bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life (QoL) assessment in patients (pts) with K-RAS wild-type (WT) chemotherapy refractory metastatic colorectal cancer (mCRC) treated with cetuximab (CET) plus brivanib alaninate (BRIV) or placebo: Results of the NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Ringash Jolie , Au Heather-Jane , Siu Lillian L. , Shapiro Jeremy D. , Jonker Derek J. , Zalcberg John Raymond , Moore Malcolm J. , Strickland Andrew H. , Kotb Rami , Jeffery Mark , Alcindor Thierry , Ng Siobhan , Salim Muhammad , Sabesan Sabe S. , Easaw Jacob C. , Shannon Jennifer Anne , El-Tahche Fabyolla , Walters Ian B. , Tu Dongsheng , O'Callaghan Christopher J. ,   the NCIC-CTG and the AGITG
Published: February 2017

542

Background: The CO.20 trial randomized pts with K-RAS WT chemotherapy refractory mCRC to receive CET + BRIV (Arm A) or CET + placebo (Arm B). Although overall survival (primary endpoint) was not significantly improved (HR=0.88, p=0.12) in this heavily pre-treated population, progression free survival (PFS) favoured Arm A (HR=0.72 p<0.0001).

Methods: Patients with K-RAS WT mCRC previously treated with or with contraindications to a fluoropyrimidine, irinotecan, and oxaliplatin were randomized to a loading dose of IV CET followed by weekly IV CET + BRIV 800 mg PO daily or CET + placebo daily. QoL, a secondary endpoint, was assessed using the EORTC QLQ-C30 at baseline and at 2, 4, 6, 8, 12, 16 and 24 weeks until progression or clinical deterioration. Co-primary QoL endpoints were defined a priori as definitive deterioration (first worsening from baseline of ≥10 points) on the physical function (PF) and Global scales. Time to QoL deterioration (DET) was measured from randomization using the Hochberg procedure to adjust for multiple testing.

Results: 721 (358 Arm A) of 750 randomized pts were assessable for QoL. QoL compliance did not differ by arm and declined in follow-up from 87% to 47% over time. Baseline Global and PF scores did not differ by arm. Median time to QoL DET was 1.6 vs 1.1 mo for Global (p=0.02) and 5.6 vs 1.7 mo. for PF (p<0.0001) in Arm B vs A, respectively. Secondary QoL response evaluation showed a greater proportion of patients on Arm A to have worsening on the PF (31 vs 17% at 6 wks) and cognitive functioning scales, and on the fatigue, nausea, appetite and diarrhea symptom scales. Clinical adverse events ≥ Grade 3 were more common on Arm A than B including fatigue (25 vs 10%), hypertension, rash, diarrhea, abdominal pain, dehydration and anorexia.

Conclusions: Despite a PFS benefit, the combination of CET + BRIV worsened time to QoL DET on the PF and Global scales of EORTC QLQ-C30 in pts with chemotherapy refractory K-RAS WT mCRC. This result may be due to higher rates of fatigue and gastrointestinal adverse events observed with the combination.
Exploratory analysis of adjuvant chemotherapy effects after preoperative chemoradiotherapy and radical resection for rectal cancer.
Authors: Park In Ja , Eng Cathy , You Y. Nancy , Kopetz Scott , Rodriguez-Bigas Miguel A. , Overman Michael J. , Skibber John Michael , Chang George J.
Published: February 2017

557

Background: Evidence regarding adjuvant chemotherapy (CTx) for patients with rectal cancer after preoperative chemoradiotherapy (CXRT) is limited. The aim of study was to explore the relationship between CXRT response and adjuvant CTx for patients with rectal cancer treated by CXRT and radical resection.

Methods: We performed a retrospective consecutive cohort study of patients with locally advanced (cStage II-III by EUS, CT, or MRI) rectal carcinoma treated with preoperative CXRT and radical resection, 1993 to 2008. To explore the late effects, we performed a landmark analysis of patients alive without recurrence at 24 months. The duration free from recurrence (FFR) was compared among patients with complete (CR, ypT0N0), intermediate (IR, ypT1-2N0), or poor (PR, ypT3-4 or N+) response according to adjuvant CTx use and type using multivariate Cox regression.

Results: A total of 725 patients met criteria and were evaluated. Median follow-up was 69 months (IQR: 39-104 months). 611 patients received adjuvant CTx: 447 with fluoropyrimidine only (FP), and 139 also received oxaliplatin (Ox). Although receipt of adjuvant chemotherapy was not associated with 5-year FFR overall, (HR: 0.91, 95% CI: 0.58-1.43), adjuvant therapy did appear to suggest a benefit in the IR group (HR, 0.49; 95%CI, 0.21-1.19). Adjusted landmark analysis showed that adjuvant CTx was associated with a significant improvement in FFR among the IR patients only (HR, 0.28; 95% CI, 0.08-1.00, P=.04). Among PR patients FP alone did not improve FFR (HR, 1.22; 95% CI, 0.7-2.12) but the addition of Ox was associated with a non-significant reversal in the direction of the effect (HR, 0.53; 95% CI, 0.16-1.79).

Conclusions: In this exploratory analysis, the addition of adjuvant FP CTx appeared to favorably affect the duration FFR only for patients with rectal cancer and intermediate response to CXRT followed by radical resection. These data support the investigation of the role for adjuvant fluoropyrimidine therapy among patients with CR or IR and oxaliplatin for PR patients.
Do patients with metastatic colorectal cancer (mCRC) with late relapse after curative surgery have a better survival?
Authors: Price Timothy Jay , Beeke Carol , Woodman Richard , Karapetis Christos Stelios , Kim Susan , Maddern Guy , Broadbridge Vy , Hakendorf Paul , Padbury Rob
Published: February 2017

558

Background: Patients who relapse after potentially curative surgery for CRC tend to relapse within 5 years, with the greatest risk said to be in the first 2 to 3 years post surgery. There is however a group of patients who relapse beyond 5 years post resection. This late relapsing group may have a different behaviour and prognosis.

Methods: A retrospective cohort study was perfomed to compare the characteristics and survival of relapsed patients with metachronous (m) mCRC. Patients were categorised into relapse at < 2yrs, 2-5 yrs and > 5yrs following their initial surgery. Univariate log-rank tests and and multivariate Cox regression was performed to determine whether time to relapse (TTR) and other factors were associated with overall survival (OS).

Results: Of 750 mmCRC, 56% percent relapsed at < 2yrs, 32.4% at 2-5yrs, and 11.6% at > 5yrs. Patient characteristics are summarised in the table. Median OS, from the time of diagnosis of the recurrence, was 17 mths, 24.8 mths, and 26.5 mths respectively. Age (HR = 1.01, 95% CI=1.005-1.02, p=0.003) and liver resection (HR = 0.2, 95% CI=0.1-0.3, p < 0.001) were significant independent predictors of OS. TTR was also significantly associated with OS (HR = 0.75, 95 % CI = 0.60-0.93 and HR = 0.73, 95% CI = 0.53-1.01 respectively for 2-5 yrs and > 5 yrs versus < 2yrs, p < 0.05). There was no significant difference in survival between patients that relapsed at 5 yrs or later compared to those who relapsed between 2 and 5 yrs (HR = 0.98, 95% CI = 0.69-1.38, p = 0.90).

Conclusions: TTR predicted shorter survival for mmCRC patients whose relapse occurred within 2 yrs. However, when comparing TTR 2-5 yrs and TTR > 5 yrs, there is no evidence that mmCRC patients with later relapse have a better prognosis.

[Table: see text]
Use of detailed pathologic characteristics of the primary colorectal tumor to predict outcome after hepatectomy for metastases.
Authors: Cardona Kenneth , D'Amico Francesco , Shia Jinru , Gönen Mithat , Weiser Martin R. , Paty Philip , Kingham T. Peter , Allen Peter J , DeMatteo Ronald P. , Fong Yuman , Jarnagin William R. , D'Angelica Michael Ian
Published: February 2017

559

Background: Outcome after hepatic resection for colorectal liver metastases (CRLM) is heterogeneous and accurate predictors of survival are lacking. The aim of our study was to analyze the prognostic relevance of pathologic details of the colorectal primary tumor in patients undergoing hepatic resection of CRLM.

Methods: Retrospective review of a prospective database identified patients who underwent potentially curative hepatic resection of CRLM. Clinicopathological variables were investigated and their association with outcome was analyzed.

Results: From 1997-2007, 1004 patients underwent hepatic resection for CRLM. The median follow-up for survivors was 59 months with a 5-year predicted survival of 47%. Ninety-two percent of patients received perioperative chemotherapy and 34% received adjuvant hepatic artery infusion chemotherapy. Univariate analysis identified 10 factors associated with poor survival. Three of these related to the pathology of the primary tumor: lymphovascular invasion (LVI, p<0.0001), perineural invasion (p=0.005), and degree of regional lymph node involvement (N0 vs N1 vs N2, p<0.0001). Multivariate analysis identified 7 factors associated with poor survival. Two of these related to the pathology of the primary tumor: LVI (HR 1.3, 95% CI 1.06-1.64, p=0.01) and degree of regional lymph node involvement where an increase in the number of metastatic regional lymph nodes from N1 (HR 1.3, 95% CI 1.04-1.69, p=0.02) to N2 (HR 1.7, 95% CI 1.27-2.21, p <0.0005) was associated with a reduced survival. LVI positive patients had a median survival of 48 months compared to 69 months for LVI negative patients (p<0.0001); moreover, patients who were LVI positive with N2 nodal disease had a reduced survival to 40 months compared to 74 months for patients who were LVI negative with no nodal disease (p<0.0001).

Conclusions: Resection of CLRM is associated with long-term survival. Pathologic details of the primary colorectal tumor, particularly LVI and the degree of lymph node involvement, are strong predictors of survival. Future biomarker studies should consider utilizing factors related to the primary colorectal tumor.
Meta-analysis of anti-VEGF class adverse events from three double-blind (Db) placebo (Pbo)-controlled phase III trials with IV aflibercept (Afl).
Authors: Allegra Carmen Joseph , Tabernero Josep , Rougier Philippe , Scagliotti Giorgio , Philip Philip Agop , Lakomy Radek , Ramlau Rodryg , Assadourian Sylvie , Chevalier Soazig , Van Cutsem Eric
Published: February 2017

561

Background: Three Db Pbo controlled studies were conducted with IV Afl in metastatic cancer patients [colorectal (CRC) Afl+FOLFIRI (WCGC 2011 abstract O-0024), lung (LC) Afl+docetaxel (WCLC 2011, abstract 511) and pancreatic (PC) Afl+gemcitabine (WCGC 2009 abstract O-0006)]. Each study used the same weekly Afl dose intensity (4 mg/kg q2w for CRC and PC; 6mg/kg q3w for LC). A safety meta-analysis of anti-VEGF class adverse events (AE) was performed on data from these studies.

Methods: A fixed-effect logistic regression model was used, including study, treatment and study-by-treatment interaction factors as covariates to test the consistency of treatment effect across studies for each of the considered AE. When no evidence of heterogeneity of treatment effects was found across studies, relative risks (RR) and 95% confidence intervals (CI) were estimated. Summary incidences (% of patients [pts]) and RR are presented for NCI grade 3-4 events.

Results: Safety data from total of 2,662 pts (Afl: 1,333; Pbo: 1,329) were included for analysis (Table). Among pts treated with Afl, 0.4 and 0.5% experienced grade 4 hypertension and nephrotic syndrome, respectively.

Conclusions: The addition of Afl to concurrent chemotherapies did not increase the risk of VTE. The risk of grade 3-4 anti-VEGF class AEs was increased when adding Afl to concurrent chemotherapies. This increased risk was statistically significant (**) only for hypertension, proteinuria and hemorrhage. Further analyses, when more data are available, should improve the precision of these results. Studies were sponsored by Sanofi NCT00561470 , NCT00532155 , and NCT00574275 .

[Table: see text]
FOCUS 3: A study to determine the feasibility of molecular selection of therapy using K-RAS, B-RAF, and topo-1 in patients with advanced colorectal cancer (ACRC).
Authors: Maughan Tim , Wilson Richard H. , Williams Geraint T , Seymour Matthew T. , Richman Susan D. , Quirke Philip , Pope Janet , Pope Malcolm , Parmar Mahesh , Nelson Annmarie , Meade Angela M. , Nichols Laura L , Jasani Bharat , Hodgkinson Elizabeth , Fisher David , Butler Rachel , Bridgewater John A. , Adams Richard A. , Kaplan Richard S.
Published: February 2017

563

Background: Molecular characteristics of cancer vary between individuals. In future increasing numbers of trials will require assessment of biomarkers in order to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The FOCUS 3 trial is a feasibility study to assess whether tumour samples could be collected from referring hospitals’ pathology departments, sent to designated reference laboratories for biomarker evaluation, and results provided to oncologists within 10 working days.

Methods: Patients with ACRC, fit for chemotherapy, were registered from 24 centres between 02.10 and 04.11. Following consent, paraffin embedded tumour samples were sent to Cardiff or Leeds for analysis of topoisomerase 1 (topo-1) by immunohistochemistry and of KRAS and BRAF mutation status, and results were forwarded to the MRC CTU. Patients were classified into 1 of 4 molecular strata, which determined the set of 2 hypothesis driven experimental therapies they could be randomised to in addition to control chemotherapy (irinotecan + 5FU). At this stage eligibility was reconfirmed and consent for randomisation obtained.

Results: 332 patients were registered to participate in FOCUS 3. Biomarker results were provided to oncologists within 10 working days (wd) in 71%, within 15 wd in 91% and within 20 wd in 99% patients. A 4 stage suite of patient information sheets (PIS) was designed and implemented to avoid patient overload; separate information sheets were provided to patients at stages during the consent process and patient understanding was assessed. 93% of eligible patients gave consent to randomisation. KRAS mutation was detected in 88 (36%), BRAF in 15 (6%), 2 patients had both mutations and 133 were double wildtype. 77% of patients were high (2-3), 19% low (0-1) and 4% inconclusive for topo-1. Tumour response and toxicity results for the 244 randomised patients will be presented.

Conclusions: Patient samples can be collected and analysed at designated reference laboratories within acceptable timeframes. Multi-arm designs can be made acceptable to patients through good PIS, ensured by patient and carer input into their design.
TJ-107 for the prevention of oxaliplatin-induced peripheral neuropathy: Results of a phase II randomized placebo-controlled clinical trial.
Authors: Kono Toru , Hata Taishi , Munemoto Yoshinori , Matsui Takanori , Kojima Hiroshi , Takemoto Hiroyoshi , Fukunaga Mutsumi , Shimada Mitsuo , Nagata Naoki , Morita Satoshi , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

567

Background: Oxaliplatin-induced peripheral neuropathy (OPN) continues to be a substantial problem for many cancer patients. In light of the promising data on TJ-107 from a previous pilot study (ASCO-GI, 2009), the present clinical trial was conducted to evaluate its efficacy for the prevention of OPN. To determine whether TJ-107 given as an adjuvant therapy effectively prevents oxaliplatin-induced peripheral neuropathy

Methods: A phase II, randomized, double-blind, placebo-controlled trial was conducted in colorectal cancer patients undergoing therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX). TJ-107 (7.5g) or matching placebo was orally administered three times daily. The primary endpoint was the incidence of grade 2 or greater OPN according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria after 8 cycles of chemotherapy. Patient-reported neurotoxicity symptoms were also assessed using the neurotoxicity subscale of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx, version 4). Secondary endpoints included the incidence of all grades of OPN after each cycle and chemotherapy response rates.

Results: A total of 93 patients were enrolled from May 1, 2009 to March 31, 2010 at 37 participating GONE trial institutions in Japan. Eighty-nine evaluable patients were randomized to either the TJ-107 group (n = 44) or the placebo group (n = 45). Placebo patients showed a significantly higher rate of neurotoxicity than that of TJ-107 patients (p < 0.001), with the median difference in NTX-12 score of 3 and 3.5 at the 8th week and 26th week, respectively. There were no significant between-group differences in response to chemotherapy (55.5% in TJ-107, 39.1% in placebo). In addition, TJ-107 treatment was well tolerated overall.

Conclusions: TJ-107 shows promise in reducing the incidence of OPN. Further investigation in a larger phase III trial is necessary before any conclusions can be drawn.

[Table: see text]
Systemic chemotherapy in the setting of unresectable appendiceal epithelial neoplasms (AEN).
Authors: Eng Cathy , Blackham Aaron Udell , Overman Michael J. , Fournier Keith F. , Royal Richard E. , Gajula Prianka , Levine Edward Allen , Wolff Robert A. , Mansfield Paul F.
Published: February 2017

568

Background: AEN is a malignancy including both indolent well-differentiated and highly aggressive signet ring carcinoma. Optimal therapy is believed to be cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet, some patients (pts) will recur, are suboptimal for surgery, and are considered for systemic chemotherapy (SC). The purpose of this study is to compare SC regimens in treatment-naïve surgically unresectable AEN pts. Currently, no standard exists.

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

Results: Of 659 pts with AEN diagnosis, 134 pts were evaluable for PFS and R. Forty-eight (36%) pts were poorly-differentiated; 29 (22%) signet ring; and 22 (16%) had both features. Thirty-four (25%) were well-differentiated. After a median follow-up of 35M, adjusting PFS for prior CRS, HIPEC, histology, ascites, and biologic therapy, pts who received 5-FU alone fared worse vs. FOLFOX [HR: 2.39; 95% CI: 1.2-4.6; p-value = 0.01]. FOLFIRI trended in favor of improved PFS, but was underpowered. No statistical difference in R was noted (Table).

Conclusions: In the treatment of surgically unresectable AEN, combination chemotherapy resulted in improved PFS vs. single agent 5-FU. Quality of life analysis will be reported at a later date. Randomized prospective analysis should be considered.

[Table: see text]
Use of MRI-defined tumor distance from the anal verge to predict tumor response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.
Authors: Yu Stanley Ka Tung , Brown Gina , Tait Diana M.
Published: February 2017

573

Background: Neoadjuvant Chemoradiotherapy (CRT) and surgical resection is the current standard management for patients with locally advanced rectal cancer (i.e. T3 or 4 N0/1 M0) (LARC). Tumour predictive factors for response to CRT in rectal cancer remain controversial. Staging investigations are not standardised and MRI has not been used consistently to approach this. The aim of this study is to investigate whether tumour distance from anal verge, as measured on MRI, is a predictive factor for response to CRT in LARC.

Methods: This is a retrospective study. Patients with LARC or low T2 N0/1 M0 rectal cancer (i.e. ≤ 5cm from anal verge measured by MRI) treated with preoperative CRT in 2003- 2009 were included. Pelvic MRIs acquired before CRT and no less than 4 weeks post CRT were reviewed. Patients with ypT0-2 in the resected specimen were classified as responders because ypT0-2 has been shown with significant OS and DFS benefit (Valentini V et al. Int J Radiat Oncol Biol Phys. 2002; 53(3): 664-74). Downstage of mrT2 low rectal cancer was defined as ypT0-1 post CRT. Univariate binary logistic regression (UBLR) was used to analyse the predictor associated between responders and non-responders to CRT treated in the same period of time.

Results: 281 patients with LARC who underwent CRT were included in the study. 96% patients in this study had T3/T4 LARC and 4% had T2 low rectal cancer. 114 (41%) were responders as defined above, 167 (59%) were non-responders to CRT. The mean MRI defined tumour distance from anal verge was significantly less in responders (6.4cm [Confidence Intervals (CI) = 5.7 -7.1]) when compared with non-responders (7.9cm [CI =7.3 – 8.6]) (P<0.05).

Conclusions: The UBLR analysis from our study indicated that an MRI measured tumour distance of ≤ 5cm from the anal verge independently predicted higher tumour downstaging rate (p < 0.001) to CRT in LARC. Further investigation is recommended regarding tumour downstaging and sphincter preserving surgical resection rate in low rectal cancer post neoadjuvant CRT.

[Table: see text]
Liver transplantation (Ltx) in patients with nonresectable liver metastases from colorectal carcinoma.
Authors: Dueland Svein , Hagness Morten , Line Pal-Dag , Scholz Tim , Jorgensen P. , Fosby Bjarte , Mathisen Ostein , Gladhaug Ivar , Foss Aksel
Published: February 2017

577

Background: Liver resection is considered the only curative treatment of liver metastases (mets) from colo-rectal (CRC) tumors. Ltx is standard of care in selected patients with hepatocellular carcinoma, cholangiocarcinoma and neuroendocrine tumors. Patients with non-resectable liver metastases (mets) from colo-rectal cancer (CRC) receiving palliative chemotherapy have a median survival of about 2 and 1 year from start of 1. and 2. line chemotherapy, respectively. Overall 5 years survival in CRC patients after start of palliative chemotherapy is about 5-10%. In this study we examined overall survival after Ltx in selected CRC patients. The primary endpoint of the study was overall survival at 2 years after Ltx

Methods: Major inclusion criteria were: non-resectable liver mets, no extra hepatic disease or local relapse determined by PET/CT scan, CT- or MRI scan and colonoscopy. No mets. on frozen section biopsies at time of surgery, ECOG 0-1, at least one line of chemotherapy for metastatic disease. Postoperative immunosuppresion: mTOR inhibitor (Rapamune), mycofpenolmofetil and tapering doses of prednisolon. Quality of life questionnaire (EORTC-C30) pre Ltx, 3, 6 and 12 months post Ltx.

Results: Thirteen men and 8 women with non-resectable liver only CRC liver mets received Ltx in the period of Nov 2006 to March 2011. Median age was 56 years (range 45-65 years). Thirteen patients had colon cancer and 8 patients had rectal cancer. The T-stage of the primary tumor was T2,T3 and T4 in 2, 16 and 3 patients, respectively. N status of the primary tumor was: pN0, pN1 and pN2 all 7 patients. Nine patients had received 1.line chemotherapy and 12 patients had received 2. or 3.line therapy. The median number of liver mets was 8 (range 2-40) and the median size of the largest lesion was 4.5cm (range 2.8-13cm). The patients had good, stabile or increased Global Health Score and Physical Function at all time points after Ltx. Fifteen patients with follow-up of 2 years or more or death within 2 years of Ltx had 2 years overall survival of 87%.

Conclusions: Long term survival is obtained after Ltx in selected patients with non-resectable liver mets from CRC. The patients reported good quality of life and physical function after Ltx.
Does phase I radiotherapy dose of 30.6Gy in 17 fractions provide adequate microscopic nodal disease control in squamous cell carcinoma of the anus?
Authors: Augustin Yolanda Sydney , Tait Diana M. , Hawkins Maria
Published: February 2017

588

Background: Definitive chemoradiation has been established as the standard of care for patients with squamous cell carcinoma of the anus. The ACT II study recommends 30.6Gy in 17 fractions for Phase I to the lower pelvis with a superior border 2 cm above the inferior aspect of the sacro-illiac joints, then a Phase II boost of 19.8Gy in 11 fractions to the tumor and involved nodes. Our goal was to retrospectively evaluate patterns of failure in the volumes that received microscopic dose 30.6Gy.

Methods: Between January 2002 and December 2008, 106 patients with non-metastatic squamous cell carcinoma of the anus were treated with definitive chemoradiation. 81 (76.45%) of these patients received Phase I dose of 30.6Gy.The tumor stage was Tx or T1 in 18 % , T2 in 36% , T3 in 29%, and T4 in 12% of patients. The nodal stage was N0 in 57%, N1 in 13%, N2 in 14% and N3 in 11% of patients. The median radiotherapy dose was 50.4 Gy (range 50.4Gy -60 Gy). Concurrent chemotherapy was given with 5-fluorouracil (5-FU) and cisplatin in 12%, 5-FU and mitomycin C in 34%, capecitabine and mitomycin C in 38% and other regimens in 8% of patients. The median follow-up interval was 43 months (range 3.2 - 112.9 months).

Results: A total of 21 patients (19.8%) experienced persistent or progressive disease during follow up. Out of this total, 16 patients received 30.6Gy in Phase I. Of these, 5 patients (4.7%) had persistent disease at the end of chemo-radiation, 4 patients (3.7%) relapsed in the anal region, 2 patients (2.4%) relapsed in the 30.6Gy area and 5 patients (6.2%) developed metastases. 8 patients with local recurrence/persistent disease underwent salvage surgery. Estimated 3 year rates for locoregional control and overall survival were 78% and 82% respectively.

Conclusions: The majority of locoregional failures involve the anus and mesorectum, while nodal recurrence occurs rarely supporting the use of 30.6Gy for microscopic nodal disease control. This makes the case for dose escalation of primary tumours in Phase II. Placing the superior border of the radiotherapy field at 2 cm above inferior sacroiliac joints for phase I could potentially spare bone marrow and small bowel toxicity with minimal risk of nodal relapse.
Prognostic factors for long-term overall survival (OS) for patients (pts) undergoing first-line treatment for metastatic colorectal cancer (mCRC) with chemotherapy (CT) plus bevacizumab (bev): Findings from a large observational study.
Authors: Arnold Dirk , Grothe Wilfried , Tummes Dirk , Kindler Manfred , Petersen Volker , Boszeit-Luft Stefanie , Seraphin Joerg , Kutscheidt Andreas
Published: February 2017

590

Background: Bev+CT has been shown to improve OS vs. CT alone in phase III and IV mCRC studies. However, as only a subset of pts experience OS >30 months (m), clinical factors may help to identify pt groups with the largest potential benefit.

Methods: This large observational study included pts receiving bev with various first-line CT regimens in Germany from 2005–2009, with predefined assessment of OS, progression free survival (PFS), toxicity and 22 baseline variables, including pt characteristics, pre-treatment duration/procedures, blood parameters, tumour characteristics. Pts with long-term OS (defined as OS >30m) were compared to those with OS <30m. Surviving pts with observations <30m were defined as ‘censored’. Association between variables and OS was explored by univariate analyses and then multivariate analysis (logistic regression) to find independent variables for long-term OS.

Results: 392 (22%) out of 1777 eligible pts had OS >30m (195 events, median OS 46.8m), 717 pts (40%) had OS <30m (median OS 14.3m), and 688 (38%) pts were censored. Median PFS was 17.7m (329 events) for pts with OS >30m, 7.7m for pts with OS <30m, and 11.8m (313 events) for censored pts. In the univariate analysis, nine variables were associated with OS >30m: age (continuous variable; p=0.0008), ECOG PS (0 vs. 1–4; p=0.0025), WBC <8.0/nL (p=0.013), CEA <20ng/mL(p<0.0001), single metastatic site (p<0.0001), initial pT4 vs. others (p<0.0001), pN0 vs. pN1/2 (p=0.0002), initial M0 vs. M1 (p=0.0021), grading G1/2 vs. G3/4 (p<0.0001). Independent variables for pts with OS <30m were found in the multivariate analysis.

Conclusions: In general, the prognostic factors identifying long-term survivors in the CT only era are confirmed in this large cohort with bev treatment. However, the predominant role of grading and CEA level are remarkable.

[Table: see text]
A phase II study of neoadjuvant chemotherapy with bevacizumab plus mFOLFOX6 for resectable synchronous liver metastasis (SLM) from colorectal cancer: The first report of the Miyagi Hepato-Biliary Pancreatic Clinical Oncology Group.
Authors: Katayose Yu , Yamauchi Junichiro , Oikawa Masaya , Sakurai Naoki , Musya Hiroaki , Shimamura Hiromune , Miura Koh , Nakagawa Kei , Egawa Shinichi , Unno Michiaki ,   Miyagi-HBPCOG
Published: February 2017

593

Background: The prognosis of synchronous liver metastases (SLM) from colorectal cancer is poor. Therefore, we conducted a phase II study of neoadjuvant chemotherapy for SLM to determine the appropriate initial treatment. Here, we assessed the effectiveness of bevacizumab combined with mFOLFOX6.

Methods: Patients with SLM within 10 nodules were enrolled after R0-resection of the primary colorectal cancer, and received 8 courses of mFOLFOX6 with bevacizumab (the first and last courses were mFOLFOX6 only). The primary endpoint was response rate (RR).

Results: Between June 2008, and November 2008, 47 patients (pts) were enrolled from 17 centers. The median age was 62 years (range 32-72 yrs). The median number of metastases was 2 nodules. Three pts were excluded from evaluation of RR because they did not receive any scheduled chemotherapy. The RR was 70.5% (2 complete responses and 29 partial responses). 11 pts (25%) showed stable disease and 2 pts (4.5%) had progressive disease. The liver resections rate was 90.9% (40 pts) and the R0-resection rate was 86.3%(38 pts). Adverse events in order of prevalence were sensory neuropathy, neutropenia, hypertension, leucopenia and so on. Grade 3 and 4 AEs occurred in 21 pts with the most common being Neutropenia. There were 3 Grade 4 AEs: renal failure and 2 pts of neutropenia. Grade 3 or 4 AEs are summarized below. There were no grade 5 AEs. Of note, liver resections were safely performed in the three pts with Grade 4 AEs.

Conclusions: Neoadjuvant chemotherapy with bevacizumab plus mFOLFOX6 for liver metastases is effective and well tolerated. The benefit of this therapy as the initial treatment of SLMneeds to be evaluated further by comparison with adjuvant therapy. (This trial is on University hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR). UMIN's unique trial number is UMIN000001568.)

[Table: see text]
Phase II study of S-1 plus leucovorin (a new 1-week treatment regimen followed by a 1-week rest period) in patients with untreated metastatic colorectal cancer in Japan and China.
Authors: Denda Tadamichi , Li Jin , Xu Ruihua , Xu Jianming , Ikejiri Koji , Shen Lin , Toh Yasushi , Shimada Ken , Kato Takeshi , Baba Hideo
Published: February 2017

598

Background: The previous phase II study of the oral S-1 plus oral Leucovorin (LV) (2 weeks’ treatment regimen followed by a 2 week rest period) for patients (pts) with untreated metastatic colorectal cancer (mCRC) have shown to be effective, but the grade 3 toxicities (diarrhea, stomatitis, and anorexia) were observed with relatively high frequency. In this phase II study, we tried to improve the administration schedule of S-1 plus LV regimens for well-tolerated toxicities and evaluated the efficacy.

Methods: Pts were eligible as follows: histologically confirmed adenocarcinoma, age≥20, ECOG PS 0-1, no prior chemotherapy, at least one measurable lesion by RECIST ver1.0 criteria, adequate organ function, and written informed consent. S-1 (40-60 mg bid) and LV (25 mg bid) were orally administered for 1 week, followed by an 1 week rest period. Treatment was repeated until the onset of disease progression or unacceptable adverse events occurred. The primary endpoint was the response rate (RR), and the secondary endpoints were efficacy and safety.

Results: From October 2008 to June 2009, 73 pts were enrolled in Japan and China. Of the eligible 71 pts, median age was 60 (range 27-84), Male/Female was 38/33, PS:0/1 was 39/32, and Japan/China was 32/39. RR as primary endpoint was 53.5% (95% CI, 41.3-65.5), and Disease Control Rate was 83.1%. With a median follow-up period of 26.4 months, the median Progression Free Survival was 6.5 months. Median Overall Survival was 24.3 months with the survival rate of 77.5 % at 1 year and 53.2 % at 2 years. The incidences of grade 3 adverse drug reactions were diarrhea 8.3 %, stomatitis 8.3%, anorexia 2.8%, neutropenia 9.7%, and there was no treatment-related death.

Conclusions: The newly improved 1 week S-1 plus LV treatment regimen showed good efficacy and better tolerability than the 2 weeks’ treatment regimen. This therapy showed promising activity in pts with untreated mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs. This trial was supported by Taiho Pharmaceutical CO., LTD. ClinicalTrials.gov Identifier: NCT00891332 .
Phase II study alternating mFOLFOX 6 and FOLFIRI (FIREFOX) plus bevacizumab (bev) regimen in first-line treatment of advanced colorectal cancer in Japanese patients (KSCC 0801).
Authors: Ogata Yutaka , Akagi Yoshito , Kakeji Yoshihiro , Emi Yasunori , Oki Eiji , Saeki Hiroshi , Touyama Tetsuo , Samura Hironori , Baba Hideo , Natsugoe Shoji , Shirouzu Kazuo , Tokunaga Shoji , Maehara Yoshihiko ,   Kyushu Study Group of Clinical Cancer
Published: February 2017

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Background: The Kyushu Study group of Clinical Cancer conducted a phase II study that evaluated the FIREFOX regimen. (KSCC0701, Akagi et al, J Clin Oncol 28:15s, 2010). This study demonstrated the efficacy and mild neurotoxicity of this regimen. The present study evaluated the efficacy and safety of the FIREFOX plus bevacizumab (bev).

Methods: Eligibility criteria included histologically confirmed advanced colorectal cancer, ECOG PS 0-2 and adequate bone marrow, renal and hepatic function. Patients (pts) received an alternating regimen of 4 cycles of mFOLFOX-6 plus bev (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bev 5 mg/kg d1 followed by 400 mg/m2 bolus 5-FU and a 46-hr 2,400 mg/m2 5-FU infusion every 2 weeks) followed by 4 cycles of FOLFIRI plus bev (oxaliplatin replaced with irinotecan 150 mg/m2 d1). This schedule was repeated until unacceptable toxicity or disease progression occurred. The primary endpoint is progression-free survival. (UMIN000001312)

Results: Of the 52 pts enrolled from May 2008 to July 2009. Two of the patients did not fulfill the eligibility criteria. M/F, 30/20; median age, 59.5 years (range 37 - 75); ECOG PS 0/1/2, 46/4/0. The median number of administration cycles was 14 (range, 2 - 44). Response rate (RECIST criteria) for CR, PR, SD, PD and NE were 2 (4%), 28 (56%), 14 (28%), 4 (8%) and 2 (4%), respectively. An overall response rate was 60% (95% CI: 45 - 74%). Median progression-free survival was14.2 M (95% CI: 10.6 M-16.3 M) and median overall survival was 27.5 M (95% CI; 22.4 M – not determined). The 2-year survival rate was 56.8%. Of the 52 pts evaluated for toxicity. The most common grade 3-4 adverse events were leukopenia (7.7%), neutropenia (32.7%), anemia (1.9%), fatigue (9.6%), anorexia (13.5%), stomatitis (3.8%), neurotoxicity (3.8%), hypertension (1.9%), diarrhea (7.7%), febrile neutropenia (3.8%), nausea (9.6%), vomiting (5.8%), hypersensitivity (3.8%), and thromboembolism (1.9%).

Conclusions: The results of this phase II study show that the FIREFOX plus bev regimen is effective and well tolerated in the first-line treatment of advanced colorectal cancer. The low rate of neurotoxicity is also promising.
Cohort study evaluating the impact of a discharge letter (DL) compared with usual care on adherence to surveillance following treatment for stage II/III colorectal cancer (CRC).
Authors: Davies Janine Marie , Batuyong Eugene , Lupichuk Sasha M. , Hilsden Robert , Eliasziw Misha , Easaw Jacob C.
Published: February 2017

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Background: The 2005 ASCO guidelines recommend surveillance testing and frequencies following surgical +/− adjuvant therapy for stage II/III CRC. In Canada, many patients are discharged from their oncologist to their primary care physician (PCP) for ongoing surveillance. However, adherence to surveillance recommendations is low. This cohort study evaluated adherence to surveillance 1 year after treatment of stage II/III CRC prior to and following implementation of a DL.

Methods: Cohort 1 (C1) patients were retrospectively identified from the Alberta Cancer Registry following adjuvant therapy (as applicable) at a tertiary cancer centre (07/2006 - 09/2007). Cohort 2 (C2) patients were prospectively identified from the Registry and clinic records following adjuvant therapy (as applicable), as those discharged from the centre (10/2007 - 4/2009); DL was sent to the patient and PCP recommending surveillance tests and dates. Clinical, laboratory, diagnostic imaging, and endoscopy data was collated. Adherence at 1 year follow-up was compared between cohorts using Kaplan-Meier time-to-event analyses.

Results: C1 (n=218) was larger than C2 (n=114) despite the longer accrual time for C2. There were no differences between cohorts by age, sex, primary site of disease, stage, or adjuvant oxaliplatin use. During year 1 of follow-up, 11.8% and 11.4% recurred (local or metastatic) and 6.5% and 2.7% died (p=0.1) in C1 and C2 respectively. Comparing C1 with C2, 14.8% vs. 23.0% of patients had one CEA test within 3 months, 45.2% vs. 72.2% within 6 months, and 71.7% vs. 85.1% within 1 year (p<0.001). Only 44.0% (C1) and 68.6% (C2) had 2 CEA tests within 1 year. Only 3.9% (C1) vs. 6.6% (C2) of patients had 4 CEA tests within the year following treatment as recommended. The rate of CT imaging was 32.3% (C1) and 56.1% (C2); endoscopy was 36.7% (C1) and 42.1% (C2).

Conclusions: Implementation of a DL improved compliance with surveillance at 1 year of follow-up following discharge from a tertiary cancer centre, although optimal adherence remains low. However, adherence to CT imaging nearly doubled. Evaluation of compliance at 3 years of follow-up is ongoing.
Phase I trial of yttrium 90 resin microspheres in the treatment of colon cancer liver metastases progressing despite hepatic arterial as well as systemic chemotherapy: Preliminary results.
Authors: Sofocleous Constantinos T , Kemeny Nancy E. , Pandit-Taskar Neeta , Do Kinh Gian , Brody Lynn A , Garcia Alessandra R , Capanu Marinela , Chou Joanne F. , Petre Elena N , Carrasquillo Jorge A.
Published: February 2017

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Background: Prospective evaluation of the safety of Selective Interval Radiation Therapy (SIRT) using yttrium 90 microspheres (Y90) in patients with colon cancer liver metastases (CLM) who failed hepatic arterial (pump) and systemic chemotherapy.

Methods: This prospective single center study, assessed the safety, dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) of Y90 in a selected, heavily pretreated population. Upon IRB and FDA approval individualized Y90 doses were calculated according to a volumetric method and the body surface area (BSA) method as instructed by the company. SIRT treatment was administered in three escalating dose levels (cohorts): the first cohort received 70%, the second 85%, and the third 100% of the calculated dose. All patients received chemotherapy as deemed by the patients' medical oncologist post SIRT treatment. DLT was defined as new, post treatment, grade 3 toxicities, and evaluated according to the NCI Common Toxicity Criteria (NCI-CTC) 3.0. Response to treatment was evaluated by imaging (using a combination of WHO, RECIST, modified RECIST and SUV changes) and CEA levels. Kaplan Meier methodology was employed to calculate Progression Free (PFS) and Overall (OS) Survival.

Results: From September 2009-2011, 19 patients received Y90. Common complaints post treatments were: grade 1-2 fatigue and grade 1 fever, which are known side effects of SIRT. No DLTs were observed. Grade 3 hyperbilirubinemia was recorded for two patients and was attributed to progressive disease; one patient in the third cohort suffered grade 3 nausea and pain. Twelve patients (70.6%) responded (defined as stable disease or better) while five (29.4%) progressed-this was based on evaluations from initial post treatment imaging. Two patients’ imaging is pending. Median PFS and OS were 6 [95%CI: 3.2-9.7] and 16 [95%CI: 5.8-17.6] months respectively.

Conclusions: It is safe to administer the entire dose of Y90 in patients with CLM who progressed despite prior pump and systemic chemotherapy. Oncologic outcomes are promising.
Use of genetic variants of LMTK3 to predict tumor recurrence in female localized gastric adenocarcinoma.
Authors: Wakatsuki Takeru , Bohanes Pierre Oliver , Zhang Wu , Gerger Armin , Yang Dongyun , Ning Yan , Winder Thomas , Labonte Melissa Janae , Wilson Peter M.D. , Benhaim Leonor , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef
Published: February 2017

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Background: Previous study suggests that high basal Lemur Tyrosine Kinase 3 (LMTK3) expression was associated with advanced stage of primary breast cancers as well as decreased overall and disease-free survival. LMTK3 was also found overexpressed in gastric cancer. Our previous data showed the mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR) in colon cancer (CC). We hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in a cohort of localized gastric cancer patients.

Methods: Either blood or FFPE tissue specimens obtained from 137 localized (stage Ib-IV) GA patients (54 females and 83 males) were included in this study. All patients were treated with surgery alone or surgery and adjuvant (radio)-chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC), the Los Angeles County/University of Southern California Medical Center, or the Memorial Sloan-Kettering Cancer Center from 1992 to 2008. The median follow-up was 3.3 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR.

Results: LMTK3 rs9989661 was significantly associated with TTR in females GA patients. Female patients with minor C allele (TC or CC) (n=25) of LMTK3 rs9989661 showed significantly longer median TTR=7.0 (95%CI: 2.1-8.3+) years compared to those harboring homozygous TT genotype. (n=28), TTR=1.7 (95%CI: 0.7-7.0+) years.( log-rank p=0.025; univariate analysis). After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.14, 95%CI: 0.02-0.94, multivariate Wald p value = 0.043 in the dominant model). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders.

Conclusions: This pilot study demonstrating LMTK3 rs9989661 may be potential molecular marker to predict TTR in female localized GA. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.
Determinants of bile acids.
Authors: LaFleur Bonnie , Tong Weiqun , Liu Junmei , Lance M Peter , Thompson Patricia
Published: February 2017

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Background: Several epidemiological studies have demonstrated an association between bile acids (BA) and colorectal cancer. Despite this evidence, there are limited studies that examine the determinants of bile acids in humans. We conducted a secondary, cross-sectional analysis on 735 adenoma formers from a phase III adenoma prevention trial of ursodeoxycholic acid (URSO) who provided a fecal sample at their baseline visit.

Methods: Fecal measures of primary bile acids cholic acid (CA) and chenodoxycholic acid (CDCA), as well as secondary bile acids, deoxycholic acid (DCA), lithocholic (LCA) were the outcome variables of interest. Dietary, non-dietary, medication use, genetic variation in the CYP7A1 gene (as single nucleotide polymorphisms (SNPs) and haplotypes), and physical activity, and characteristics of baseline adenoma were evaluated as correlates of fecal BAs. We used maximum likelihood methods to incorporate left-censoring in the BAs that had concentrations below the detection limit (BDL). These log-normal parametric survival models were used to fit potential predictors of fecal BA levels, stratifying by sex. The Akaike information criterion (AIC) was used to choose the best predictive model from each BA outcome. Model accuracy was assessed using leave-one-out cross validation and a likelihood-based measure of R2 and the Brier score.

Results: LDL and cholesterol were predictors for primary bile acid CDCA in men and women, as was the use of pain medication (use of medication lowered BA levels). Genetic variation in CYP7A1 (as haplotypes and individual SNP's) was a significant determinant of CA level in both men and women. BMI was an important predictor for both men and women for DCA and CA. Presentation with tubular-villous histology was associated with LCA levels whereas proximal adenoma was an important predictor for CA levels, in men and women.

Conclusions: This secondary analysis of a uniquely large dataset validates previous studies that suggest lifestyle and genetic factors influence colonic exposure to carcinogenic BAs. These findings also importantly highlight gender-specific differences in BA determinants that may explain colorectal cancer incidence differences between men and women.
IMPACT study: A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcincoma.
Authors: Tschaika Marina , Schmoll Hans-Joachim , Riera-Knorrenschild Jorge , Nitsche Dieter , Trojan Jorg , Kröning H. , Maiwirth Fritz Albert , Reiser Marcel , Schroff Matthias , Weith Ekaterina , Schmidt Manuel , Wittig Burghardt
Published: February 2017

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Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III study was initiated in patients with advanced CRC having disease control after first-line therapy. The objective of the study is to assess efficacy and safety of the MGN1703 treatment in comparison to placebo.

Methods: The IMPACT study is designed as a randomized double-blind placebo-controlled phase II-III study, which is conducted in patients with advanced CRC showing disease control after first-line therapy with standard chemotherapy regimen. The treatment is administered subcutaneously twice weekly in a ratio 2:1 (60 mg MGN1703 or placebo). The study is conducted in Germany, Austria, France, UK, Czech Republic and Russia, and 129 patients will be recruited into the study. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment will be continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent.

Results: The majority of adverse events were assessed as not drug-related by the investigator. The remaining AEs include mild night sweat (not assessable), mild fever (at three occasions, possible related), and mild arthralgia (certain related) in one patient each. Three SAE have been reported so far of which one was assessed as probably drug-related – atypical pneumonia. Only in single patients local reactions such as mild redness and swelling at injection site were reported. No laboratory or clinical signs of autoimmunity or dose-limiting toxicities were reported, so far.

Conclusions: With these preliminary safety results of the ongoing clinical study in patients with advanced CRC it could be shown that ttreatment with MGN1703 at the dosage of 60 mg is well tolerated and safe. Reported adverse events assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs. These events were not accompanied by any signs of autoimmunity.