bluuebunny/crossref_metadata_2025 huggingface dataset:
Early and long-term outcome data on 2,298 patients with pseudomyxoma peritonei of appendiceal origin treated by a strategy of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Authors: Chua Terence C. , Moran Brendan J. , Sugarbaker Paul H. , Levine Edward Allen , Glehen Olivier , Gilly Francois N. , Elias Dominique , Baratti Dario , Deraco Marcello , Sardi Armando , Morris David L. ,   Peritoneal Surface Oncology Group International
Published: February 2017

532

Background: Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of this study was to evaluate the outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an International Registry study.

Methods: A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International (PSOGI).

Results: 2298 patients from 16 specialized units underwent CRS for PMP. Treatment related mortality was 2% and major operative complication was 24%. The median survival was 196 months (16.3 years) and the median progression-free survival was 98 months (8.2 years) with a 10- and 15-year survival rate of 63% and 59% respectively. Multivariate analysis identified prior chemotherapy treatment (P<0.001), PMCA histopathological subtype (P<0.001), major postoperative complication (P=0.008), high PCI (P=0.013), debulking surgery (CCR2/3) (P<0.001), not using HIPEC (P=0.030) as independent predictors for a poorer progression-free survival. Older age (P=0.006), major postoperative complication (P<0.001), debulking surgery (CCR2/3) (P<0.001), prior chemotherapy treatment (P=0.001) and PMCA histopathological subtype (P<0.001) were independent predictors of a poorer overall survival.

Conclusions: The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10-years. Minimizing non-definitive operative and systemic chemotherapy treatments prior to definitive cytoreduction may facilitate the feasibility and outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.
Predictive value of the antiangiogenic VEGF splice variant expression for bevacizumab efficacy in the phase III trial of bevacizumab and FOLFOX4 versus FOLFOX4 in previously treated patients with advanced colorectal cancer (ECOG E3200T2).
Authors: Bates David O. , Catalano Paul J. , Symonds Kirsty E. , Varey Alexander H. R. , Ramani Pramila , O'Dwyer Peter James , Giantonio Bruce J. , Meropol Neal J. , Benson Al Bowen , Harper Steven J.
Published: February 2017

545

Background: Treatment of metastatic colorectal cancer (CRC) with bevacizumab (anti-VEGF) in combination with chemotherapy increases survival in a proportion of patients, but it is not possible a priori to predict which patients will receive benefit. The VEGF-A gene is alternatively spliced into two families by alternative splice site usage in exon 8. The pro-angiogenic (e.g. VEGF165) isoforms are generated by proximal splice site selection, and the anti-angiogenic (e.g. VEGF165b) by distal splice site selection. The relative levels of the isoforms vary in CRC. VEGF165b over-expression in mice inhibits bevacizumab treatment.We tested the hypothesis that survival would be better in patients with low VEGF165b levels on bevacizumab than placebo.

Methods: To determine whether survival was better in patietns with low VEGF165b when treated with FOLFOX4+bevacizumab (Arm A) than FOLFOX4 + placebo (Arm B), 108 coded patient samples from the E3200 trial of FOLFOX4±bevacizumab (NCT NCT00897754 ) were successfully stained for VEGF-A165b and scored in well differentiated tissue relative to normal tissue blind to outcome. The VEGF165b expression relative to normal tissue was calculated. 108 cases were analysed for VEGF165b/Normal, 48 in arm A, 60 in Arm B.

Results: Adjusted Cox Binary analysis of VEGF165b/Normal comparing staining ratio in bevacizumab versus placebo treated patients demonstrated significantly better survival for the less than median ratios (HR=0.28, p=0.0031, median progression free survival, 8.4 versus 5.1 months in placebo), whereas in the higher than median VEGF165b/Normal group there was no effect of bevacizumab (HR=0.96, median PFS, 11.9 compared with 11.0months). Results held after adjustment for other clinical and demographic features in proportional hazards regression modelling.

Conclusions: In conclusion, these results indicate that low VEGF165b levels in well-differentiated tumours may predict response to bevacizumab.
Influence of age on chemoradiotherapy outcome in patients with rectal cancer: Exploratory analysis from the phase III study ACCORD 12/0405 PRODIGE 2.
Authors: Francois Eric , Azria David , Gourgou-Bourgade Sophie , Martel-Lafay Isabelle , Hennequin Christophe , Etienne Pierre-Luc , Vendrely Veronique , Seitz Jean Francois , Conroy Thierry , Juzyna Beata , Gerard Jean-Pierce
Published: February 2017

550

Background: Preoperative radiochemotherapy (RCT) is the standard of care for patients (pts) with locally advanced rectal adenocarcinoma. However elderly pts may have an increased risk of adverse events after combined modality treatment. The randomized trial ACCORD 12/0405 PRODIGE 2 compared 5 weeks of treatment with radiotherapy 45 Gy/25 fractions (f) with concurrent capecitabine 800 mg/m² twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 f with capecitabine 800 mg/m2 twice daily, 5 days per week and oxaliplatin 50 mg/m2 once weekly (Capox 50), results of efficacy (complete pathologic response) were not different between the two arms. We analyzed the results of RCT according to pts age.

Methods: All eligible pts (n=584) were included in this exploratory analysis. Pts were divided in 2 groups: <70 y and ≥70 y. Toxicity and tumor regression scores were compared between the 2 groups.

Results: 442 pts were <70 y and 142 were ≥70 y. Pts characteristics were well balanced between groups (gender, ECOG performance status, primary tumor, histology). Tolerance was worse in pts ≥70 y as shown in the table. Surgical procedures were not different between the 2 groups. Results on histological response were similar between the 2 groups: complete pathologic response was 16.9% (95% CI 13.1 to 20.2%) for pts <70 y and 14.7% (95% CI 9.2 to 21.8%) for pts ≥70 y, (p=0.55) and rates of R0 surgery for pts < 70 y and pts ≥ 70 y were respectively: 90.6% and 88.2%, (p=0.54).

Conclusions: As tolerance of elderly pts treated with preoperative RTCT is worse than in younger pts, appropriate therapeutic schedule are warranted for these pts.

[Table: see text]
Ten-year results of the Lyon R96-2 randomized trial in distal rectal cancer: Radiation dose escalation to increase organ preservation.
Authors: Gérard Jean-Pierre , Ortholan Cecile , Chapet Olivier , Romestaing Pascale
Published: February 2017

556

Background: This trial was designed to test the role of a radiation dose escalation to increase conservative treatment in distal rectal cancer. The early results showed a significant increase of sphincter saving surgery (Gerard JP et al. J Clin Oncol. 2004;22:2404-2409). We present here clinical results with a 10 years follow up.

Methods: Between 199- and 2001, 88 patients were included. Inclusion criteria were: adenocarcinoma of the distal rectal, T2-3 N0 M0 less not exceeding half circumference. Treatment allocation was betweeen 1) external beam radiotherapy(EBRT) (39 Gy/13 fractions/17 days) followed 6 weeks later by surgery. 2) same EBRT with Contact X-Ray 50 Kv boost (CXRT) (90 Gy /3fr/4 weeks). A careful evaluation of the clinical response was performed with digital examination and rigid rectoscopy one week before surgery. Type of surgery was left to the surgeon decision.

Results: Median follow-up was 132 months. At 10 years there was no difference between both groups for overall survival and local recurrence but significantly less colostomy in the CXRT group (table). In patient with cCR the cumulated rate of colostomy was 17 % vs 42 % with cPR and 77 % with no response (p=0.014) out of 11 pts in cCR with EBRT + CXRT, 9 were treated with organ preservation (RT alone : 6, transanal local excision 3). Anorectal function was good or excellent in all these 9 patients.

Conclusions: After 10 years follow up increased preservation of the anal sphincter due to CXRT has no detrimental effect on local control and survival. These results stress the importance to achieve a clinical complete response (cCR) in order to modify the surgeon decision and to increase the chance of organ preservation with a well preserved function.

[Table: see text]
Macroscopic tumor size as an independent prognostic factor for patients with stage II/III gastric cancer who underwent D2 gastrectomy followed by adjuvant chemotherapy with S-1.
Authors: Aoyama Toru , Yoshikawa Takaki , Hayashi Tsutomu , Kuwabara Hiroshi , Mikayama Yo , Ogata Takashi , Cho Haruhiko , Tsuburaya Akira
Published: February 2017

56

Background: In patients with stage II/III gastric cancer, tumors often recur even after curative D2 gastrectomy followed by adjuvant S-1 chemotherapy. The objective of this retrospective study was to clarify the prognostic factors in these patients that might be useful for future patients.

Methods: Overall survival was examined in 82 gastric cancer patients who underwent curative D2 surgery, were diagnosed with stage IIA, II B, IIIA, IIIB, or IIIC pathologically, and received adjuvant S-1 after surgery between June of 2002 and March of 2010.

Results: When overall survival was compared by the log-rank test, a significant difference was observed with regard to macroscopic tumor diameter and the depth of tumor invasion. A macroscopic tumor diameter greater than 70mm was regarded as a critical point of classification considering the survival. Uni- and muliti-variate Cox’s proportional hazard analyses demonstrated that macroscopic tumor diameter was the only significant independent prognosticator. The five-year survival was 64.9% in patients with a macroscopic tumor diameter <70mm, and 33.1% in patients with a macroscopic tumor diameter ≥70mm (P=0.022).

Conclusions: The macroscopic tumor diameter was the most important prognostic factor for survival in patients with stage II/III gastric cancer who underwent D2 gastrectomy followed by adjuvant S-1 chemotherapy. Prognostic factors can be affected by adjuvant chemotherapy.
Systemic therapy for advanced appendiceal adenocarcinoma: An analysis from the National Comprehensive Cancer Network (NCCN) database.
Authors: Tejani Mohamedtaki Abdulaziz , ter Veer Anna , Milne Dana , Ottsesen Rebecca , Bekaii-Saab Tanios S. , Benson Al Bowen , Schrag Deborah , Shibata Stephen , Skibber John Michael , Weiser Martin R. , Wilkinson Neal W. , Cohen Steven J.
Published: February 2017

562

Background: Appendiceal neoplasms are rare and represent 1% of intestinal tumors in the United States. The role and efficacy of modern systemic therapy in advanced appendiceal adenocarcinoma has not been established.

Methods: Patients with recurrent or metastatic appendiceal adenocarcinoma in the NCCN Colorectal Database (2005-2010) were analyzed. Study objectives were to describe and evaluate the efficacy of systemic therapy and investigate relationships with clinicopathologic features. Cox regression analysis was performed to identify predictors of PFS and OS. The hazard ratio and 95% CI from Cox models and median PFS and OS from Kaplan-Meier curves were reported.

Results: Of 177 patients with advanced appendiceal carcinoma, 81 (46%) received systemic therapy for measurable disease and are the focus of this report (patients undergoing IP chemotherapy excluded). Patient/tumor characteristics: median age 50 (range 20-82), ECOG PS 0/1 (67%/22%), mucinous/non-mucinous (44 %/ 51%), 91% peritoneal and 15% liver metastases. 70% of patients had primary surgical debulking. Common chemotherapy regimens included FOLFOX with or without bevacizumab (n=30 and n=28), FOLFIRI (n=11), and single-agent fluoropyrimidine (n=7). Among 70 patients with a recorded best response, the response rate (RR) was 46% with 31% stable disease. Median PFS was 1.0 year (95% CI: 0.7-1.9) and OS was 2.1 years (95% CI: 1.7-2.6). Patients with non-mucinous histology, high grade tumors and non-debulking surgery had worse PFS and OS (Table).

Conclusions: Treatment of advanced appendiceal adenocarcinoma at NCCN centers commonly incorporates agents utilized for colorectal cancer. RR, PFS and OS are comparable to those achieved in the treatment of metastatic CRC and support routine use of these regimens in clinical practice. Poor prognostic factors include non-mucinous histology, high grade and not undergoing debulking surgery.

[Table: see text]
Use of bevacizumab to reduce the rate of oxaliplatin-induced thrombocytopenia and splenomegaly.
Authors: Overman Michael J. , George Binsah , Kalil Karime , Ferrarotto Renata , Eng Cathy , Garrett Chris R. , Loyer Evelyn , Hoff Paulo Marcelo , Charnsangavej Chusilp , Kopetz Scott
Published: February 2017

564

Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. In the NSABP C-08 study a reduced rate of thrombocytopenia (1.4% vs 3.4%, P <0.01) was seen in the bevacizumab arm. Evidence suggests that bevacizumab may protect against HSI, though the clinical impact of this has not been well examined.

Methods: A retrospective review of metastatic colorectal cancer patients treated at MD Anderson Cancer Center from 1/2003 to 1/2010 with ≥3 months of frontline fluoropyrimidine and oxaliplatin (FOLFOX) with or without bevacizumab was conducted. Presence of known liver disease, prior liver surgery, absence of spleen, or adjuvant oxaliplatin were exclusion criteria. Splenic volumes pre, during, and post FOLFOX treatment were determined from CT scans and correlated with platelet counts and treatment.

Results: 184 pts (138 FOLFOX/Bev; 46 FOLFOX) were identified. The median number of cycles (9 for each cohort) and the total oxaliplatin dose (P = 0.78) did not differ between the two cohorts. The development of splenomegaly (spleen volume increase of ≥30%) was more common in the non-Bev cohort, 48% vs 32%, P=0.013. The median time to splenomegaly was longer in the Bev cohort, 7.6 vs 5.5 months, P=0.023. When comparing patients with and without splenomegaly, the presence of splenomegaly correlated with thrombocytopenia (<150 platelet count) at 3 months (40% vs. 16%, P=0.0005) and beyond (lower mean platelet counts during 3 to 6 months of treatment, P <0.0001 by Two-way ANOVA). A correlation with thrombocytopenia was also seen in the non-Bev vs. Bev cohort at both 3 months (43% vs 24%, P = 0.006) and beyond (P = 0.003).

Conclusions: The addition of bevacizumab to oxaliplatin chemotherapy reduces the frequency of splenic enlargement, which directly correlates with a reduced rate of thrombocytopenia. Further study to understand the hepato-protective mechanism of anti-VEGF therapy is needed.
Dose-painted intensity-modulated radiation therapy (DP-IMRT) for anal cancer: No differences in treatment toxicity and early outcomes between human immunodeficiency virus (HIV) positive and negative patients.
Authors: Romesser Paul B. , Mancias Joseph D. , Qureshi Muhammad M. , Hartshorn Kevan L. , Willins John D. , Hong Theodore S. , Kachnic Lisa A.
Published: February 2017

565

Background: HIV-infected patients are reported to experience increased treatment toxicity with standard concurrent chemoradiation (CRT) protocols for anal cancer. IMRT is a novel radiation (RT) delivery technique that allows the oncologist to conform or “dose paint (DP)” the RT dose to the tumor while sparing surrounding normal organs. We report our multi-institutional experience with DP-IMRT in regards to acute toxicities and treatment outcomes in HIV positive (HIV+) patients on highly active antiretroviral therapy (HAART).

Methods: From August 2005 to December 2010, 63 patients, (10 HIV+), were treated with CRT for biopsy-proven, squamous cell carcinoma of the anal canal at two academic medical centers. HIV+ and HIV- patients received a median DP-IMRT dose of 50.4 Gy over 43.5 and 42.0 days, respectively. Acute toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events, version 3.0. Two year actuarial control and survival rates were calculated using the Kaplan-Meier method.

Results: The median follow-up was 29.3 and 24.3 months for HIV+ and HIV- patients, respectively. No significant differences were noted in acute grade 3+ toxicity in HIV+ versus HIV- patients: dermatologic 10.0% vs. 13.21%, p=1.0; genitourinary 10.0% vs. 3.77%, p=0.410; gastrointestinal 20.0% vs. 15.09%, p=0.653; and hematologic 80.0% vs. 64.15%, p=0.474. Multivariate analysis confirmed that HIV infection was not predictive of acute grade 3/4 toxicity. No significant differences were noted in 2-year local control (90.0% vs. 95.0%), distant control (90.0% vs. 89.7%), overall survival (90.0% vs. 89.2%), and colostomy-free survival (90.0% vs. 83.7%) rates among HIV+ vs. HIV- patients.

Conclusions: HIV+ patients on HAART receiving concurrent chemotherapy with DP-IMRT for anal canal cancer showed similar two-year outcomes and no significant differences in acute toxicity compared to HIV- patients. As such, HIV+ patients with anal cancer should be considered eligible for all national trials in which IMRT is employed.
Preplanned initial safety analysis of ACTS-CC 02 trial: A large randomized phase III trial of SOX versus UFT/LV as adjuvant chemotherapy for high-risk stage III colon cancer.
Authors: Takiuchi Hiroya , Tomita Naohiro , Boku Narikazu , Watanabe Toshiaki , Kotake Kenjiro , Itabashi Michio , Takahashi Keiichi , Baba Hideo , Morita Satoshi , Sugihara Kenichi
Published: February 2017

572

Background: The ACTS-CC 02 trial is designed to verify the superiority of postoperative adjuvant chemotherapy of S-1/Oxaliplatin (SOX) for patients with anyT, N2 colon cancer compared with UFT/Leucovorin (UFT/LV), which is one of standard adjuvant chemotherapies in Japan. To date, there have been no reported phase III trials evaluating SOX as postoperative adjuvant chemotherapy. This report presents initial safety data obtained from 50 patients who received SOX in the trial.

Methods: Patients who underwent curative resection for anyT, N2 colon cancer were randomly assigned to receive either SOX (100 mg/m2 of oxaliplatin on day1, and 80 to 120 mg/day according to body surface area (BSA) of S-1 on days 1-14, every 21 days, 8 courses) or UFT/LV (300 to 600 mg/day according to BSA of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 courses). Data were collected from initial consecutive 50 patients assigned to the SOX group and analyzed when they were considered evaluable for safety as planned in the protocol. This ongoing trial is designed to accrue 1200 patients. As of September 15, 2011, 319 patients have been accrued.

Results: Of 50 patients assigned to receive SOX, 48 were evaluable for safety. The median number of treatment courses was 5 (range: 1-8). The relative dose intensity of S-1 was 83.8% and that of oxaliplatin was 86.6%. Grade 3 adverse events were neutropenia (14.6%), thrombocytopenia (2.1%), ALT elevation (2.1%), diarrhea (8.3%), fatigue (2.1%), and peripheral sensory neuropathy (2.1%). Grade 4 adverse effects were not observed.

Conclusions: In this initial safety analysis, the incidence and severity of adverse events with SOX were acceptable in patients with high risk stage III colon cancer after curative resection. Enrollment of patients is ongoing.
Validating the prognostic relevance of initial change in tumor size using a series of therapeutic regimens for patients with metastatic colorectal cancer (mCRC).
Authors: Mansmann Ulrich Robert , Laubender Ruediger P. , Giessen Clemens Albrecht , Sartorius Ute , Heinemann Volker
Published: February 2017

580

Background: Piessevaux et al. (ESMO 2010, Abstr. #596P) proposed a decrease in tumor size of 20% at week 8 following 1st-line therapy for mCRC as a predictor of clinical outcome (PFS and OS). Based on the results of a single study Suzuki et al. (Ann. Oncol. 2011) also claimed that change in tumor size at the first follow-up CT scan was strongly prognostic for PFS and OS in mCRC. It is of interest to validate these findings in different treatment regimens.

Methods: Based on data from 4 randomized trials (FIRE-1, n = 479; CIOX, n = 185; OPUS, n = 337; CRYSTAL, n = 1198) a total of 6 treatment regimens were studied (mIROX/FUFIRI, CAPIRI/CAPOX + cetuximab, FOLFOX4 + cetuximab, FOLFOX4, FOLFIRI + cetuximab, FOLFIRI). A joint model was used to quantify the non-linear, J-shaped individual relationships between time and largest diameter (LD) and incorporate them into the formal risk calculation for PFS and OS. The first radiological tumor assessment was performed weeks 7-9 after the start of treatment and relative tumor shrinkage compared to baseline evaluated.

Results: All 6 groups showed a consistent pattern for PFS and OS. Distinctive shrinkage week 8 (weeks 7-9) was associated with an improved individual prognosis (p<0.0001 in each group). This was even more pronounced for larger sized tumors (LD >100 mm) at baseline (p<0.01 in each group). Distinctive individual shrinkage for a corresponding treatment was defined as shrinkage exceeding the 8 week shrinkage of its mean tumor kinetics. Distinctive shrinkage for the 3 combination chemotherapy regimens was observed with individual shrinkage above 16%, 23%, or 26%. For the 3 combination chemotherapy regimens + cetuximab distinctive shrinkage was reached if individual shrinkage was greater than 21%, 24%, and 29% respectively, independent of KRAS status. Predictivity has not yet been examined.

Conclusions: Our results validate the prognostic relevance of the 20% cut-off for shrinkage at week 8. Early tumor shrinkage is a promising surrogate for PFS and OS using a variety of therapeutic regimens for mCRC. These data may serve as a basis for modifying the widely adopted RECIST criteria in favor of modified response evaluation criteria.
Health care utilization and economic burden of dermatologic adverse drug reactions (ADRs) in patients with colorectal cancer treated with an epidermal growth factor receptor inhibitor (EGFRI).
Authors: Bonthapally Vijayveer , Guerin Annie , Wu Eric Q. , Gauthier Genevieve , Holen Kyle D. , Ray Saurabh
Published: February 2017

584

Background: Colorectal cancer patients with EGFRI therapies may develop dermatologic ADRs. ADRs negatively affect patients’ quality of life, require medical care, and may lead to a substantial economic burden. The objective of this study is to assess the economic burden of dermatologic ADRs in patients with colorectal cancer (CRC).

Methods: Continuously enrolled adult patients with ≥ 1 CRC diagnosis initiated on an FDA-approved EGFRI therapy (i.e., cetuximab, panitumumab) were selected from a large US claims dataset. Patients were classified into two mutually exclusive cohorts depending on whether or not they had dermatologic ADR during the period following EGFRI initiation. Dermatologic ADRs were identified using ICD-9-CM codes. Patients were observed from the index date up to the end of the health plan enrollment, or data availability, or 90 days after the EGFRI discontinuation, whichever occurred first. Incidence rate ratios (IRRs) for healthcare resource utilization were estimated using Poisson regression models. Incremental costs (2010 USD) were estimated on a monthly basis using generalized linear or two-part models. Multivariate regressions controlled for age, gender, comorbidities, and baseline healthcare utilization and costs.

Results: A total of 746 and 1,720 patients were included in the dermatologic ADR and ADR-free cohorts, respectively. After adjusting for confounding factors, compared to patients in the ADR-free cohort, patients in the ADR cohort had higher incidence of emergency room visits (IRR=1.2; p=.009) and higher incidence of outpatient visits (IRR=1.13; p<.001). Moreover, patients in the ADR cohort incurred higher total healthcare costs by $2,532 (p=.009) per patient per month mainly due to higher emergency care costs by $566 (p<.001).

Conclusions: Compared to ADR-free patients, dermatologic ADR patients with colorectal cancer incurred a substantial economic burden related to higher healthcare resource utilization and costs. Efforts to improve the dermatologic side effect profile of EGFRI are needed to control this burden.
Updated survival results of the randomized phase II study of S-1, oral leucovorin, and oxaliplatin combination therapy (SOL) versus mFOLFOX6 in patients with untreated metastatic colorectal cancer (mCRC).
Authors: Otsuji Toshio , Yamazaki Kentaro , Ojima Hitoshi , Kuwano Hiroyuki , Kato Takeshi , Shimada Ken , Denda Tadamichi , Esaki Taito , Hyodo Ichinosuke , Boku Narikazu
Published: February 2017

586

Background: We previously reported short term results of a randomized phase II study comparing SOL with mFOLFOX6 in terms of progression-free survival (PFS) by central review. The median PFS for SOL and mFOLFOX6 was 9.6 and 6.9 months (HR= 0.83; 95%CI, 0.49-1.40) with median follow-up time 14 months (Ojima et al, ESMO 2011). Here, we report updated overall survival (OS) results with 29 months follow-up.

Methods: The inclusion criteria were; 1) histologically proved adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (Pts) were randomized to receive either S-1 (40-60 mg bid) and oral LV (25 mg bid) for one week and L-OHP (85 mg/m2) on day 1, repeated every 2 weeks (SOL; Group A) or L-OHP (85 mg/m2), l-LV (200 mg/m2), and 5-FU (400 mg/m2, bolus) on day 1, followed by 5-FU (2400 mg/m2, ci, 46 hours), repeated every 2 weeks (mFOLFOX6; Group B). This trial was supported by Taiho Pharmaceutical CO., LTD and Yakult Honsha CO., LTD. ClinicalTrials.gov Identifier: NCT00721916

Results: From July 2008 to July 2009, 107 pts were randomized, and 105 were eligible (56 to Group A and 49 to Group B). When survival data were updated 2 years after the last patient’s enrollment, with no lost cases, median OS for Group A and Group B was 28.5 and 25.9 months (HR= 0.76; 95%CI, 0.45-1.31), 2-year survival rate was 71.4% and 59.2%, respectively. The incidences of grade 3/4 adverse drug reactions were; neutropenia (19.6% Group A, 41.2% Group B), lymphopenia (14.3% and 5.9%), sensory neuropathy (19.6% and 2.0%), anorexia (12.5% and 7.8%), fatigue (10.7% and 5.9%) and diarrhea (10.7% and 3.9%). Post treatments with or without molecular target agents were performed for 80.4 % of Group A, and 75.5 % of Group B.

Conclusions: The results of the present analysis show that SOL might be more effective than mFOLFOX6 in terms of both PFS and OS as the first line chemotherapy for mCRC. Further investigation of the SOL regimen, a phase III trial of its combination with molecular target agents should be considered.
Randomized phase II study of oxaliplatin and S-1 (OS) versus oxaliplatin and capecitabine (XELOX) in patients with advanced or recurrent colorectal cancer.
Authors: Zang Dae Young , Chung Ik-Joo , OH HO-Suk , Park Keon Uk , Lee Kyung Hee , Han Boram
Published: February 2017

595

Background: Combination oxaliplatin and S-1 or oxaliplatin and capecitabine chemotherapy have shown significant efficacy in advanced colorectal cancer. To evaluate those efficacy and safety, we performed a randomized phase II study in patients with metastatic or recurrent colorectal cancer.

Methods: Eligible patients were those who had measurable lesions and had no previous history of chemotherapy except adjuvant chemotherapy. The patients of age greater than 18 were enrolled to this study. Oxaliplatin 130 mg/m2 was administered intravenously on day 1 and S-1 80 mg/m2 (OS, Arm A) or capecitabine 2,000 mg/m2 (XELOX, Arm B) was administered orally on days 1-14. Cycles were repeated every 21 days. Patients were treated until proved to have disease progression or unacceptable toxicity. The primary endpoint of the study was to assess the overall response rate (ORR).

Results: Eight-two patients (male/ female 57/ 31; median age 67, range 29-83; median ECOG PS 1; Arm A/ B 43/45) were enrolled to this study. Twenty-five patients had recurred cancer after surgery and 63 patients were diagnosed as metastatic diseases. A total of 268 cycles (median 5, range 1-34) in Arm A; 278 cycles (median 5, range 1-18) in Arm B were administered. Eighty-two (41 for each arm) patients were evaluated for toxicity and response. The main toxicities were thrombocytopenia [grade 1/ 2/ 3/ 4 = 11/ 7/ 6/ 1 patients (A); 9/ 10/ 7/ 5 (B)], neutropenia [grade 1/ 2/ 3/ 4 = 8/ 6/ 1/ 0 (A); 9/ 9/ 5/ 2 (B)], anemia [grade 1/ 2/ 3/ 4 = 21/ 13/ 3/ 1 (A); 20/ 10/ 3/ 0 (B)], peripheral neuropathy [grade 1/ 2/ 3 = 11/ 8/ 0 (A); 10/ 8/ 2 (B)], and hand-foot syndrome [grade 1/ 2/ /3 = 2/ 0/ 0 (A); 7/ 1/ 2 (B)]. There were 3 CR, 10 PR, 27 SD and 1 PD (A); 3 CR, 15 PR, 17 SD and 6 PD (B). The confirmed ORR in the intention-to-treat population was 30.2 (95% CI: 16.5-43.9) % (A); 40.0 (95% CI, 25.7-54.3) % (B). The median time to progression was 6.6 (95% CI, 4.4-8.8) months (A); 8.1 (95% CI, 6.3-10.0) months (B). The median survival time was 19.0 (95% CI, 7.3-30.8) months (A); 22.0 (95% CI, 12.1-32.0) months in (B).

Conclusions: These data suggest that both OS and XELOX regimen are active and are well tolerated regimens in patients with advanced colorectal cancer.
Induction chemotherapy followed by chemoradiotherapy and TME for high-risk locally advanced rectal cancer with and without synchronous resectable metastases.
Authors: Hajj Carla , Weiser Martin R. , McErlean Aoife , Gollub Marc , Cercek Andrea , Ding Pei-Rong , Saltz Leonard , Goodman Karyn A.
Published: February 2017

599

Background: Induction chemotherapy (ICT) followed by chemoradiation (CRT) may improve tumor downsizing and disease control among patients (pts) with locally advanced rectal cancer (LARC). We retrospectively assessed the safety and short-term efficacy of ICT followed by CRT and total mesorectal excision (TME) in pts with high-risk LARC with or without synchronous resectable metastases.

Methods: We reviewed records of 44 consecutive stage III (n=23) or stage IV synchronous (n=27) pts with LARC treated with ICT followed by CRT between 12/06 – 12/10. Pts had high-risk primary tumors based on advanced T and/or N stage by endorectal ultrasound and/or MRI: T3 (n= 35), T4 (n=7) and N1 (N=18), N2 (n=19). Recurrence-free (RFS) and overall survival (OS) were estimated by Kaplan-Meier methods.

Results: Median age was 52 yrs, 66% were female. Pts received a median of 6 cycles of 5-FU based ICT combined with oxaliplatin (n=44). CRT (median dose 50.4 Gy) was delivered with continuous infusion 5-FU; two pts did not complete the prescribed CRT. During induction CT, 10 (22.7%) pts experienced grade 3+ neutropenia. Grade 3+ neutropenia or GI toxicity occurred in 3 (6.8%) and 3 (6.8%) pts, respectively during CRT. Imaging or endoscopic assessment showed that 35 pts had disease regression after ICT, whereas 1 pt progressed and 2 had stable disease. Response to ICT was not assessed in 6 pts. 7 pts did not undergo surgery due to: progression of disease (n=2); comorbid disease (n=2); or pt refusal (n=3). 37 pts proceeded to TME including 17 with known distant metastasis, 16 of whom underwent metastasectomy. 17 pts had tumor response > 90% including 8 with pathologic CR. With a median follow-up of 29.4 mos, 1 pt who underwent TME developed local recurrence. Amongst the 9 pts who had distant recurrences, 7 had initial stage IV disease. The 3-yr RFS among the resected stage III pts was 95%; the 3-yr OS for stage III pts and stage IV pts were 100% and 80% respectively.

Conclusions: In this retrospective series, ICT prior to CRT was associated with acceptable toxicity and a substantial incidence of tumor regression. OS and RFS appear promising in this high-risk group of patients.
HER2 evaluation in a specific gastric cancer population with the highest rate of mortality in Spain.
Authors: Una Cidon Esther
Published: February 2017

60

Background: Gastric Cancer (GC) still represents the second cause of cancer-related death worldwide. Radical resection is the mainstay of early stages treatment with few impact in overall survival (OS) in the advanced ones. HER-2 is the most relevant biological factor involved. Purpose: This study aims to show the relationship between HER-2 positivity and survival in patients with completely resected GC.

Methods: Retrospective study of GC patients diagnosed in 2003-2005 at our institution. Surgical specimens underwent immunohistochemistry (IHC) and in cases +/++/+++ samples underwent also fluorescence in situ hibridysation (FISH) analyses of HER-2 and graduated according experts consensus.

Results: 120 cases included. Overall expression detected in 7.5%. Correlation between HER-2 positive and female sex, advanced stages or histological grades or intestinal type was detected. Early recurrences higher in HER-2 positive (66.6% vs 35.4%, p 0.048). The median DFS for c-erbB-2 positive was 15 months (range 2-67 months) and OS was 25 months (range 10-67 months). In the case of patients with c-erbB-2 negative median DFS was 27 months (range 5-67 months) and OS for this sample is 47 months (range 29-67 months).

Conclusions: These results emphasize the relevance of HER-2 positivity in GC as independent prognostic factor and supports its current analyses in daily practice.
Phase I study of mFOLFOX-6, bevacizumab, and mTOR inhibitor RAD001 as first-line treatment of metastatic colorectal cancer.
Authors: Gilcrease Glynn Weldon , Weis John R. , Jones Kimberly , Davis Thaylon , Mitchell Marlene , Davidson Cynthia , Sharma Sunil
Published: February 2017

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Background: This study was designed to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and efficacy of the mTOR inhibitor RAD001 in combination with mFOLFOX-6 and bevacizumab in metastatic colorectal cancer.

Methods: Twenty patients with previously untreated metastatic colorectal cancer received mFOLFOX-6, bevacizumab and RAD001 using a standard three patient cohort dose escalation schema. Seventeen of the twenty patients were evaluable with a median age of 52 (ten females and seven males). RAD001 was administered orally at escalating doses of 2.5 mg, 5 mg and 10 mg daily. mFOLFOX-6 and bevacizumab were administered in standard fashion.

Results: The most common grade 3/4 hematological adverse events (AEs) were neutropenia (59%), leucopenia (29%) and thrombocytopenia (12%). The most common grade 3 non-hematological AEs were diarrhea (24%) and hypokalemia (18%). One dose-limiting toxicity was noted at 10 mg/day due to grade 3 anorexia, grade 3 diarrhea, and grade 3 hypokalemia. Grade 1 mucositis was noted in 12% of patients and grade 2 mucositis was noted in 47% of patients. There was no grade 3/4 mucositis. Fourteen patients are evaluable for efficacy. The RR is 86% including 2 CRs, 7 PRs, and 3 SDs.

Conclusions: RAD001 in combination with mFOLFOX6 and bevacizumab is well-tolerated at a dose of 10 mg/day. The regimen appears to be effective. Evidence of anti-tumor activity correlated with mutation status (k-ras, BRAF, PIK3CA) and PTEN deletion status will be presented.
Efficacity and safety of panitumumab in mCRC patients: A post-AMM OMIT study.
Authors: Grude Francoise , Ramée Jean François , Guivarch Laurent , Douillard Jean-Yves , Rochard Sophie , Dupuis Olivier , Grollier Chrystelle , Guerin-Meyer Veronique , Leynia Pierre , Porneuf Marc , Peguet Elodie , Raoul Jean Luc , Bertrand Claude , Deguiral Philippe , Derenne Laurent , Achour Nacredine , Person Bernadette , Metges Jean-Philippe , Lebot Marie-Annick , Riche Christian
Published: February 2017

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Background: Metastatic colorectal cancer (mCRC) management has been improved by targeted therapies. The evaluation of the use of panitumumab (PANI), after approval, in the real life is strategic to assess health politics. OMIT Bretagne - Pays de Loire is a network of private and public cancer centers.

Methods: Data from patients treated with PANI in mCRC were collected. Previously published data are recited. Sex, age, primary tumor, Kras status, line of treatment, toxicity, reason of discontinuation, response, progression free survival (PFS) and overall survival (OS) have been studied.

Results: Data of 322 patients treated between second half of 2008 and end of 2010 have been collected. PANI was used alone (85.5%) or with chemotherapy (14.5%) : mainly FOLFIRI, IRINOTECAN or FOLFOX). KRAS status was wild-type (WT 96.5%), mutated (0.5%), undetermined (2.5%) or not searched (0.5%). Only KRAS WT patients treated with monotherapy of PANI at 6 mg/kg every 2 weeks were analysed (n=263). Sexe : 177 men and 86 women. Median age : 67 years [36-90] (Van Custem JCO 2007: 62 years [27-83]). Primary tumor of patients was : colon (75%), rectum (22%) and others (3%). They received PANI mostly at line 2 (25%), 3 (46%) or 4 (19%). Discontinuation of treatment was mostly due to disease progression : 64%, death: 15% and toxicities : 7% (skin toxicities 3.7%). Clinical response was evaluated for the first 84 patients: partial response (PR): 30%, stable disease (SD): 14% and progression (P): 56%. In KRAS WT patients treated by PANI, Amado described 17% of PR, 34% of SD and 49% of P (Amado JCO 2008). Median duration of treatment was 69 days [0;360] (n=249). Median duration between end of treatment and death when death is the cause of end of treatment was 13 days [0;54] (n=35). Median of OS was 137 days [0;816] (n=143) which is lower than previously described (Van Cutsem JCO 2007 : 192 days regardless of KRAS status ; Amado JCO 2008 : 243 days in KRAS WT).

Conclusions: The OMIT analysis of patients treated by PANI in Bretagne/Pays de Loire for a mCRC allows to assess the good use, according to its label, in the real life. Complete results about clinical response, PFS (cut-off 01/12/2011), OS and safety as well as previously published data will be shown at the meeting.
Phase II study of S-1, oral leucovorin, oxaliplatin, and bevacizumab combination therapy (SOL+BV; SOLA) in patients with unresectable metastatic colorectal cancer (mCRC).
Authors: Kato Takeshi , Nishina Tomohiro , Yamazaki Kentaro , Yoshino Takayuki , Miyata Yoshinori , Esaki Taito , Moriwaki Toshikazu , Hyodo Ichinosuke
Published: February 2017

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Background: The results from a randomized phase II trial in the first-line treatment of mCRC indicated that SOL regimen (S-1, Oral Leucovorin; LV, and Oxaliplatin) had promising activity with well-tolerated toxicities compared to mFOLFOX6 (Ojima et al, ESMO 2011). The median progression-free survival (PFS) for SOL and mFOLFOX6 was 9.6 and 6.9 months, respectively (HR=0.83). We evaluated the efficacy and safety of adding BV to SOL regimen in this study.

Methods: The inclusion criteria were; 1) histologically proven adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment for metastatic disease, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (pts) received S-1 (40-60 mg bid) and LV (25 mg bid) orally for one week and L-OHP (85 mg/m2), and BV (5 mg/kg) on day 1, every 2 weeks. The primary endpoint was the response rate (RR).

Results: From October 2009 to April 2010, 31 pts were enrolled, and 29 pts were regarded as the population of full analysis set. Present data included the results of efficacy and safety up to 24 cycles. RR assessed by the independent review committee was 86.2 % (CR: 0 pts, PR: 25 pts), and disease control rate (DCR) was 100%. The median PFS assessed by investigators was 12.5 months, while further follow up is ongoing. One year survival rate was 100%. The incidence of grade 3/4 adverse drug reactions were; neutropenia 16.7%, diarrhea 10.0%, hypertension 16.7%, and sensory neuropathy 53.3%. The median cumulative oxaliplatin dose was 915.0 mg/m2 (range 330-1735 mg/m2). The high prevalence of grade 3 neuropathy seemed due to the prolonged treatment duration. Reasons for discontinuation were progressive disease in 13 pts, and metastatectomy by tumor regression in 6 pts. The resection rate was 17.2 %.

Conclusions: SOL+BV showed promising activity with high RR, DCR, PFS and resection rate with well tolerated toxicities in pts with unresectable mCRC. This trial was supported by Taiho Pharmaceutical CO.,LTD. (JAPIC Clinical Trials information Identifier: JapicCTI-090881).
The role of palliative resection in metastatic colorectal cancer: 10 years of experiences from a single institute.
Authors: Park Jin Hyun , Lee Kyung-Hun , Han Sae-Won , Oh Do-Youn , Im Seock-Ah , Kang Gyeong Hoon , Chie Eui Kyu , Jeong Seung-Yong , Park Kyu Joo , Park Jae-Gahb , Kim Tae-You
Published: February 2017

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Background: Systemic chemotherapy is still mainstay of treatment of metastatic colorectal cancer (mCRC), while the role of palliative resection is not convincing. We intended to find out the role of palliative resection in mCRC.

Methods: A total of 1,015 patients were diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009. Except 169 patients who received curative metastectomy of liver and/or lung, 847 patients were retrospectively analyzed.

Results: Out of 847 patients, 556 (65.6%) had metastasis at the time of diagnosis and 291 (34.4%) had recurrence after surgery. The median age was 61 (range, 16-88) and 491 (58.0%) were male. The median number of metastatic site was 1 (range, 1-6) and 738 (87.1%) had limited metastasis (number of metastatic site ≤2). The liver was most frequently involved site (451, 53.2%). Surgery was done in 527 (62.2%). One hundred three patients received resection of both primary and metastatic sites (group 1), while 347 and 78 received resection of primary (group 2) and metastatic sties (group 3), respectively. R0 resection was done in 95 patients (G1: 53, G3: 42), while R1/2 was done 431 in patients (G1: 56, G2: 336, G3:39). Of 95 patients with R0 resection, 93 (97.8%) had limited metastasis (number of metastatic organ ≤2) in the peritoneum, lymph nodes, liver, or lung. The median overall survival (OS) was 19.0 months (95% CI, 17.8-20.1) and resected patients had prolonged median OS compared with patients never resected (21.3 vs 14.1 months, p < 0.001). In multivariate analysis, R0 resection was associated with superior OS compared to R2 resection (51.3 vs 18.7 months; HR, 3.0; 95% CI, 1.86 to 4.85, P<0.001), and no resection (51.3 vs 14.1 months; HR, 2.93; 95% CI, 1.73 to 4.96, P<0.001). Palliative chemotherapy was administered in 746 (88.1%), while chemotherapy was not performed in 101 (11.9%) due to patient’s refusal and poor performance status. In multivariate analysis, chemotherapy was also independent prognostic factor for OS (20.4 vs 5.4 months, HR, 3.47; 95% CI, 2.25 to 5.35, P<0.001).

Conclusions: Palliative resection with curative intent and chemotherapy confer long-term survival on subsets of mCRC with limited metastasis.
Role of biologic therapy in the treatment of unresectable appendiceal epithelial neoplasms (AEN).
Authors: Eng Cathy , Overman Michael J. , Fournier Keith F. , Royal Richard E. , Ohinata Aki , Rafeeq Safia , Phillips Jonathan , Wolff Robert A. , Mansfield Paul F.
Published: February 2017

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Background: AEN ranges from benign appearing cells to poorly differentiated signet cell adenocarcinoma. Currently, cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is believed to be optimal treatment. Systemic chemotherapy (SC) +/- biologic therapy (BT) is considered when CRS is not feasible. VEGF expression reportedly is a poor prognostic indicator in AEN pts. The purpose of this analysis is to determine the benefit of BT in chemotherapy naïve suboptimal candidates for CRS.

Methods: A retrospective chart review of AEN pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, stage, SC + BT, CEA, CA-125, and/or CA 19-9, response (R), and progression-free survival (PFS). All patients were required to be radiographically restaged at MDACC. R was defined as clinical or radiographic benefit. K-M method, Log-Rank, and Cox proportional hazard regression models were used for statistical analysis.

Results: Of 625 pts with a diagnosis of AEN, 132 (21%) fulfilled the inclusion criteria and were evaluable for PFS and R. Sixty-five (49%) pts received SC + BT; 67 (51%) pts received SC alone. SC included: 5-FU = 28 (21%), FOLFIRI = 20 (15%), FOLFOX = 71 (54%), and other = 13 (10%). BT included: bevacizumab = 58 (89%), EGFR inhibitor = 6 (9%); 1 pt (2%) received both. Median lines of BT = 1 (range: 1-3). Histologically, 51 (38%) were poorly differentiated and 33 (25%) were signet ring; 26 (20%) had both features. After a median follow-up of 33M, 40 (62%) had stable disease, 12 (19%) partial response, and 12 (19%) progressive disease. Biologic therapy improved median PFS and OS (17M vs. 7M, p-value = 0.007; 68M vs. 50M, p-value = 0.08, respectively). Multivariate analysis indicated improved PFS (HR: 0.49; 95% CI: 0.3-0.8; p-value: <0.001) and OS (HR: 0.52; 95% CI: 0.3-0.8; p value = 0.007) in favor of biologic therapy.

Conclusions: Biologic therapy in combination with chemotherapy appears to have a role in surgically unresectable AEN pts with improvement in PFS and OS. Tissue/blood correlatives and quality of life analysis are underway. Prospective analysis including cost-benefit should be considered.
Morbidity of staged proctectomy after hepatectomy for colorectal cancer: A matched case-control analysis.
Authors: Tzeng Ching-Wei David , Chang George J. , Curley Steven A. , Vauthey Jean-Nicolas , Ellis Lee M. , Skibber John Michael , Feig Barry W. , Abdalla Eddie K. , Aloia Thomas A. , You Y. Nancy , Rodriguez-Bigas Miguel A.
Published: February 2017

629

Background: Proctectomy after hepatectomy, or the “reverse approach,” is an alternative to traditional sequencing for advanced liver metastases with asymptomatic colorectal primaries. However, perioperative morbidity from staged proctectomy remains uncharacterized. We sought to identify risk factors for morbidity in these patients.

Methods: A single-institution colorectal database was queried for patients treated with proctectomy after previous hepatectomy from 2003-2011. Reverse approach patients (31) were matched 1:2 with a cohort of standard proctectomy patients (62), using operation, age, sex, and surgeon. Perioperative factors were analyzed by univariate/multivariate models for associations with complications graded by Dindo-Clavien criteria.

Results: 31 patients with adenocarcinoma ≤20 cm from the anal verge underwent proctectomy after hepatectomy. Median time from hepatectomy to proctectomy was 5.1 mo. Median tumor distance was 8.5 cm from the anal verge. No patients with primary tumors in situ recurred in the liver while awaiting proctectomy after hepatectomy. Prior to proctectomy, there were 28 (90%) major hepatectomies and 7 (22%) portal vein embolizations. Grade ≥2 complications developed in 42% of reverse approach and 27% of standard proctectomies (p=0.17). Grade 3 complications developed in 10% and 8%, respectively (p=1.00). There were no perioperative deaths. Reverse approach patients did not differ from the control cohort in operation, demographics, body mass index (BMI), comorbidities, tumor distance, operative time, estimated blood loss (EBL), length of stay, or complication rates (p>0.05). Independent predictors of Grade ≥2 complications were BMI ≥30 (p=0.007), operative time ≥300 min (p=0.012), intraoperative transfusion (p=0.044), concurrent procedures (p=0.024), and age ≥50 (p=0.030). Independent factors for Grade 3 complications were operative time ≥300 min (p=0.015), intraoperative transfusion (p=0.011), and EBL ≥300 ml (p=0.047).

Conclusions: Risk factors for morbidity of staged proctectomy are similar to those for standard proctectomy. When applied to selected patients, the reverse approach is safe with acceptable morbidity.