 2017

482

Background: Metastasectomy for liver limited metastases from colorectal cancer (CRC) provides excellent 5-year overall survival (OS) rates. The presence of extra-hepatic metastases (EHM) has traditionally been a contraindication to surgery. On this basis, as many as 80% of patients are deemed ineligible for liver resection. Due to the improved safety of hepatic surgery, there is a growing interest in multi-site metastasectomy for patients with intra-hepatic and extra-hepatic metastases (IHM, and EHM). The objective of this study was to evaluate the results of complete metastasectomy for patients with IHM and EHM from CRC. Methods: A phase II study of metastasectomy for both IHM and EHM from CRC was conducted at 2 high volume hepato-pancreato-biliary (HPB) centers. Eligible patients with any number resectable IHM and up to 3 foci of EHM, resectable with RO intent were offered metastasectomy. Clinical and survival data was analyzed using standard statistical methods. Results: Twenty-five patients were enrolled with a median age of 57 (32-84) years; 14/25 (56%) patients presented with synchronous disease. The median number of IHM, EHM and combined sites were 2, 1 and 3, respectively. The lung was the most common site of EHM (12/25, 48%). Protocol surgery was completed in 18/25 (72%) including 11/25 (44%) planned sequential resections. Perioperative morbidity and mortality was 11/25 (44%) and 1/25 (4%), respectively. The median disease free survival was 6 months. The median OS from the time of CRC diagnosis, first metastasectomy and completion metastasectomy was 47, 27 and 23 months, respectively. Conclusions: Complete metastasectomy of multi-site CRC is feasible and safe. However, disease will recur in the majority of patients. The impact to aggressive multi-site metastasectomy is modest but may provide OS benefit in selected patients.
Adjuvant treatment and outcomes in patients with stage III colon cancer (CC) who do not fit clinical trial eligibility criteria (CTEC).
Authors: Rasool Javaheri Khodadad , Kennecke Hagen F. , Renouf Daniel John , Lim Howard John , Hsu Tina , Speers Caroline , Goktepe Ozge , Cheung Winson Y.
Published: February 2017

486

Background: Trials have strict inclusion and exclusion criteria to maintain internal validity. However, study findings are often applied to pts in clinical practice who do not satisfy all of the CTEC. Whether these pts benefit from treatment is unclear. Our objectives were 1) to characterize cancer-specific (CSS) and overall survival (OS) in a population-based cohort of trial-eligible (TE) and trial-ineligible (TI) pts receiving adjuvant chemotherapy (CT) and 2) to compare their outcomes with those not treated with CT. Methods: Pts diagnosed with stage III CC between 2006 and 2008, referred to 1 of 5 regional cancer centers in British Columbia, and evaluated for possible adjuvant CT within 12 weeks of curative surgery were reviewed. Pts were defined as TE if aged 18 to 79 years, ECOG 0 to 1, CEA <10 ng/ml, had not received prior CT or radiation, and had adequate blood counts, cardiac, liver, and kidney function. All other pts were considered TI. Using Kaplan-Meier and Cox regression analyses, we compared outcomes between TE and TI pts who received CT vs. those who did not. Results: A total of 821 pts were identified: median age was 68 years, 52% were men, 85% were ECOG 0 to1, and 71% received adjuvant CT. Among pts treated with CT, 405 (70%) were TE and 177 (30%) were TI. Compared to TI pts, those who were TE were younger (p<0.01) and more likely to receive FOLFOX than capecitabine (65 vs. 46%, p<0.01). CSS and OS were significantly different among pts who were TE, TI, and those who did not receive CT (p<0.01) (Table). In multivariate analyses that adjusted for confounders, both TI pts and those not treated with CT had worse prognoses than TE pts (HR for CC deaths 1.32, 95%CI 0.86-2.02 and 2.77, 95%CI 1.92-3.99, respectively, p trend <0.01; HR for all deaths 1.24, 95%CI 0.85-1.80 and 2.95, 95%CI 2.17-4.00, respectively, p trend <0.01). Conclusions: A considerable number of stage III CC pts who did not fit CTEC were treated with adjuvant CT. While outcomes in the TI group were worse than those in the TE group, CSS and OS were still better than the subset that did not receive any CT. [Table: see text]
Patterns of recurrence after resection of rectal gastrointestinal stromal tumors and the effect of adjuvant therapy.
Authors: Yasui Masayoshi , Mori Masaki , Takahashi Tsuyoshi , Nakashima Yasuo , Dousei Tsutomu , Yamashita Yoshito , Fujita Junya , Hiramatsu Masako , Kawabata Ryohei , Nakai Koji , Nakai Takuya , Nishida Toshirou , Noguchi Miki , Orita Hajime , Shono Yoshiharu , Souma Yoshihito , Takagi Masakazu , Ueda Shugo , Yamamoto Kazuyoshi , Tsujinaka Toshimasa ,   Kinki GIST Study Group
Published: February 2017

531

Background: Since gastrointestinal stromal tumors (GISTs) of the rectum are rare, clinical features and treatment outcome have not been well documented. Methods: Data from patients with rectal GIST diagnosed and primarily treated between 2003-2007 at 17 institutions in Japan were collected and analyzed on clinical characteristics, pathologic features and recurrence patterns. Results: Twenty-five patients (11 men and 14 women) with rectal GISTs were collected. Median age was 67years old. Pathological examinations disclosed that the median number of mitoses and the size of tumors were 4 counts/50HPF and 4.5cm, respectively. By the Miettinen criteria, 44 percent (n = 11) were classified as high-risk, 32 percent (n = 8) as low-risk and 16 percent (n = 4) as none-risk gastrointestinal stromal tumors. Sixty-three percent (7/11) of patients with high-risk GISTs had developed recurrence. None of patients (n = 12) with low or none-risk gastrointestinal stromal tumors have recurred after a median follow-up of 1699 (range, 135-3871) days. 85 percent (6/7) of recurrent patients showed loco-regional recurrence. Twelve patients with rectal GISTs received local excision and thirteen patients received extended resection (abdominoperineal resection or low anterior resection). Loco-regional recurrence rate following local excision was 25% (3/12), which was similar with that of extended resection (23%, 3/13).7 patients received neoadjuvant and/or adjuvant imatinib. Only one patient of 7 patients who received perioperative imatinib treatment developed recurrence. Conclusions: Loco-regional recurrence was the most predominant pattern of recurrence after surgical resection of rectal GISTs. The Miettinen criteria were useful to differentiate the high risk group. Recurrence rate was lower in patients treated with perioperative imatinib. Rectal GIST may be optimally managed by perioperative multimodal treatment instead of extending surgical resection.
Thrombotic events in patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.
Authors: Al-Shamsi Humaid O. , Anjum Mahraz , Al Farsi Abdulaziz , Shen Hua , Linkins Lori-Ann , Cook Richard J. , Major Pierre
Published: February 2017

540

Background: The rate of venous thromboembolism (VTE) in (mCRC) with bevacizumab was reported in a meta-analysis as 19.1%. We estimated and compared the rate of VTE among mCRC patients receiving FOLFIRI and bevacizumab with patients receiving FOLFIRI without bevacizumab. Methods: We conducted a retrospective cohort study assessing the rate of VTE in a group of 450 mCRC patients seen consecutively at the Juravinski Cancer Center. Patients were classified according to their treatment: chemotherapy plus bevacizumab group (n=261) and control group (n=189) who received only FOLFIRI during the years 2004 to 2012. Demographic, pathologic and treatment data were abstracted. Multivariate analysis was used to adjust for the effect potential confounding variables associated with treatment and VTE and to assess the effect of these variables risk of VTEs in this population. The primary end point was the occurrence of a VTE. Secondary analyses involved classifying site of VTE. Results: The percentage of male, mean age and mean BMI were 64.8%, 60.1 years and 27.2 for the bevacizumab group and 61.9%, 63.69 years and 27.6 are for the control group. The crude incidence of VTEs was 13.1% in bevacizumab and 10.5% in the control groups (p = NS). Multivariate analysis controlled for age, BMI, gender, malignancy, metastatic disease and line of treatment did not suggest a significant increase in risk of VTE associated with bevacizumab (OR=0.83 95% CI: 0.40, 1.70; p=0.602). The only significant factor for thrombosis in bevacizumab group was BMI (OR=1.05; 95% CI: 1.01, 1.10; p=0.016). Other risk factors such as previous VTE, stroke, smoking, and hypertension were not statistically significant when assessed through a composite covariate. For anatomical location of VTEs, see the Table. Conclusions:The rate of VTEs overall was lower in our sample than has been reported in previous studies. We excluded upper limb DVTs associated with central lines which may explain the lower VTEs overall. The incidence of VTEs was not significantly different between the bevacizumab and the control groups. bevacizumab was not associated with increase risk of VTES . This support the safety of bevacizumab in regards to VTEs risk in this population. The incidence of venous thromboembolism (VTE) in FOLFIRI with and without bevacizumab.

[Table: see text]
Randomized comparisons of IL-6 and lean body mass between open versus laparoscopic distal gastrectomy for gastric cancer.
Authors: Yoshikawa Takaki , Hayashi Tsutomu , Aoyama Toru , Shirai Junya , Fujikawa Hirohito , Ogata Takashi , Cho Haruhiko , Oshima Takashi , Rino Yasushi , Masuda Munetaka , Tsuburaya Akira
Published: February 2017

55

Background: Laparoscopic distal gastrectomy (LA) for gastric cancer may reduce breakdown of the muscle protein due to less surgical stress, compared with open surgery (OP). Methods: This study was performed as an exploratory analysis of a phase III trial comparing OP and LA for stage I gastric cancer in KCCH by limiting the period between May and Dec of 2011. IL-6 was measured before and 12 hours after surgery. Prealbumin and body composition were examined before and 7 days after surgery. %LBM was defined as percentile of LBM at 7 days to LBM before surgery. Values were expressed as median and range. Results: Twenty-seven patients were randomized to OP in 14 and LA in 13. Baseline: Body weight, LBM, prealbumin, and IL-6 were similar between both. Surgery and pathology D1/D1+/D2 lymph node dissections were 0/9/5 in OP and 0/9/4 in LA (p=0.785). Blood loss (g, range) and operation time (minutes, range) were 160 (50-475) and 174.5 (85-276) in OP, respectively, and 40 (5-270) and 267 (168-360) in LA, respectively, which were both significantly different (p=0.009 and 0005, respectively). Pathological T and N were similar between both. Morbidity and mortality: Any complications > grade 2 defined by Clavien-Dindo classification were 2 (14.3%) including grade 3B anastomotic stenosis and 3A pancreatic fistula in OP and 1 (7.7%) grade 2 transient ischemic attack in LA (p=0.586). Measurements: IL-6 (pg/ml, range) after 12 hours was 36.3 (14.4-405.0) in OP and 53.3 (24.1-217.0) in LA (p=1.000). Prealubumin (mg/dl, range) was 17.3 (11.7-23.7) in OP and 17.8 (10.5-28.7) in LA (p=0.680). %LBM (range) was 96.9 (93-101) in OP and 96.5 (93-100) in LA (p=1.000). When excluding the patients who developed morbidity > grade 2, IL-6 (range) was 32.1 (14.4-405.0) in OP and 49.5 (24.1-217.0) in LA (p=0.356). Prealubumin (mg/dl, range) was 17.7 (13.7-23.7) in OP and 17.8 (10.5-28.7) in LA (p=0.729). %LBM (range) was 97.1 (93-101) in OP and 97.2 (94-100) in LA (p=1.000). Conclusions: Laparoscopic approach has no impact on surgical stress and breakdown of the muscle protein after distal gastrectomy.
Panitumumab (pmab) in patients (pts) with chemorefractory metastatic colorectal cancer (mCRC): Final analysis from a community-based, observational study (VECTOR) in Germany.
Authors: Lerchenmuller Christian A. , Groschek Matthias , Kroening Hendrik , Scheuer Burkhard , Stauch Martina , Kuhn Anja , Hellebrand Eva , Vehling-Kaiser Ursula
Published: February 2017

550

Background: Pmab monotherapy significantly improves progression-free survival versus best supportive care in pts with chemorefractory KRAS wild-type (WT) mCRC. This study evaluated the efficacy and safety of pmab in routine clinical practice in Germany. Methods: To ensure a representative sample, eligibility criteria were largely unrestricted. Consenting pts were >18 years old, had histologically confirmed KRAS WT mCRC, >4 weeks pmab therapy, failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy (CTx) regimens, and women of child-bearing age received contraception. Predefined endpoints were overall response rate (ORR; investigator`s assessment) and skin toxicity (NCI Common Terminology Criteria for Adverse Events v3.0). Results: A total of 428 pts were included in the full analysis set. At the start of pmab therapy, median age was 69 (range 22-89) years, 268 pts (63%) were male and 343 (80%) had an ECOG performance status of 0-1. Overall, 400 pts (93%) had undergone prior surgery and 154 (36%) had received ≥1 cycle of adjuvant CTx. Pts had received a median of 3 cycles (range: 1‑12) of prior CTx for mCRC. The most common regimens were FOLFOX/FOLFIRI ±antibody therapy; 65% of regimens were given with palliative, 32% with curative/palliative and 3% with curative intent. The median pmab dose was 6 mg/kg (range 2.4-7.2) q2w for a median of 8 (range 2‑45) cycles, with 143 pts (33%) receiving >10 cycles. The ORR during pmab therapy was 20% (complete response: n=7 [2%]; partial response: n=77 [18%]); disease control (including stable disease) was achieved in 261 pts (61%). Skin reactions occurred in 324 pts (67%) with 52% experiencing a maximum grade ≥2. Most pts had some type of rash (48% acne, 5% desquamation, 4% hand-foot skin reaction, 1% erythema multiforme). Overall, 21% of pts had other toxicities. Three serious adverse drug reactions (infection/fever; thrombosis/embolism; erythema multiforme) and two grade 1 infusion reactions were reported. Conclusions: In this observational study, pmab monotherapy had efficacy at least as good as was seen in the randomised pmab trial and safety was also similar.
The efficacy and safety of XELOX plus bevacizumab with oxaliplatin stop-and-go strategy in first-line treatment for metastatic colorectal cancer: CCOG 0902 study.
Authors: Watanabe Takuya , Nakayama Goro , Ishigure Kiyoshi , Hayashi Naomi , Yaguchi Toyohisa , Kojima Hiroshi , Tsuboi Kenji , Ito Akihiro , Deguchi Tomohiro , Sekiya Masanori , Tanaka Chie , Ando Yuichi , Ohashi Norifumi , Kodera Yasuhiro ,   Chubu Clinical Oncology Group
Published: February 2017

564

Background: XELOX plus bevacizumab (BEV) is an established first-line therapy for metastatic colorectal cancer (mCRC). However, the cumulative neurotoxicity of oxaliplatin often requires therapy to be discontinued while the patient is still responding. The aim of this study was to evaluate efficacy and safety of XELOX plus BEV with oxaliplatin stop and go strategy. Methods: Fifty four patients with unresectable mCRC were enrolled as first-line treatment. They were treated with four cycles of XELOX plus BEV, followed by maintenance therapy with capecitabine (Cape) plus BEV. Reintroduction of oxaliplatin was scheduled after eight cycles of Cape plus BEV or upon tumor progression. The primary endpoint was progression free survival (PFS). Results: Forty nine patients (90%) achieved to the maintenance therapy and thirty one patients (59%) were reintroducted oxaliplatin. The response rates and disease control rates were 57% and 96% in the initial XELOX plus BEV, 6.1% and 73% in Cape plus BEV maintenance therapy. Median PFS in initial XELOX plus BEV was 11.0 months (95%CI: 7.8-14.1). One year survival rate was 86%. Conclusions: XELOX plus BEV was feasible as a first line treatment with mCRC. The most cases achieved disease control during Cape plus BEV maintenance therapy. Clinical trial information: UMIN000006478.
Neoadjuvant capecitabine and oxaliplatin (XELOX) with bevacizumab for locally advanced rectal cancer.
Authors: Hasegawa Junichi , Mizushima Tsunekazu , Kim Ho Min , Miyake Yasuhiro , Takemoto Hiroyoshi , Tamagawa Hiroshi , Noura Shingo , Ohue Masayuki , Fujii Makoto , Fujie Yuichiro , Ota Hirofumi , Kato Takeshi , Fukunaga Mutsumi , Takemasa Ichiro , Ikeda Masataka , Yamamoto Hirofumi , Sekimoto Mistugu , Nezu Riichiro , Doki Yuichiro , Mori Masaki ,   Multicenter Clinical Study Group of Osaka University, Colorectal Cancer Treatment Group
Published: February 2017

566

Background: Chemoradiotherapy (CRT) followed by surgery is a standard treatment for locally advanced rectal cancer. Although preoperative CRT decreases local recurrence (LR), pelvic radiation is associated with long-term morbidity. We conducted this study to evaluate the feasibility of neoadjuvant XELOX with bevacizumab (Bmab) in patients (pts) with locally advanced rectal cancer. Methods: Pts with T4 or lymph node (LN) positive rectal cancer were treated with 3 cycles of XELOX with Bmab and one additional cycle of XELOX. Total mesorectal excision was performed 3-8 weeks after the last chemotherapy. The primary endpoint was to assess feasibility and secondary endpoints were R0 resection rate, down staging rate, pathological complete response (pCR) rate and pathological effect over grade 2 (tumor cell death in more than two-thirds of the entire lesion). Results: Twenty five pts were recruited between December 2009 and November 2011. Characteristics of pts were as the following: male/female, 18/7; median age, 63 years (range, 37-75); median diameter of tumor, 52.8mm (range, 38.3-110); T2-T3/T4a/T4b, 7/8/10 and N0/N1/N2, 3/14/8. In 4% of the pts (7 pts), following grade 3-4 adverse events occurred; neutropenia, hypertension, bleeding, rectal obstruction, pelvic infection, anorexia and nausea. The down staging rate of T2-T3/T4a/T4b and N1/N2 were 29/63/50 % and 86/63 %, respectively. Seven pts (28%) discontinued the treatment after 2-3 cycles of XELOX with Bmab (13% in T2-T4a, 50% in T4b). The rate of conducting surgery was 92% and all of them had R0 resections. Postoperative complications were found in 9 pts (39%). The pCR rate was 4%, and the rate of pathological effect over grade 2 was 61%. Two LR (LN positive) and two distant recurrences (1 lung, 1 liver) were reported. Conclusions: XELOX with Bmab followed by surgery was safely performed for locally advanced rectal cancer. The down staging rate was 50% even in T4b pts although half of T4b pts discontinued the study treatment. Based on these preliminary results, we are planning a phase II trial of perioperative XELOX and surgery in locally advanced rectal cancer. Clinical trial information: 000003219.
Phase I study of ursodeoxycholic acid in combination with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab for metastatic colorectal cancer.
Authors: Lai Lily L. , Chiu Ken , Lim Dean , Chao Joseph , Frankel Paul Henry
Published: February 2017

569

Background: Emerging data links cancer growth with aberrant metabolism. These findings suggest that treatment directed against CRC metabolism may improve survival outcomes. Bile acids are involved in the metabolism of cholesterol and glucose. The bile acid, ursodeoxycholic acid (UDCA), protects against intestinal polyp development in animal and human studies. UDCA effects may be mediated through the nuclear receptor, farnesoid X receptor (FXR), since bile acids are the receptor’s endogenous ligands. FXR is a tumor suppressor in mouse models and a prognostic biomarker in patients with CRC. Bile acid activation of FXR in mouse models suppresses intestinal tumorigenesis. We sought to determine dose and safety of UDCA when added to standard therapy for mCRC. Methods: Patients with mCRC were accrued to an institutionally approved Phase I study. At the end of a 7-day run-in period of oral UDCA, standard doses of 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab were added. UDCA doses were escalated using a 3+3 design to determine MTD. The use of a run-in period allowed for correlative studies to identify serum biomarkers of FXR activation. Results: 11 patients were treated on three dose levels (250, 500, and 750 mg/day in divided doses). Patients were treated on protocol for a median time of 6 months with a median follow-up of 15 months. Patients were taken off protocol for progression of disease (n = 7); for declining performance status (n = 1); for toxicity (n=1); for patient refusal (n= 1). One patient remains on protocol at this time. No Grade 4 or higher toxicity was identified. Grade 3 toxicities were recorded in 5 patients; the majority was hematologic. Oral glucose tolerance tests, serum glucose and insulin levels, and serum FGF-19 were determined before and after UDCA treatment. Conclusions: UDCA, given with standard chemotherapy and biologic treatment, is safe and well tolerated in patients with mCRC. Further studies are needed to determine the efficacy of targeting FXR and cancer metabolism in mCRC. Supported by a grant from The Phase One Foundation. Clinical trial information: NCT00873275.
Patient evaluation of community nurse-led follow-up clinics for colon cancer.
Authors: Samuel Leslie M. , West Bernice ,   Aberdeenshire Community Cancer Clinics Steering Group
Published: February 2017

587

Background: Health services face an ever increasing demand for quality patient focussed healthcare with limited financial resources. Our group has designed and implemented, using non-specialist community nurses, a nurse led follow up service for patients with potentially cured colon and prostate cancers in 4 community hospitals in North East Scotland. Nurses use a structured questionnaire, take tumour specific blood tests & order some imaging. Results communicated to patients via letter from oncologist. Methods: A user-group & professionals were consulted and a customised questionnaire designed. Topic sections were-basic demographic data; mode of transport; perceptions of parking; travel; continuity of care; timing of appointments; satisfaction with service attributes; any concerns; suggestions for improvement and an overall rating score. Details of the evaluation were considered by the ethics committee as 'service evaluation'. Results: The questionnaire was successfully piloted in 5 patients. The main study targetted 100 patients, & data-collection ran from August 2010 until July 2011, the 4th year of the service. 103 questionnaires returned, all useable, from 216 sent out across 4 community clinic sites. The 48% return rate was consistent across all sites. The findings were grouped together rather than presented by clinic, due to lack of response variation by site. Verbatim comments were recorded. Returns from colon cancer patients were 75% of the total (47% M, 28% F) & 25% prostate patients. Median age 71, range 41 - 90 years. Travel was by car 87%, foot 8% & public transport 5%. Topics covered included, own health 96%, appt times 79%, tests & results 75%, patient support 37%, carer support 12% & 'other' 16%. Ranking of statements suggests 90% satisfaction with administration & 94% quality of clinic, and 85% prefer local proximity of clinic. Only 36% accompanied to clinic, less than when at central clinic. Only 8% expressed concerns, usually about scan results. Conclusions: an overwhelmingly positive patient evaluation provides evidence that non-specialist community nurses can deliver a follow up service in the community for potentially cured colon (& prostate) cancer patients.
Sentinel lymph node (SLN) mapping (M) in colon cancer (CCa) by da Vinci robotic system (DRS): First pilot study.
Authors: Saha Sukamal , Korant Alpesh , Abadeer Benjamin , Gomez-Seoane Andrew , Shaik Mohammed , Krishnamoorthy Madhumitha , Kaushal Sunil , Ganatra B. K. , Wiese David
Published: February 2017

589

Background: SLNM in CCa has been established as an aid to the pathologist to identify the nodes most likely to harbor micrometastasis. The technique has been well- established by in vivo and ex vivo technique. No such technique has been described by DRS in CCa. Hence, a pilot study was undertaken to identify if SLNM can be performed by DRS during robotically assisted colectomy as in open cases. Methods: Patients (Pts) with CCa were randomly selected for either robotic or open surgery. During each case, 1% methylene blue dye was injected in vivo subserosally around the tumor. Standard oncologic operations were done in each case. The first 1-4 blue nodes near the tumor were tagged with suture as SLNs. Data was collected for demographics, tumor pathology and peri-operative events. Results: There were a total of 11 consecutive robotic pts and 15 open pts. The data was compared between the robotic vs open groups as follows: Primary sites including Cecum (1 vs 3), Ascending Colon (3 vs 4), Transverse Colon (4 vs 5), Sigmoid Colon (2 vs 3); Average number of LNs (18.5 vs 17.6); Average number of SLNs (3.3 vs 3.0), and nodal positivity (50% vs 50%). The success rate was 100% in each group. Conclusions: There are great similarities for SLNM between robotic and open surgeries for CCa in regards to success rate, nodal harvest, SLNs, and nodal positivity. Hence, SLNM should be pursued when robotic surgeries are performed for CCa pts as in open cases. [Table: see text]
Retrospective cohort study on the safety and efficacy of panitumumab (Pmab) for patients with metastatic colorectal cancer (mCRC): The HGCSG1002 study—Analysis of clinical early predictor for the efficacy.
Authors: Sogabe Susumu , Fukushima Hiraku , Yuki Satoshi , Kobayashi Yoshimitsu , Miyagishima Takuto , Okuda Hiroyuki , Kusumi Takaya , Doi Ayako , Tsuji Yasushi , Kawamoto Yasuyuki , Ehira Nobuyuki , Koike Masahiko , Meguro Takashi , Takahashi Yasuo , Yoshizaki Koji , Muto Shuichi , Ishiguro Atsushi , Kato Sosuke , Sakata Yuh , Komatsu Yoshito ,   Hokkaido Gastrointestinal Cancer Study Group
Published: February 2017

593

Background: Inhibition of the EGFR pathway has become a key part in the treatment of colorectal cancer. There were few studies for clinical early predictive markers. To investigate the early magnesium (Mg2+), calcium (Ca2+), albumin (Alb), CEA and CA 19-9 plasma level reductions as a predictor for clinical outcome in terms of progression free survival (PFS) and overall survival (OS). Methods: 200 patients (pts) with mCRC treated by Pmab contained chemotherapy were retrospectively registered from 20 centers in Japan (HGCSG 1002 study). Of these, the pts that were refractory to or intolerant for 5-FU/ irinotecan/ oxaliplatin, and were never administered anti-EGFR-antibody, were included in this analysis. Mg2+, Ca2+, Alb, CEA and CA19-9 plasma levels were obtained from medical records. The differences in terms of PFS and OS according to the presence of Mg2+, Ca2+, Alb, CEA and CA19-9 reductions were evaluated by the log-rank test. Results: Of 67 pts were able to evaluate for this analysis. Pts’ characteristics were as follows: male/female 38/29, median age 64 (range 45-81), ECOG PS (0/1/2- ) 45/17/5. Response rate and disease control rate were 16.4% and 65.7%, PFS and OS were 4.3 m and 12.4 m, respectively. There were no correlations between Ca/Alb plasma level reductions and PFS/OS. Mg2+ reduction of at least 50% respect to the basal value during the course of treatment was significantly correlated with improved OS and PFS (OS, P=0.03; PFS, P=0.01), but the early reduction (until the 4th week or the 8th week after start of chemotherapy) was not correlated with OS and PFS. An early CEA serum level reduction of at least 40% until the 8th week was significantly correlated with improved OS and PFS (OS, P=0.04; PFS, P=0.07), moreover of at least 30% until the 4th week was correlated to longer PFS (P=0.053). Similar results were seen in CA19-9. Conclusions: An early CEA plasma level reduction of at least 30% or 40% was suggested to be a predictor for PFS in Pmab containing chemotherapy for mCRC pts. Although Mg2+ serum level reduction was correlated to clinical outcome, but could not show that is an early predictor for PFS and OS in our study.
A randomized phase II study of vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led study.
Authors: Cohen Deirdre Jill , Christos Paul J. , Sparano Joseph A. , Kindler Hedy Lee , Catenacci Daniel Virgil Thomas , Bekaii-Saab Tanios B. , Tahiri Sanaa , Janjigian Yelena Yuriy , Gibson Michael K. , Chan Emily , Rajdev Lakshmi , Urba Susan , Wade James Lloyd , Kozuch Peter , Love Erica , Vandris Katherine , Takebe Naoko , Hochster Howard S. ,   New York Cancer Consortium
Published: February 2017

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Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated, metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts (V/P 60/64) enrolled at 20 sites between 10/09-2/12. Pt characteristics (V/P): median age 58/62; ECOG PS 0: 23 (40%) / 30 (47%); male 39 (65%) / 53 (83%); GEJ 37 (62%) / 39 (61%); diffuse histology 20 (43%) / 14 (30%). Median number of FOLFOX cycles 9.5/11. Most common Gr ≥3 toxicities: (% pts V/P) neutropenia 50.0/31.7 (p=0.07), neuropathy 23.1/14.3 (p=0.33), fatigue 15.4/9.5 (p=0.50), thrombosis 13.5/11.1 (p=0.92), anemia 9.6/9.5 (p=0.99), hypokalemia 9.6/4.8 (p=0.52), nausea 7.7/9.5 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in ITT population 11.5/9.3 mo (95% CI 8.5-14.4/6.7-11.9; p=0.34) and median OS 12.2/13.9 mo (95% CI 10.2-14.3/11.5-16.3; p=0.48). Non-statistically significant trends toward improved PFS with V were noted in female pts, diffuse histology, and PS 1 (p≤ 0.08). RR (%) 33/27 (p=0.64). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06 Clinical trial information: NCT00982592.
A phase ll study of trastuzumab in combination with triweekly S-1 plus CDDP in HER2-positive advanced gastric cancer (HERBIS-1).
Authors: Sugimoto Naotoshi , Tanaka Junji , Tsuda Masahiro , Okamoto Wataru , Okuda Hiroyuki , Imamura Hiroshi , Shimokawa Toshio , Sakai Daisuke , Kurokawa Yukinori , Komatsu Yoshito , Ishioka Chikashi , Tsujinaka Toshimasa , Takiuchi Hiroya , Furukawa Hiroshi
Published: February 2017

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Background: S-1, an oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer (AGC). Although ToGA study demonstrated that trastuzumab (T-mab) in combination with capecitabine plus cisplatin or fluorouracil plus cisplatin improved the overall survival of patients (pts) with HER2-positive AGC, there was no study evaluating the efficacy and the safety of T-mab in combination with SP regimen. Methods: Eligibility criteria included gastric or esophagogastric junction adenocarcinoma; HER2-positive confirmed by IHC and/or FISH (IHC 3+ or IHC 2+ and FISH positive); unresectable or recurrent; measurable lesion; no history of chemotherapy or radiotherapy; age≤75; ECOG PS of 0-1; and adequate organ function. Pts received S-1 at 40–60 mg depending on body surface area, po bid, day 1-14, and cisplatin 60 mg/m2, iv, day 1, plus T-mab 8 mg/ kg, iv, day 1 (6 mg/ kg, iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate assessed by the RECIST (ver 1.1). The planned sample size was 50 based on the threshold response rate of 35%, the expected rate of 50%, power of 80%, and 1-sided α of 0.1. Results: A total of 56 pts were enrolled from July 2011 to May 2012. Two pts were ineligible with inadequate renal function and no measurable lesion. Characteristics of 54 eligible pts were as follows: median age of 66 (range 34-75), M/F: 42/12, PS0/1: 42/12, unresectable/recuurent: 51/3, and IHC 2+/3+: 9/45. As one patient did not receive the protocol treatment due to the rapid progression of tumor, the efficacy and the safety analyses were conducted in the full analysis set of 53 pts. The confirmed response rate assessed by the independent review committee was 68%, and the disease control rate was 94%. The response rate without interval confirmation was 75%. The grade 3/4 adverse events (>5% of pts) were as follows: neutropenia 30%, leucopenia 8%, anorexia 21%, diarrhea 8%, hypoalbuminemia 8%, vomiting 6%, and increased creatinine 6%. Conclusions: T-mab in combination with triweekly SP regimen showed promising antitumor activity and manageable toxicities in pts with HER2-positiveAGC. Clinical trial information: UMIN000005739.
Induction of pathologic complete response by long-term neoadjuvant chemotherapy for gastric cancer: Early results of a randomized phase II study—A COMPASS trial.
Authors: Tanabe Kazuaki , Yoshikawa Takaki , Tsuburaya Akira , Nishikawa Kazuhiro , Ito Seiji , Matsui Takanori , Cho Haruhiko , Ito Yuichi , Suzuki Takahisa , Morita Satoshi , Miyashita Yumi , Sakamoto Junichi
Published: February 2017

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Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy followed by S-1 adjuvant chemotherapy. Neoadjuvant chemotherapy will be another promising approach to improve the survival as demonstrated in some European trials, however, optimal duration and regimen have not been clarified yet. Methods: This trial compared efficacy of neoadjuvant chemotherapy using two and four courses of SC regimen; S-1 (80 mg/m2 for 21 days with 1 week rest) / cisplatin (60 mg/m2 at day 8), or PC regimen; paclitaxel / cisplatin (80 mg/m2 and 30 mg/m2, respectively at days 1, 8, and 15 with 1 week rest), by a two by two factorial design for stage II schirrhous / junctional tumors, stage III, or resectable stage IV. The primary endpoint was 3-year OS. Key secondary endpoints included pathological / clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n=21), arm B (4 courses of SC, n=20), arm C (2 courses of PC, n=21), and arm D (4 courses of PC, n=21). Clinical response (arm A/B/C/D) was 29%/40%/33%/24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/0%/5%). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: This randomized phase II study suggested that pathological complete response could be induced by long-term neoadjuvant chemotherapy without increase of toxicities regardless of SC or PC regimen. Clinical trial information: UMIN000002595.
Impact of pretreatment systemic inflammatory response on survival in AGC patients receiving first-line chemotherapy.
Authors: Fujitani Kazumasa , Takiuchi Hiroya , Sugimoto Naotoshi , Imamura Hiroshi , Iijima Shohei , Imano Motohiro , Kimura Yutaka , Kurokawa Yukinori , Shimokawa Toshio , Tsujinaka Toshimasa , Furukawa Hiroshi
Published: February 2017

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Background: Systemic inflammatory response plays an important role in cancer progression. However, little is known about how it affects the advanced gastric cancer (AGC) patients receiving first-line chemotherapy. We assessed the impact of pre-treatment systemic inflammatory response on survival in AGC patients receiving S-1 based first-line chemotherapy. Methods: OGSG 0402 multi-institutional phase II trial randomly assigned 102 patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma to receive S-1 plus irinotecan (SI arm) (n=51) or S1 plus paclitaxel (SP arm) (n=51) to evaluate these two S-1 based regimens as first-line treatment for AGC [ASCO-GI 2009: abstract 9.]. Among these patients, 99 patients were identified in this study excluding 2 patients who had died before receiving the allocated treatment and one patient who was lost to follow-up. All patients had performance status (PS) of 0-1 except for one with PS of 2. Pre-treatment clinical findings, such as gender, age, body mass index (BMI), tumor status (unresectable vs. recurrent, intestinal vs. diffuse), number of metastatic sites, serum levels of albumin (Alb) and C-reactive protein (CRP), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR), were assessed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in univariate and multivariate analyses. Results: Median OS and PFS were 390 days and 175 days for SI arm, and 363 days and 140 days for SP arm, respectively. Multivariate analysis identified the CRP level of 0.5 mg/dl or above (hazard ratio 1.96, 95% confidence interval 1.08 to 3.55, P=0.026) as a significant prognosticator for poor OS, and age of 60 years or greater (hazard ratio 1.92, 95% confidence interval 1.06–3.47, P=0.032) for shorter PFS. Conclusions: Pre-treatment CRP level was a most potent prognosticator for OS, reflecting the impact of systemic inflammatory response on survival, in AGC patients receiving first-line chemotherapy.
Phase II study of preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in patients with locally advanced gastric and GEJ adenocarcinoma.
Authors: Won Elizabeth , Ilson David , Kelsen David Paul , Strong Vivian E. , Schöder Heiko , Janjigian Yelena Yuriy , Shah Manish A. , Coit Daniel G. , Brennan Murray F. , Capanu Marinela
Published: February 2017

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Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. PET non-responders do poorly whether they continue the same chemotherapy or proceed directly to surgery [JCO 24: 4692; 2006, Lancet Onc 8:797;2007) Early identification of treatment failure using PET scan may spare patients (pts) from inactive therapy and allow for cross-over to alternative therapies. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2 year disease free survival (DFS) in the PET non-responding group. Methods: Pts with PET avid, EUS and laparoscopically staged T3 or Node positive resectable gastric or GEJ adenocarcinoma received induction with epirubicin 50mg/m2, cisplatin 60mg/m2, capecitabine 625mg/m2 bid days 2-21(ECX) and bevacizumab 15mg/kg day 1. PET scan was repeated at week 3. PET responders (≥35% decline in SUV) continued ECX for 2 more cycles. PET non-responders switched to 2 cycles of salvage therapy: docetaxel 30mg/m2 d1, d8 q21 days, irinotecan 50mg/m2 d1, d8 q21 days and bevacizumab 15mg/kg day 1. Pts had surgery 4 weeks after cycle 3. Results: 20 of planned 60 pts were enrolled before the study closed for poor accrual. 14 male (64%), 8 female (39%), median age 62, median KPS 90. 11(55%) had a PET response after the first cycle. 10/11 (91%) underwent R0 resection: 1/10 pathologic CR, 3/10 pathologic PR. 9/20 PET non-responders switched to the salvage regimen. 7/9 Non-responders had R0 resection, none achieved a pathological response. The DFS for PET responders was 27.8mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p= 0.4). Follow up for overall survival is ongoing. Biologic correlative studies are pending. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Supported by a grant from Genentech. Clinical trial information: NCT00737438.
Gastrectomy after intravenous and intraperitoneal paclitaxel combined with oral S-1 for gastric cancer with peritoneal metastasis.
Authors: Kitayama Joji , Ishigami Hironori , Yamaguchi Hironori , Emoto Shigenobu , Watanabe Toshiaki
Published: February 2017

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Background: A new regimen of intravenous (IV) and intraperitoneal (IP) Paclitaxel (PTX) combined with oral S-1 is effective as the first line chemotherapy for gastric cancer with peritoneal metastasis. However, no information is available for the benefit of gastrectomy at salvage setting for the patients with clinical downstage. Methods: A total of 100 patients with peritoneal metastasis of gastric cancer received combination chemotherapy of PTX from both IV (50 mg/m2) and IP (20 mg/m2) routes using subcutaneous implanted peritoneal access ports at on days 1 and 8. S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Gastrectomy was performed in 60 patients who showed apparent shrinkage of peritoneal nodules as well as negative peritoneal cytology at 2nd look laparoscopy. In 30 of the 60 patients with gastrectomy, mRNA of carcinoembryonic antigen (CEA) in peritoneal lavages obtained from the port were quantitatively evaluated by CEA-mRNA Index (CmRI: CEA mRNA/ PBGD mRNA×104) at each chemotherapeutic cycle. Results: MST of the 100 patients was 23.5 months. MST and 1y-OS of the 60 patients with gastrectomy were 34.5 months and 83%, while those of the other 40 patients were 13.0 months and 39%, respectively. In all of the 30 gastrectomized patients, CmRI at the initial laparoscopy was considerably high (median=15368, 145-398179), which was fairly reduced after 3 courses of the combination chemotherapy before surgery (median=25, 0-10286, p=<0.001). Among them, 2y-OS of 22 patients whose CmRI was reduced to the value <200 after 3 course of chemotherapy was significantly better than that of the other 8 patients with CmRI >200 (76% vs 25% p=0.02), suggesting the volume of tumor cells in peritoneal cavity may be a critical determinant for postoperative outcome. Conclusions: Combination chemotherapy of S-1 plus IV and IP PTX followed by gastrectomy is a promising strategy for peritoneal metastasis of gastric cancer. Periodical measurement of CEA-mRNA levels in peritoneal cavity can be a useful biomarker to predict the clinical efficacy of conversion gastrectomy.