bluuebunny/crossref_metadata_2025 huggingface dataset:
Does the addition of biologic agents to chemotherapy in patients with unresectable colorectal cancer metastases result in a higher proportion of patients undergoing resection? A systematic review and meta-analysis.
Authors: Bogach Jessica , Levine Oren Hannun , Ruo Leyo , Serrano Aybar Pablo Emilio
Published: March 2017

690

Background: The likelihood of converting unresectable metastatic colorectal cancer (CRC) to operable disease with systemic therapy is unknown. The purpose of this study was to determine the proportion of patients with unresectable CRC metastases that become resectable on combination systemic therapy, and whether biologic agents (antiantiogenics, anti-EGFR and multitargeted agents) improve the rate of resection (primary outcome). Methods: We searched Medline, Embase, CENTRAL and PubMed for randomized controlled trials comparing chemotherapy and biologics (intervention) vs. combination chemotherapy alone (control) in patients with unresectable CRC metastases. Study selection, data abstraction, risk of bias and quality of the evidence assessment were carried out in duplicate. Secondary outcomes included overall survival (OS) and progression free survival (PFS). Risk of bias was assessed using the Cochrane tool. Statistical heterogeneity was calculated using chi-squared and I2. Clinical heterogeneity was explored via subgroup analyses. The quality of the evidence was assessed using GRADE. Protocol was published in PROSPERO. Results: Of 7954 abstracts retrieved, 12 studies were analyzed and 8 reported the primary outcome, with 2604 intervention and 2661 control patients. The proportion of patients resected was higher in the intervention group, Relative Risk 1.36, 95% confidence interval (CI) 1.08-1.69, p = 0.008. The absolute risk of undergoing resection was 48 per 1000 (control); compared to 65 per 1000 (intervention). There was no difference in OS, Hazard Ratio (HR) 0.91, 95% CI 0.82-1.01. PFS was better in the intervention group (HR 0.83, 95% CI 0.74-0.92). Overall the risk of bias for the included studies was low. Statistical test for heterogeneity was low (I2 was 0%, p = 0.72). There was significant clinical heterogeneity, which was not explained with subgroup analyses. The quality of the evidence (GRADE) was moderate. Conclusions: The addition of biologic agents to systemic chemotherapy in patients with unresectable CRC metastasis improves resectability and PFS but not OS.
Cost of colon cancer care: Results of nationwide inpatient sample (NIS) data.
Authors: Bansal Pranshu , Rabinowitz Ian , Boumber Yanis , Bansal Dhruv
Published: March 2017

692

Background: Cost of cancer care including colon cancer continues to rise. Most of the recent advances in colon cancer inlcude biologics and targeted agents which are adminstered in an oupatient setting and more commonly thought to be responsible for increasing economic burden. Cost of care for cancer patients in an inpatient setting however continues to be a significant factor that needs to be identified better to help adopt cost effective quality improvement in future. Methods: We used NIS to extract data for patients hospitalized with primary diagnosis of colon cancer using clinical classification software code 14, and corresponding ICD9 codes for the years 2003-2013. ICD codes for colorectal and rectal cancer were eliminated. NIS is a nationally representative survey of hospitalizations conducted by the Healthcare Cost and Utilization Project. It represents 20% of all hospital data in US. Trend of rate of hospitalization, mean length of stay (LOS), mean cost of hospitalization and mean cost of hospitalization based on owner type- government, private not for profit (PNFP) and private for profit (PFP) was performed. Results: From the year 2003 to 2013 rate of hospitalizations for colon cancer decreased from 37.4 to 28.1 per 100,000 hospital admissions. Mean LOS declined from 9.06 to 7.76 between 2003-2013. In the same time period the mean cost of hospital stay increased from $39,430 to $73,219. The mean cost of hospitalization based on owner type in 2003 was government $33,507; PNFP $33,735 and PFP was $55,553 and in 2013 the mean costs were $63,194; $68,555 and $107,428 respectively. Conclusions: In the decade of 2003-2013 the rate of hospitalization decreased by approximately 25%, LOS decreased by 14% but the mean cost of hospitalization continued to increase throughout the decade with a mean increase of approximately 85% in hospital costs. The increase was observed across the spectrum of all owner types with the maximum increase of 104% in PNFP followed by PFP owner type at 93%, national inflation rate was 26% during this time. Progress made in decreasing LOS has not directly translated into reducing hospital costs and further studies focusing on factors in addition to cost of biologic agents that contribute to cancer care costs should be considered.
Impact of primary tumor sidedness on survival after resection of colorectal liver metastases (CRLM).
Authors: Lee-Ying Richard M. , Bosma Nicholas , Tang Patricia A.
Published: March 2017

694

Background: The impact of primary tumour sidedness has recently been demonstrated in patients with metastatic colorectal cancer (mCRC). Differences in right (R) versus left (L) sided mCRC may be due to differences in consensus molecular subtyping. Clinically predictive mutations in ras, ( kras, nras and braf) may also help drive some of the differences in outcome. However, patients with mCRC who undergo surgical resection of CRLM often have a good prognosis. The aim of this study was to assess the impact of tumour sidedness on OS after resection of CRLM. Methods: Patients who underwent resection of CRLM in the province of Alberta, Canada were identified from 2004-2016. Tumour sidedness was determined by chart review, with R from the cecum to transverse and L from splenic flexure to sigmoid. Where available, ras mutational status was collected. OS was measured from the time of CRLM resection to death or last follow-up using the Kaplan-meier method. R and L were compared using the log-rank test and a Cox regression model. Results: 471 patients were identified who underwent resection of CRLM for mCRC, including 204 R and 267 L. Median age was 65, 63% male, with 54% synchronous metastatic disease, and 67% with a Charleson comorbidity index of 0. All ras wildtype was present in 22% of cases, any ras mutation was detected in 21% and 57% were unknown at the time of analysis. The median OS of R was 45 months, compared to 72 months for L, log-rank p = 0.01. After adjusting for potential confounders with a Cox-proportional hazard model, R compared to L remained significant, with a HR of 1.4 (95% CI 1.0-1.9, p = 0.02). ras mutational status was also significant for ras mutant, HR 2.4 (95% CI 1.7-3.3) and ras unknown HR 2.2 (95% CI 1.5-3.1) compared to ras wildtype p < 0.01. Conclusions: Primary tumour sidedness continues to have an impact on OS in mCRC, even when disease is managed surgically with resection of CRLM. Though limited by numbers, the impact remained significant even after controlling for potential confounders, including ras mutational status. Additional ras testing is underway. Further molecular classification may provide a biologic rationale for the observed differences.
Institutional variation in the thoroughness of pathologic assessment and pathologic complete response rates for locally advanced rectal cancers treated with neoadjuvant chemoradiation.
Authors: Chow Oliver S , Patil Sujata , Keskin Metin , Smith Jesse Joshua , Widmar Maria , Smith David D. , Avila Karin , Shia Jinru , Chu Peiguo , Garcia-Aguilar Julio
Published: March 2017

696

Background: A pathologic complete response (pCR) after neoadjuvant therapy and surgical excision is associated with a better prognosis and guides the management of patients with locally advanced rectal cancer. It is not known whether the thoroughness of pathologic assessment correlates with the finding of pCR. Methods: We introduce a surrogate measure for the thoroughness of pathologic assessment by taking the ratio of maximum residual tumor size and the number of cassettes prepared from the tumor: the Tumor Size to Cassette Ratio (TSCR). We retrospectively reviewed pathology reports from 259 patients with Stage II/III rectal cancer enrolled in a multicenter prospective clinical trial to determine whether TSCR is associated with pCR. Results: Of 247 included patients, 71 (29%) had a pCR. The pCR rate ranged from 0-45% and TSCR ranged from 0.0004 to 1.67 across the twelve trial sites. TSCR was significantly associated with pCR on univariable analysis. On multivariable analysis, TSCR remained significantly associated with pCR (odds ratio of 0.05; 95% CI 0.008-0.302) after adjusting for clinical stage, tumor size, distance from anal verge, radiation dose, and the number of neoadjuvant cycles of FOLFOX received. Conclusions: Pathologists tend to assess rectal cancer specimens with a pCR more thoroughly, but the thoroughness of pathologic assessment of residual tumor specimens varies between institutions. The thoroughness of pathologic assessment is associated with pCR. This raises the need for further standardization in the assessment of rectal cancer specimens after neoadjuvant chemoradiation.
QTWIST analysis in the RECOURSE trial.
Authors: Tabernero Josep , Van Cutsem Eric , Ohtsu Atsushi , Amellal Nadia , Cadour Stéphanie , Fougeray Ronan , Haffemeyer Benjamin , Mayer Robert J.
Published: March 2017

698

Background: RECOURSE showed that treatment with trifluridine/tipiracil in patients in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival vs placebo. As quality of life (QoL) was not captured in the trial, other methods were used to evaluate potential impact on QoL. Methods: We used the QTWIST method, i.e. quality-adjusted TWIST (time without symptoms of disease or toxicity), to explore survival adjusted for QoL with trifluridine/tipiracil vs placebo in the RECOURSE population. QTWIST incorporates a trade-off between time spent with treatment-related adverse events versus improvement in progression-free survival, and combines an estimate of the mean duration of each health state (TOX, TWIST, and RELAPSE [REL]), weighted by a utility coefficient, into a global QTWIST score. TOX represents time with grade 3/4 treatment-related adverse events that are expected to impact QoL (i.e. nausea, vomiting, diarrhea, fatigue/asthenia, anorexia, febrile neutropenia) before progression, TWIST represents time without symptoms or toxicity; and REL represents time from progression (as defined in the RECOURSE trial) until death. We applied a utility coefficient of 1 for TWIST and values of 0.5 for TOX and REL. A sensitivity analysis varied the utility coefficients for TOX and REL from 0 to 1. Results: 798 pts (533 trifluridine/tipiracil vs 265 placebo) were included with median follow-up time of 11.8 mo. The between-group difference in the global QTWIST score was 1.5 mo (95% CI, 1.49–1.52) in favor of trifluridine/tipiracil. Using varying utility coefficients for TOX and REL from 0 to 1 as a sensitivity analysis, the between-group difference in the global QTWIST score ranged from 1.3 to 1.7 mo, always in favor of trifluridine/tipiracil. Conclusions: The median overall survival benefit observed with trifluridine/tipiracil vs placebo in RECOURSE was 1.8 months. Consistently, patients' QoL as evaluated by QTWIST showed that quality-adjusted survival with Lonsurf is significantly improved by 1.5 months vs placebo. Clinical trial information: NCT01607957. [Table: see text]
Impact of country-specific health economic guidelines on cost-effectiveness (CE) estimates: An illustrative study of the CE of cetuximab in the first-line (1L) treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Harty Gerard , Fujii Ronaldo Kenzou , Ostawal Amrita , Pescott Chris P
Published: March 2017

702

Background: Adding cetuximab to conventional 1L chemotherapy (FOLFIRI or FOLFOX) improves survival outcomes in patients with RASwt mCRC. Conflicting evidence exists regarding the CE of cetuximab in mCRC, due in part to differences in country-specific health technology assessment (HTA) guidelines. Methods: CE estimates for the 1L treatment of RASwt mCRC with FOLFIRI or FOLFOX ± cetuximab were calculated for the UK (NICE), Brazil, Netherlands, and Belgium using a Markov cohort model populated with country-specific HTA requirement inputs and assumptions. Model outcomes were treatment costs, life-years (LY) or quality-adjusted LY (QALY) gained, and the incremental CE ratio (ICER). ICERs were compared against CE thresholds. Results: Country-specific HTA guidance resulted in differing CE outcomes for patients with RASwt mCRC receiving FOLFIRI or FOLFOX ± cetuximab (Table). Conclusions: We applied our Markov model to four markets, incorporating country-specific HTA requirements into our calculations. Although our analyses with similar comparators led to a varying range of CE estimates, they met the HTA threshold guidelines in the four markets. [Table: see text]
Treatment outcome and recovery from peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer (JFMC41-1001-C2: JOIN Trial).
Authors: Manaka Dai , Kotaka Masahito , Shinozaki Katsunori , Touyama Tetsuo , Matsui Takanori , Ishigure Kiyoshi , Hasegawa Junichi , Inoue Keiji , Munemoto Yoshinori , Takagane Akinori , Ishikawa Hiroshi , Ishida Hideyuki , Ogata Yutaka , Oba Koji , Goto Koichi , Sakamoto Junichi , Saji Shigetoyo , Ohtsu Atsushi , Watanabe Toshiaki , Yoshino Takayuki
Published: March 2017

703

Background: The JOIN Trial investigated safety and efficacy of modified FOLFOX6 (mFOLFOX6) in Japanese patients (pts) with stage II/III colon cancer. In the initial safety report, incidence of ≥ grade 3 (G3) peripheral sensory neuropathy (PSN) was 5.8% during treatment. Methods: Twelve cycles of mFOLFOX6 were given to pts with the following criteria: stage II/III curatively resected colon cancer; ECOG Performance Status (PS) of 0–1; age, ≥ 20 years; and adequate organ function. We report the treatment outcome results, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery from PSN during 3-year follow-up. Results: From November 2010 to March 2012, 882 pts were enrolled. In the efficacy group (N = 864; median follow-up, 3 years), pt characteristics were as follows: median age, 64 years; male, 53.8%; PS 0, 93.8%; stage II/IIIA/IIIB/IIIC (TNM), 18.5/7.3/52.5/21.6%; and lymph nodes examined, < 12/ > 12/unknown: 17.2/82.5/0.2%, respectively. Three-year DFS, RFS, and OS were 76.1, 77.3, and 92.7%, respectively. Favorable 3-year DFS, RFS, and OS were 92.1, 92.8, and 97.4% in stage II patients; 76.4, 77.9, and 93.8% in stage IIIA/B; and 61.6, 62.7, and 85.9% in stage IIIC, respectively. The main recurrent sites were liver (7.6%), lung (7.3%), and lymph nodes (5.2%). In multivariate Cox regression analysis, tumor histology, venous invasion, and lymph node metastatic ratio were statistically significant prognostic factors for DFS, RFS, and OS. Cumulative incidence of PSN during treatment was 47.8% in G1, 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 and G2 residual PSN after 3 years was observed in 21.0% of pts (18.7%, G1; 2.3%, G2). Conclusions: Efficacy and safety of adjuvant mFOLFOX6 in pts with stage II/III colon cancer can be confirmed. Most pts successfully recovered from G3 PSN related to oxaliplatin, but G1 and G2 PSN was irreversible in one-fifth of pts at the 3-year follow-up. Clinical trial information: UMIN000004443.
Incidence and outcomes of hospitalized patients with gastrointestinal malignancies and Clostridium difficile infection: A nationwide analysis.
Authors: Gupta Arjun , Tariq Raseen , Arora Nivedita , Frank Ryan D. , Beg Muhammad S. , Pardi Darrell S. , Johnson David H. , Khanna Sahil
Published: March 2017

704

Background: Inpatients with gastrointestinal (GI) malignancies are at a high risk for Clostridium difficile infection (CDI) but the impact of CDI on outcomes in these patients needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in GI cancer patients using the National Hospital Discharge Survey (NHDS) database from 2001 - 2010. Methods: NHDS collects clinical information on patients dismissed from non-Federal short-stay United States hospitals. Demographics, diagnoses (GI malignancies, CDI and comorbidities), length of stay (LOS), and dismissal information were abstracted using ICD-9 diagnosis and procedure codes. Weighted analyses were performed using SAS version 9.4. Results: Of an estimated 317.9 million unique hospitalizations; 4.6 million had a diagnosis of a GI malignancy (1.4%); median age 68 years, 46.1% female. CDI was more common in patients with GI malignancies compared to patients with no GI malignancy (1.05% vs 0.69%, aOR 1.16, 95% CI 1.15- 1.17, p < 0.0001). There was a significant increase in CDI incidence in GI cancer patients over the 10-year study period (72.7 in 2001-2002 to 109.1 in 2009-2010, per 10,000 discharges, p < 0001). In multivariable analysis, compared to GI cancer patients without CDI, GI cancer patients with CDI had a longer mean LOS (3.94 more days, 95% CI 3.31-4.56) and dismissal to a care facility (adjusted OR, 1.75; 95% CI, 1.71-1.79), but lower all-cause in-hospital mortality (adjusted OR, 0.76; 95% CI, 0.74-0.79), all p < 0.0001 Conclusions: In this national database of hospitalized patients, an increasing incidence of CDI in patients with GI malignancies was noted over the study period. CDI prolonged hospitalization, and was associated with increased dismissal to a care-facility. Lower rates of in-hospital mortality may represent early diagnosis due to vigilance or a milder form of CDI. Despite increased attention over the last few decades, CDI remained a serious infection in GI cancer patients, and merits appropriate prevention, management and follow-up.
A phase II study of ziv-aflibercept (Z) + FOLFIRI in Japanese patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Satoh Taroh , Denda Tadamichi , Hamaguchi Tetsuya , Sugimoto Naotoshi , Ura Takashi , Yamazaki Kentaro , Fujii Hirofumi , Kajiwara Takeshi , Nakajima Takako Eguchi , Takahashi Shin , Otsu Satoshi , Komatsu Yoshito , Sasaki Toru , Sunaga Yoshinori , Yoshino Takayuki
Published: March 2017

707

Background: VEGF promotes tumor angiogenesis and metastasis. Z blocks the activity of VEGF-A/-B, and placental growth factor and was shown in the VELOUR phase III study (NCT00561470) outside of Japan to significantly improve overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in mCRC pts as a second-line treatment given with FOLFIRI. Goals of the current open-label, multicenter phase II study were to assess the efficacy and safety of Z + FOLFIRI in a post-oxaliplatin setting in mCRC pts in Japan. Methods: Pts received Z (4 mg/kg) + FOLFIRI (400 mg/m2 bolus 5-fluorouracil [FU]; 2400 mg/m2 continuous infusion 5-FU; 200 mg/m2 levofolinate; 180 mg/m2 irinotecan) every 2 weeks until progression, unacceptable toxicity, or study withdrawal. Primary endpoint: ORR (required 60 pts in order to obtain a 95% CI width of 16–20%, assuming an ORR of 10–20%). Secondary endpoints: PFS, OS, and safety. Tumors were assessed by independent reviewers every 6 ± 1 weeks until progression. Results: Study enrolled 62 pts; 50 pts (83.3%) had received prior bevacizumab. Of 60 pts evaluable for response, 5 had a partial response and none had a complete response, resulting in an ORR of 8.3% (95% CI: 1.3–15.3%). The median PFS was 5.42 months (95% CI: 4.140–6.702), and the median OS was 15.59 months (range 11.20–19.81). Forty-one pts (66.1%) died due to progression; none died due to study treatment. Pts underwent a median of 8 treatment cycles (range 1–31) lasting a median of 21.8 weeks (range 2–73). The median relative dose intensity was 0.99 (range 0.2–1.0) for Z, 0.87 (range 0.4–1.0) for irinotecan, and 0.96 (range 0.7–1.0) for 5-FU. All pts had ≥1 treatment emergent adverse event (TEAE; see table). Conclusions: The ORR was 8.3% (95% CI: 1.3–15.3%), and the median OS was 15.59 months. The safety profile was consistent with that reported previously. Registered as NCT01882868. Clinical trial information: NCT01882868. [Table: see text]
Preoperative chemoradiotherapy for advanced lower rectal cancer using SOX+Bev regimen.
Authors: Higashijima Jun , Shimada Mitsuo , Yoshikawa Kozo , Nishi Masaaki , Kashihara Hideya , Takasu Chie
Published: March 2017

708

Background: We have performed preoperative CRT for advanced lower rectal cancer patients using S-1 or UFT. To improve response rate, we are performing phase 2 trial of preoperative CRT using S-1/ Oxaliplatin /Bevacizumab (SOX+Bev) regimen. In this study, we show the results of the trial and the promising predictive factor. Methods: Twenty-five patients (SOX+Bev) and 59 patients (S-1 or UFT) were included in this study. S-1(80mg/m2), UFT(300mg/m2) were administered orally every day on radiation therapy, and S-1(80mg/m2,Oxaliplatin(40-60mg/m2),Bevacizumab(5mg/kg) were administered in SOX+Bev group. Total dose of radiation was 40Gy with four field technique. As a predictive factor, we measured miR-223 with real-time PCR using pre CRT biopsy specimens. Results: Clinical response by RECIST were as follows: SOX+Bev group: CR/PR/SD/PD = 1/21/3/0, S-1/UFT group: CR/PR/SD/PD = 1/32/26/0. Clinical response rate were 88% in SOX+Bev group, higher than 56.0% in S-1/UFT group. Pathological response grade were as follows: SOX+Bev group: 1a/1b/2/3 = 5/4/10/6,S-1/UFT group :1a/1b/2/3 = 13/16/27/3. Pathological response rate was 64% in SOX+Bev group, 51% in S-1/UFT group and there was no significant difference. The pCR rate was 24% in SOX+Bev group, significantly higher than 5% in S-1/UFT group (p < 0.05)B In S-1 group, miR-223 in responder group tended to be higher than non-responder group (p = 0.06). And in SOX+Bev group, miR-223 in Grade 3 group(8.89±9.41) was significantly higher than other group (3.19±4.64) (p = 0.05). Conclusions: Preoperative CRT with SOX+Bev regimen can improve response rate and bring high pCR rate. miR-223 may be promising predictive factor and useful to perform order made therapy. Clinical trial information: 13267.
Overexpression of SETDB1 in relation to poor outcome in gastric carcinoma.
Authors: Okajima Wataru , Komatsu Shuhei , Ichikawa Daisuke , Ohashi Takuma , Imamura Taisuke , Nishibeppu Keiji , Otsuji Eigo
Published: March 2017

71

Background: SETDB1 is a Histone H3 lysine 9-specific Methyl Transferase belonging to the SET domain. In this study, we tested whether SETDB1 acts as a cancer-promoting gene through its overexpression in gastric cancer (GC). Methods: We analyzed5 GC cell lines and 135 primary GC samples curatively resected in our hospital. Results: Overexpression of the SETDB1 protein was detected in all GC cell lines and primary GC samples (115/135 cases, 85%). Knockdown of SETDB1 using specific siRNA inhibited the proliferation, migration and invasion. Overexpression of the SETDB1 was significantly correlated with lymphatic invasion, deeper tumor depth and higher recurrence rate. Patients with SETDB1-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.0041, log-rank test) in an intensity and proportion score-dependent manner. Moreover, multivariate analysis demonstrated that SETDB1 was independently associated with worse outcome (P = 0.0178, HR 3.1 (1.20-9.83)). Conclusions: These findings suggest that SETDB1 has a crucial role in tumor cell proliferation and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
Survival impact of CAPOX versus FOLFOX in the adjuvant treatment of stage III colon cancer.
Authors: Loree Jonathan M. , Sha Aaron , Soleimani Maryam , Ho Maria Yi , Kennecke Hagen F. , Cheung Winson Y. , Mulder Karen E. , Abadi Shirin , Spratlin Jennifer L. , Gill Sharlene
Published: March 2017

710

Background: CAPOX and FOLFOX are used interchangeably in the adjuvant treatment of colon cancer despite the lack of comparative phase III trials.We aimed to compare toxicities, relative dose intensity (RDI), disease free (DFS) and overall survival (OS) of these regimens in the real world. Methods: We identified consecutively treated patients (pts) with stage III colon cancer at two centers who received either CAPOX or mFOLFOX6 when either option was accessible to pts. RDI was defined as total dose received divided by the total intended dose if all cycles had been delivered. Dose limiting toxicities (DLTs) were toxicities that resulted in a dose reduction of an agent. Survival was compared with the log-rank test and Cox models that adjusted for age, gender, ECOG, T-stage, and N-stage. Results: Of 394 pts, 61.7% received FOLFOX. Age, gender, ECOG, T-stage, N-stage, and time between surgery and start of therapy did not differ between groups. However, RDI and toxicity profiles differed between treatment groups (see Table). With a median follow up of 45 months, there was no difference in OS (HR 0.73, 95%CI 0.45-1.22; P= 0.24); however, CAPOX was associated with a more favorable DFS (HR 0.61, 95% CI 0.40-0.93; P= 0.022). In multivariate analysis, treatment with CAPOX showed trends towards improved OS (HR 0.61, 95% CI 0.34-1.07; P= 0.086). A significant association with improved DFS (HR 0.53, 95% CI 0.33-0.87; P= 0.012) persisted. Exploratory analysis comparing outcomes stratified by the presence of any DLT, neutropenia, thrombocytopenia, and neuropathy failed to show an association with either OS or DFS. (See table.) Conclusions: Our findings suggest that the use of adjuvant CAPOX is associated with an improved DFS despite greater toxicity and lower RDI. Patient selection, the higher starting dose of oxaliplatin in CAPOX, or the metronomic nature of capecitabine may be contributing to improved efficacy of CAPOX. [Table: see text]
Minimally invasive surgery to improve time to chemotherapy in colon cancer: Compliance to the American College of Surgeons Commission on Cancer quality metrics.
Authors: Dumitra Sinziana , Nelson Rebecca A. , Zheleva Vasilena , Raoof Mustafa , Lai Lily L.
Published: March 2017

712

Background: One of the American College of Surgeons Commission on Cancer (ACS CoC) quality measures in colon cancer is receipt of chemotherapy (CT) in Stage III disease within 120 days of diagnosis. Minimally invasive surgery (MIS) has been associated with faster recovery times. The aim of this study is to assess whether MIS improves compliance to this metric. Methods: Stage III colon cancer patients 80 years old and younger from 2010 to 2012 were identified in the National Cancer Database. Demographic, tumor and treatment characteristics were evaluated including receipt of CT and surgical approach. Uni- and multi-variate logistic regression was used to assess factors associated with CT compliance. Results: Of the 19,963 patients identified, 14,901(74.6%) were compliant while 5,062 (25.3%) were not. Of the patients who were non-compliant, 956 (4.8%) received CT after 120 days. Surgical approach was significantly different between CT compliant and non-compliant groups (MIS 28% vs 32%,p < 0.000). Uni- and multi-variate analyses identified MIS as a significant factor associated with improved compliance to CT with an OR of 1.31 (95%CI 1.22-1.41). Other factors associated with CT compliance were nodal and tumor stage and treatment in an academic program. Non-compliance was associated with age 50-64 (OR 0.76; 95%CI 0.68-0.86), age 65-79 (OR 0.49; 95%CI 0.43-0.56) and increased co-morbidities (OR 0.60; 95%CI 0.53-0.67). Lack of insurance (OR 0.69; 95%CI 0.58-0.81) or Medicaid (OR 0.54; 95%CI 0.47-0.62) and Medicare (OR 0.69; 95%CI 0.63-0.77) as well as distance to hospital of more than 44 miles were also associated with non-compliance to CT (OR 0.86; 95%CI 0.76-0.97). Conclusions: This is the first study to demonstrate that MIS for Stage III colon cancer improves compliance to receipt of CT within the 120 days. Given the potential survival benefits as a result of adherence to ACS CoC cancer care quality metrics, MIS may benefit patients not only in faster return to recovery but also in improved cancer outcomes.
Baseline absolute neutrophil counts (ANC) and survival in second-line metastatic colorectal cancer (mCRC) patients (pts).
Authors: Grothey Axel , Tabernero Josep , Mytelka Daniel S , Li Li , Nasroulah Federico , Yoshino Takayuki
Published: March 2017

713

Background: Exploratory analyses from RAISE (NCT01183780), FOLFIRI with ramucirumab or placebo in previously treated mCRC pts, suggested pts with treatment-emergent neutropenia may have improved overall survival (OS) compared to pts who did not experience neutropenia on study (Ciuleanu T, et al. abst. 2475, ESMO 2016). Subsequent analyses suggested an even stronger association between baseline ANC and OS, with high baseline ANC associated with shorter OS. A retrospective observational study was conducted to test this association as a pre-specified hypothesis. Methods: The IMS Oncology Database (electronic medical record data from US community practices) was used to identify pts ≥ 18 yrs with mCRC (ICD-9 code 153.x, 154.0 or 154.1) who initiated second-line fluoropyrimidine and irinotecan (+/- bevacizumab; bev) in 2007-2013, following progression during or after first-line fluoropyrimidine and oxaliplatin (+/- biologic). Eligible pts had ≥ 1 ANC in the 60 days prior to second-line therapy. Pts were stratified by second-line bev use and high/low baseline ANC ( ≥ or < 5.5x109/L) and matched by propensity scores. OS based on a validated proxy was analyzed using the Kaplan-Meier method and a Cox proportional hazards model, adjusted for age, gender, ECOG PS, stage, length of first-line treatment, and BMI. Results: 747 eligible pts were identified, of whom 617 were matched. Pts with baseline characteristic data had a median age of 59 yr, 57% were male, 67% were Caucasian, 74% had stage IV disease at diagnosis, and 63% had ECOG PS of 0/1 at start of second-line. Bev-treated pts with high baseline ANC (n = 122) had a median OS (mOS) of 7.7 mo vs 14.7 mo in pts with low baseline ANC (n = 323); adjusted HR 1.69 (95% CI, 1.35, 2.12; p < 0.0001). Pts with high baseline ANC not treated with bev (n = 59) had a mOS 5.4 mo vs 14.4 mo in pts with low baseline ANC (n = 113); adjusted HR 2.73 (95% CI, 1.89, 3.93; p < 0.0001). There was a modest interaction effect between bev treatment and baseline ANC (p = 0.012), indicating greater bev benefit in the high ANC group. Conclusions: Baseline ANC appears to be a strong prognostic factor and potentially a weak predictive factor for antiangiogenic therapy for OS in pts with previously treated mCRC.
Minimally invasive complete mesocolic excision and central vascular ligation for right colon cancer: Defining the radicality of central lymphadenectomy.
Authors: Sammour Tarik , Malakorn Songphol , Thampy Rajesh , Kaur Harmeet , Bednarski Brian , Messick Craig , Chang George J. , You Y. Nancy
Published: March 2017

715

Background: Complete mesocolic excision (CME) with central vascular ligation (CVL) has been advocated for right colon cancer (RC), but the radicality of lymphadenectomy remains controversial. Optimal D2 lymphadenectomy removes all intermediate nodes with high ligation (HL) of feeding vessels, while D3 lymphadenectomy additionally exposes and retrieves nodes along ventral superior mesenteric vessels (SMA/V). We aim to evaluate minimally invasive CME-CVL, explicitly defining the radicality of central lymphadenectomy. Methods: Patients who underwent minimally invasive resection for RC between 2008 and 2016 were identified from a prospective institutional database. CME was standard. The radicality of central lymphadenectomy was defined as high ligation (HL, optimal D2) vs central node dissection (CND, D3) after review of operative reports and/or videos. A blinded radiologist evaluated the pre- and post-operative CT scans for radiographically abnormal nodes. Results: Among 200 patients, 169 (84.5%) underwent laparoscopic and 31 (15.5%) robotic resection. Central lymphadenectomy was performed as HL in 58 (29%) and as CND in 142 (71%) patients. Preoperative imaging identified abnormal D2 nodes in 33.0% and D3 nodes in 2.6%. CND was performed in 73% of those with abnormal D2 and 100% of those with abnormal D3 nodes. Pathologically positive nodes were identified in 41% (37.9% of the HL and 42.3% of the CND, p=0.64). The median number of nodes retrieved was 27 and 32, respectively. No patient had residual abnormal node on post-operative imaging. The 30 day mortality rate was 0%, and morbidity rate was 15% (4% grade 3, 11% grades 1-2). After a median of 22 months, one (0.5%) patient recurred locally at the anastomosis. Conclusions: Minimally invasive CME-CVL can be safely performed with excellent nodal yield with both optimal D2 as well as D3 lymphadenectomy. With imperfect clinical nodal staging, the near-zero local recurrence rate observed supports CME with optimal D2 lymphadenectomy as a minimum standard and D3 lymphadenectomy when radiographically abnormal nodes are identified.
Association of adjuvant chemotherapy with improved overall survival for patients with locally advanced rectal cancer (LARC) who achieve a pathologic complete response (pCR) to neoadjuvant chemoradiation (nCRT).
Authors: Shahab Danish , Gabriel Emmanuel M. , Attwood Kristopher , Francescutti Valerie , Ma Wen Wee , Nurkin Steven J. , Boland Patrick McKay
Published: March 2017

716

Background: 15-20% of patients with locally advanced rectal adenocarcinoma (LARC) achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation (nCRT). The role of adjuvant chemotherapy has been questioned. Methods: Patients with rectal cancer receiving nCRT in the National Cancer Data Base (NCDB) 2006-2013 data set were evaluated. The primary outcome was overall survival (OS). The association between OS and patient characteristics were examined using multivariable Cox regression models. Results: 2,903 patients were identified who achieved a pCR. The median follow up was 43.2 months. 2,102 received nCRT and 789 received nCRT + adjuvant chemotherapy. Factors significantly associated with OS included age (p<0.001), gender (p=0.011), Charlson-Deyo comorbidity score (CDI) (p<0.001), grade (p=0.029), clinical T stage (p=0.030), and CEA negativity (p=0.002), but not nodal status. The 3-year OS rate was 94% in the adjuvant therapy group as compared to 84% in the nCRT alone group (p<0.001). In considering clinical N-stage, the benefit was comparable for both N+ and N- tumors. Adjuvant chemotherapy was more likely to be given for younger patients (age < 60), lower comorbidity score, higher grade, positive CEA status, higher clinical T stage, and higher clinical N stage. When stratifying by these factors, similar benefits in OS were observed in the adjuvant cohort. Conclusions: Following nCRT and achievement of a pCR, the receipt of adjuvant chemotherapy is associated with improved OS. Patients receiving adjuvant therapy were more likely to be younger and have a low CDI, but have more advanced stage disease. Thus, a selection bias may be present. Nonetheless, in the setting of the already excellent outcome associated with pCR, the additional benefit of adjuvant chemotherapy should be weighed against toxicity.
Impact of time to surgery in locally advanced rectal cancer patients.
Authors: Naseem Madiha , Yeung Manwah , Senthilvel Suruthi , Dibajnia Pooya , Naila Doshina , Singh Brendan , De Montbrun Sandra , Burnstein Marcus J. , Baxter Nancy N. , Brezden Christine B.
Published: March 2017

719

Background: Patients with locally advanced rectal cancer (LARC) undergo surgery at 6-8 weeks after neoadjuvant chemoradiation based on standard protocol. However, the optimal time to undergo surgery remains debatable. The goal of this study was to identify associations between time to surgery and additional variables with overall survival (OS) and recurrence rates in LARC patients. Methods: A retrospective chart review was conducted for 80 LARC patients with T3 or node positive disease, who have undergone neoadjuvant chemoradiation and surgery at St. Michael’s Hospital from January 1st 2005-December 31st 2015. Patients were divided into 4 groups based on time to surgery: 4-6 weeks (group 1), 6-8 weeks (group 2), 8-10 weeks (group 3), and > 10 weeks (group 4). Cox proportional hazards model was used to find associations with recurrence and OS. Results: Of the 80 patients, 67.5% (n = 54) were male and 32.5% (n = 26) were female. Median age at diagnosis was 59 years (range, 28-80 years). Median follow-up was 4.84 years. Recurrence occurred in 29% (n = 23) of patients. Incidence of death was 11% (n = 9). Pathologic complete response (pCR) was achieved in 15% (n = 12) of patients. Statin use during chemoradiation was prevalent in 25% (n = 20) of patients. Compared to group 1, patients in group 2 had a 14% reduction in the risk of recurrence (hazard ratio (HR): 0.86, 95% CI: 0.252.91); group 3 had a 69% reduction (HR: 0.31, 95% CI: 0.081.22) and group 4 had a 55% reduction (HR: 0.45, 95% CI: 0.073.08). There was no statistically significant difference in OS between the 4 groups. Furthermore, patients who took statins during chemoradiation had improved OS (HR: 5.42, 95% CI: 39.27.48, p < 0.019) with no difference in pCR rate. Conclusions: This study shows that surgery at 8-10 weeks after chemoradiation offers the best disease-free survival outcome. It also highlights a mortality benefit conferred by statin use during chemoradiation. This could be attributed to the radiosensitizing effects of statins, which allow tumor stem cells to undergo enhanced autophagy. Further prospective studies are warranted to investigate this therapeutic benefit.
Plasma biomarker analysis of ramucirumab in Japanese patients with advanced gastric cancer: Preliminary results.
Authors: Takahari Daisuke , Wakatsuki Takeru , Mashima Tetsuo , Ichimura Takashi , Chin Keisho , Ogura Mariko , Nakayama Izuma , Matsushima Tomohiro , Osumi Hiroki , Ozaka Masato , Suenaga Mitsukuni , Shinozaki Eiji , Seimiya Hiroyuki , Fujita Naoya , Yamaguchi Kensei
Published: March 2017

72

Background: Ramucirumab, anti-VEGFR2 receptor antibody, showed significantly improved survivals of gastric cancer in the second line with paclitaxel or single use; however, no validated biomarker has been available until today. The aim of this study is 1) to reveal the dynamics of plasma biomarkers, 2) to assess the associations between these baseline levels or dynamics and efficacy. Methods: Plasma samples were collected at three points: base line, day 8, and after disease progression. Nine kinds of plasma biomarker involved in angiogenesis were measured by means of ELISA. Progression-free survival (PFS) was estimated using Kaplan-Meier methods and compared using the log-rank test. Comparisons of plasma biomarker levels were performed using Mann-Whitney-U test. Results: Samples were collected from 35 patients. Among them, 25 patients were evaluated when analyzed and 6 patients showed disease progression at the first evaluation. In VEGF-A and PlGF, plasma biomarker levels of day 8 were dramatically elevated in all patients; Day8/ baseline ratios were 18.1 folds in VEGF-A and 19.3 folds in PlGF. On the other hand, Day8/ baseline ratio of VEGFR1 and NRP1 were 0.7 and 0.8, respectively. The others appeared to show variable change at day 8. In survival analysis, lower than median Day8/ baseline ratios of VEGF-A were significantly associated with longer PFS with 6.3 months in < median vs. 2.4 months in ≥ median (p = 0.004). In addition, patients with disease progression at the first evaluation by CT showed higher Day8/ baseline ratios of VEGF-C, Angiopoietin 1, and lower baseline NRP1 levels than those of patients with non-disease progression. Conclusions: Dramatic changes of biomarker levels at day 8 were observed among patients in each biomarker. These changes in VEGF-A, C, and Angiopoietin-1 may be candidate predictive marker of ramucirumab in Japanese patients with gastric cancer.
Examining progression-free survival in first- and second-line treatment for BRAF-mutant metastatic colorectal cancer (CRC).
Authors: Lee Belinda , Anton Angelyn , Lee Margaret , Wong Rachel , Parente Phillip , Shapiro Jeremy David , Yip Desmond , Steel Simone Anne , Nott Louise M. , Stefanou Greg , Iddawela Mahesh Y. , Gibbs Peter , Tran Ben
Published: March 2017

728

Background: BRAF mutated (BRAFm) CRC represents ~10% of all CRC and is associated with significantly poorer prognosis. However, responses to chemotherapy do still occur. Some data suggest that the poor prognosis associated with BRAFm CRC is dominated by substantially poorer second line PFS (PFS2), whereas first line PFS (PFS1) was similar for both BRAFm and BRAF wildtype (BRAFwt) CRC. Using a large multicenter dataset, our study aimed to examine PFS1 and PFS2 in BRAFm versus BRAFwt CRC. Methods: Prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) database was interrogated. PFS was calculated and compared in patients with BRAFm versus BRAFwt CRC. Median survival was determined by the Kaplan-Meier method and compared using the log rank test. Results: TRACC identified 523 CRC patients with known BRAF mutation status, who received first-line chemotherapy: 53 (10%) were BRAFm, while 470 (90%) were BRAFwt. At the time of data analysis, only 231 (44%) CRC patients had received second-line chemotherapy, of which 21 (9%) were BRAFm and 210 (91%) were BRAFwt. PFS1 analyses demonstrated significantly poorer survival in the BRAFm population (Median 7.8mo versus 11.5mo, HR 1.72, p = 0.0026). PFS2 analyses revealed similar findings for the BRAFm population, albeit non-significant due to smaller numbers (Median 5.5mo versus 7.7mo, HR1.26, p = 0.44). Conclusions: Our study demonstrated that BRAFm CRC was associated with poorer PFS in both first- and second-line settings. Additional analyses will be performed to examine the impact of different treatment strategies and other clinicopathological features.
Cetuximab and bevacizumab in addition to chemotherapy first-line for left-side metastatic colorectal cancer: A cost-effectiveness analysis.
Authors: Zhang Yanqiao , Zheng Tongsen , Liu Maobai , Li Te , Wu Bin
Published: March 2017

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Background: To test the cost-effectiveness of cetuximab and bevacizumab treatment as first-line treatment for patients with left-side metastatic colorectal cancer (mCRC). Methods: A Markov model was developed to Chinese clinical practice. The model incorporated clinical and utility data from published literatures, resource utilization and unit prices based on local charge. The lifetime horizontal was used and sensitivity analyses were carried out to test the robustness of the model results. The impact of patient assistance program (PAP) was also evaluated in scenario analyses. Results: Baseline analysis showed that the addition of cetuximab gained additional 0.364 QALYs with more $39,450 relative to bevacizumab therapy, resulting in an ICER of $108,287 /QALY. When PAP was available, the incremental cost decreased to $2,464, which yielded an ICER of $6,764 /QALY, which indicated that the strategy might be very cost-effective at a willingness-to-pay (WTP) threshold of 3 times the per capita GDP of China ($22,200/QALY). Sensitivity analyses found that the costs of cetuximab and bevacizumab were the most influential parameters. Conclusions: When PAP was available in Chinese context, cetuximab treatment is likely to be cost-effective versus bevacizumab therapy for patients with left-side mCRC.
Oncologic outcome and morbidity for elderly rectal cancer patients compared to younger patients after preoperative chemoradiotherapy and curative surgery: A multi-institutional and case-matched control study.
Authors: Sung Soo Yoon , Lee Jong Hoon , Kim Sung Hwan
Published: March 2017

736

Background: To elucidate the toxicity and survival outcome of neoadjuvant chemoradiotherapy (CRT) followed by curative total mesorectal excision (TME) in elderly rectal cancer patients compared to younger patients. Methods: A total of 1232 rectal cancer patients who received neoadjuvant CRT and curative surgery were collected from 7 tertiary institutions. After propensity-score matching, 310 patients of < 70 years for younger arm and 310 patients of ≥ 70 years for elderly arm were identified, respectively and matched with 1:1 manner. Treatment response and toxicity, surgical outcome, recurrence, and survival were assessed and compared between two arms. Results: The two younger (< 70 years) and elderly (≥ 70 years) arms were well-matched and had similar baseline characteristics. Median ages were 58 years for younger arm and 74 years for elderly arm, respectively. Pathologic complete response rates were not significantly different between younger arm and elderly arm (17.1% vs. 14.8%, P = 0.443). The 5-year recurrence-free survival (70.0% vs. 69.8%, P = 0.773) and overall survival (79.5% vs. 82.9%, P = 0.270) rates were not significantly different between two arms. Adjuvant chemotherapy after surgery was less frequently delivered to elderly arm than younger arm (69.0% vs. 83.9%, P = 0.773). Grade 3 or higher acute hematologic toxicity was observed more frequently in elderly arm than in younger arm (9.0% vs. 16.1%, P = 0.008 ), but late complication was not significantly increased in elderly arm (2.6% vs. 4.5%, P = 0.193). Conclusions: Despite an increased acute toxicity, elderly rectal cancer patients with good performance status would have equivalent tumor response and recurrence-free survival compared to younger patients.
Ziv-aflibercept (A) combined to FOLFIRI as first line treatment for metastatic colorectal cancer (mCRC): Interim safety and efficacy results of the phase II PULSAR trial.
Authors: Adenis Antoine , Ghiringhelli Francois , Raoul Jean Luc , Tresch Emmanuelle , Thirot-Bidault Anne , Vincent Julie , El Hajbi Farid , Hebbar Mohamed , Bouchahda Mohamed , Jarraya Hajer , Feutray Sylvaine , Amela Eric , Laestadius Fredrik , Le Deley Marie-Cécile , Taieb Sophie , Soncin Fabrice , Dochy Emmanuelle , Delaine Stephanie Clisant , Penel Nicolas , Lassau Nathalie
Published: March 2017

737

Background: A is approved in combination with FOLFIRI (A-FOLFIRI) for the treatment of mCRC patients (pts) previously treated with oxaliplatin. PULSAR trial (NCT02173990) aims to measure the activity A-FOLFIRI as 1st-line mCRC treatment. Key secondary objectives are safety, as well as circulating biomarkers and dynamic contrast-enhanced ultrasound measurements as PFS prognosticators. We present here interim analysis of safety and activity. Methods: Pts received A (4 mg/kg I.V.) every 2 weeks in combination with FOLFIRI (Irinotecan: 180 mg/m2, leucovorin: 200 mg/m2, Bolus FU: 400 mg/m2, infusional FU: 2400 mg/m2 over 46hrs). The primary endpoint is 10-month [m] PFS (RECIST 1.1). The target sample size is 72 pts for the following assumptions: P0 = 0.40, P1 = 0.55, α = β = 0.1. Results: Among the first 30 recruited mCRC pts with unresectable metastases (mets), 29 received at least 1 cycle of A-FOLFIRI. 30, 23, and 28 pts were evaluable for survival (intent-to-treat), tumor response, and safety, respectively. Median age was 61.5 (45-82), 70% pts were men. ECOG PS was 0, 1, and 2, in 47%, 43%, and 10% of the pts. 6/30 pts received previous adjuvant chemotherapy. 22/30 pts presented with synchronous mets. 26/30 pts presented with liver mets. Median treatment duration was 6.3m (0.5-24.3) and pts (n = 29) received a median number of 10 cycles (1-37) of A and of 11 cycles (1-43) of FOLFIRI. Median follow-up was 7.2m (1.6-23.9). The 10-m PFS was 59.9% [95%-CI: 37.5-76.5]. Median PFS was 12.9m (95% CI: 6.1-…). 12-m OS rate was 73.7% (95% CI: 48.3-87.9). 5 pts died from PD, and 1 from treatment-related toxicity (colon perforation). 27/28 pts presented at least one severe Adverse Event (AE). Most frequent severe AE (related or not) were hypertension (43%), neutropenia (29%), diarrhea (18%), alkaline phosphatase increase (18%), fatigue (18%), GGT increase (14%), and weight loss (14%). Conclusions: A-FOLFIRI seems promising in 1st line setting mCRC, with respect to PFS. Due to high rates of severe AEs, dose modifications have to be proceeded in a coming protocol amendment. Funded by Sanofi. Clinical trial information: NCT02173990.