bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of a 12-gene assay on treatment recommendations in patients with stage II colon cancer.
Authors: Srivastava Geetika , Renfro Lindsay Anne , Behrens Robert J. , Lopatin Margarita , Chao Calvin , Soori Gamini S. , Dakhil Shaker R. , Mowat Rex Bradford , Kuebler J. Phillip , Kim George P. , Mazurczak Miroslaw , Lee Mark , Alberts Steven R.
Published: February 2017

453

Background: A 12-gene assay (Oncotype DX Colon Cancer) has been clinically validated as a predictor of recurrence risk in stage 2 colon cancer patients following surgery. We conducted the first prospective study to characterize the impact of Recurrence Score results on medical oncologists’ recommendations regarding adjuvant chemotherapy in T3, Mismatch Repair-proficient (MMR-P) stage 2 colon cancer patients. Methods: Consecutive patients with resected stage 2A colon cancer who were candidates for adjuvant chemotherapy were consented and enrolled by 105 medical oncologists from 17 sites in the Mayo Clinic Cancer Research Consortium. Each patient’s tumor specimen was assessed by the Recurrence Score test (quantitative RT-PCR) and MMR (IHC). Prior to and after receiving these results, physicians completed surveys indicating their planned treatments given hypothetical or known MMR results, recorded as Observation (Obs), 5FU-based chemotherapy (5FU), or 5FU + Oxaliplatin (Oxal). Change in treatment recommendation intensity from baseline to follow-up was defined as: increased if change from Obs to 5FU +/- Oxal or from 5FU to 5FU+Oxal, decreased if change from 5FU + Oxal to 5FU or Obs, or from 5FU to Obs, or no change. Results: 187 of 221 patients enrolled were evaluable including 141 who were MMR-P (avg age 63, 65% ECOG PS 0, med tumor size 5 cm, 11% high grade, 91% with 12+ nodes examined). In the primary analysis treatment recommendations changed for 63 (45%) of 141 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy (5-FU +/- Oxal) decreased from 73 (52%) patients pre-assay to 42 (30%) post-assay. Increased treatment intensity was more likely at higher Recurrence Score values and decreased intensity at lower Recurrence Score values (p=0.011), and any change was more likely when MMR status was unknown at baseline (p = 0.041). Conclusions: In this prospective study, quantitative recurrence risk information provided by the Recurrence Score test was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients. Use of the 12-gene assay may lead to overall reductions in chemotherapy.
The role of miRNA-145 in esophageal adenocarcinoma.
Authors: Derouet Mathieu Francois , Ko Michael Augustine , Waddell Thomas K. , Liu Geoffrey , Darling Gail
Published: February 2017

46

Background: Carcinoma of the esophagus has become one of the fastest growing solid tumors in the world over the past 20 years and the 6th most common cause of death in the world. We previously conducted a study to profile the expression of miRNAs in esophageal adenocarcinoma (EAC) pre and post induction therapy. Out of the miRNAs discovered, miR-145, a known tumor suppressor miRNA, was upregulated 8-fold upon induction therapy however its expression was associated with shorter disease-free survival. This unexpected result was explored. Methods: In order to study the role of miR-145 in EAC, miRNA-145 was overexpressed in the EAC cell line OE33 (OE33 miR145). After validation of the expression of miR-145, several hallmarks of cancer such as cell proliferation, resistance to apoptosis and cell adhesion were analyzed. Results: There was no difference in cell proliferation and resistance to radiation between OE33 miR145 and OE33 control. However, there was a significant difference in cell adhesion. OE33 miR145 cells reattach faster than the OE33 control (72.3% cells reattached against 40.5% cells reattached after 3h, n=3, p<0.05). Furthermore, OE33 miR145 cells are able to recover better than OE33 control cells after 72 hours culture in suspension (126.5 colonies against 63.5 colonies after 5 days of culture, n=2, p<0.05). Conclusions: While there was no difference between the two OE33 populations in an attached state, clear differences appeared when cells were in a detached state. Although more work is required to confirm this effect, expression of miR-145 could help EAC cells in circulation by protecting them against apoptosis and helping them to reattach faster which could in turn facilitate distant metastasis.
Racial inequality with radiation oncology referral and treatment in metastatic colorectal cancer.
Authors: Murphy James Don , Le Quynh-Thu
Published: February 2017

470

Background: Black patients with colorectal cancer have worse outcomes compared to white patients, however the underlying source of this racial disparity remains unclear. This population-based study evaluates the impact of race on referral patterns and subsequent treatment with chemotherapy or radiotherapy in metastatic colorectal cancer. Methods: This study used the Surveillance, Epidemiology, and End Results–Medicare linked database to identify 11,125 patients with stage IV colorectal cancer diagnosed between 2000-2007. Patient demographic data were abstracted from the SEER database, and referral and treatment information were derived from Medicare claims data. Multivariate logistic regression models determined the impact of race on 1) consultation patterns with medical oncology and radiation oncology, and 2) subsequent treatment with chemotherapy and radiation therapy. Results are presented as adjusted odds ratios (OR) that control for potential confounding factors including age, comorbidity, socioeconomic status, geography, gender, marital status, and year of diagnosis. Results: Of the entire patient cohort, 2,025 (18%) were seen in consultation by a radiation oncologist, and among these patients, 1,221 (60%) ultimately received radiotherapy. Black patients had significantly lower rates of consultation with a radiation oncologist compared to white patients (OR=0.79, 95% CI=0.65-0.96; p=0.016). Among patients with a radiation oncology consultation, fewer black patients were subsequently treated with radiotherapy (OR=0.67, 95% CI=0.46-0.99; p=0.046). There was no difference between black and white patients in time from diagnosis to radiation treatment, and no difference in radiation treatment duration. We found no race-related difference in medical oncology consultation rates (p=0.24), nor in subsequent treatment with chemotherapy (p=0.95). Conclusions: This study shows racial disparity in radiation oncology consultation rates, and in radiation therapy treatment. Further research evaluating these barriers to care will help us achieve equality in treatment of metastatic colorectal cancer.
Survival trends of 89,543 patients with metastatic colorectal cancer: A population-based analysis.
Authors: Guller Ulrich , Tarantino Ignazio , Castleberry Anthony W. , Brugger Lukas , Koeberle Dieter , Cerny Thomas , Pietrobon Ricardo , Mantyh Christopher , Worni Mathias
Published: February 2017

476

Background: Metastatic colorectal cancer remains among the most common causes for cancer death and is a major public health problem. While overall survival improvements have been achieved in clinical trials, it is unknown how much this progress translated into increased survival on a population-based level. Methods: The SEER (Surveillance Epidemiology and End Results) registry was queried from 1988 to 2008. Patients with metastatic colorectal cancer were included. Multivariable adjusted Cox proportional hazards regression analyses were used. Results: In total, 89,543 patients were included. Median age was 67.1 years, 47.2% were female, 79.7% Caucasian. Median overall survival was 11 months, which increased from 8 months in 1988 to 14 months in 2008 (75% increase). In patients <= 65 years, overall survival increased from 9 months in 1988 to 20 months in 2008 (122% increase), in patients above 65 years from 7 months in 1988 to 9 months in 2008 (29% increase). In Cox proportional analyses, later year of treatment (hazard ratio=HR: 0.973 per year [95% CI: 0.972-0.975], p<0.001), tumor location in the rectum (HR: 0.72 [95% CI: 0.71 - 0.74]; p<0.001), married civil status (HR: 0.85, [95% CI: 0.84 - 0.86]; p<0.001), and cancer-directed surgery (HR: 0.44, [95% CI: 0.43 – 0.45]; p<0.001) were associated with better overall survival, while patients above 65 years (HR: 1.48, [95% CI: 1.46 - 1.51]; p<0.001) and African-Americans (HR: 1.08, [95%CI: 1.06 - 1.11], p<0.001) had worse survival. Conclusions: Tumor location in the rectum, married civil status and cancer-directed surgery are associated with significantly improved overall survival while elderly and African-Americans have worse outcomes. Moreover, a statistically significant and clinically relevant overall survival increase from 1988 to 2008 was found for metastatic colorectal cancer patients. However, most progress is observed in patients aged below 65 years, while the overall survival increase in the elderly is modest. Further studies among elderly patients assessing the reasons for the lack of a parallel survival increase are warranted.
Is adjuvant oxaliplatin (Ox) overutilized in colon cancer (CC)? 408 cases from the practices of 102 oncologists.
Authors: Love Neil , Grothey Axel , Venook Alan Paul , Hussein Atif Mahmoud , Moss Jonathan , Ziel Kathryn
Published: February 2017

479

Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox. (O’Connell ASCO 2012) In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: US-based oncologists were recruited to complete a survey and contribute treatment data for their last 3 patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the 2 groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed extensively in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]
Natural history and outcomes in a population-based cohort of synchronous and metachronous colorectal cancers (CRC).
Authors: Chu Jackson , Goktepe Ozge , Cheung Winson Y.
Published: February 2017

485

Background: Early data suggest that synchronous and metachronous CRC may portend a worse prognosis when compared to solitary CRC. Our study objectives were to 1) characterize the clinical features and treatment patterns of synchronous and metachronous CRC and 2) compare their survival outcomes with those of solitary CRC. Methods: All patients diagnosed with either synchronous or metachronous CRC between 1999 and 2008 and referred to 1 of 5 regional cancer centers in British Columbia were reviewed. Synchronous and metachronous CRC were defined as multiple (2 or more) distinct tumors that were diagnosed within and beyond 6 months of the date of index CRC diagnosis, respectively. Patients with liver metastases at initial diagnosis were excluded. Kaplan-Meier and multivariate Cox regression analyses were used to estimate survival for synchronous and metachronous CRC, and to compare outcomes with solitary CRC. Results: A total of 213 patients with 388 synchronous and 69 metachronous cases of CRC were included: median age was 70 (range 26-94), 55% were men, and 30% were ECOG 0 to 1 at index diagnosis. At initial presentaiton, 35% and 51% of patients who manifested with synchronous and metachronous tumors, respectively, were TNM stage III. Concurrent colorectal adenomas were found in 45% of synchronous and 33% of metachronous cases. The most prevalent symptoms experienced by patients included changes in bowel movements and abdominal pain. The majority of patients underwent a curative resection (99% of synchronous and 97% of metachronous). Adjuvant chemotherapy was used to treat 44% of both synchronous and metachronous tumors. Compared to solitary CRC, patients with synchronous and metachronous CRC had similar 3-year relapse-free survival (66 vs. 66 vs. 56%, p=0.20), 5-year cancer-specific survival (69 vs. 67 vs. 53%, p=0.34), and 5-year overall survival (62 vs. 59 vs. 49%), p=0.74. Similar observations persisted in the multivariate Cox regression model. Conclusions: There appears to be no differences in survival outcomes in patients with solitary, synchronous, or metachronous CRC. Patients who present with multiple CRC tumors should be managed similarly to those who only present with an isolated tumor.
A phase II trial of combination oxaliplatin, capecitabine, and celecoxib with concurrent radiation for patients with newly diagnosed resectable rectal cancer.
Authors: Murad Waheed , Fekrazad M Houman , Schrader Ronald , Liem Benny J. , Patt Yehuda Z. , Lee Fa-Chyi
Published: February 2017

487

Background: The goal of preoperative chemoradiation in rectal cancer is complete surgical resection without impairing sphincter function and to decrease local recurrence. The primary objective of the study was to determine complete pathological response rate (pCR) with capecitabine, oxaliplatin and celecoxib with concurrent radiation therapy. The secondary objectives were down staging rate, sphincter preservation rate, incidence and severity of adverse events. Methods: A total 37 out of 55 planned patients (pts) were enrolled by New Mexico cancer center consortium from 2005 to 2012. Inclusion criteria were: Resectable adenocarcinoma of the rectum within 12 cm of the anal verge, biopsy proven T3-4 N1-2 M0 based on endoscopic ultrasound, performance status of 0-2, adequate bone marrow reserve and liver functions. The neoadjuvant chemoradiation treatment was: capecitabine 850 mg/m2 bid Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 IV, celecoxib 200 mg bid with concurrent 45 gray radiation therapy in 25 fractions over 5 weeks. Results: Only 21 of 37 pathology reports were assessable for the primary objective of pCR. 7/21 pts (33%, 95% CI, 0.14-0.56) had pCR and 4 had only microscopic residual disease. Thus, 11/21 pts (52%, 95% CI, 0.30-0.74) had an excellent response following chemoradiation. The secondary outcome analysis showed 19/21 pts (90%, 95% CI, 0.69-0.98) were down staged. Sphincter preservation rate was 71% (15/21) (95% CI, 0.47-0.88). Grade 3 and 4 toxicities were observed in 23% and included nausea, vomiting, diarrhea, dehydration, hypokalemia, lymphopenia and fatigue. Conclusions: We report the highest pathological CR so far in stage III rectal cancer with these early results. This could be due to anti-inflammatory activity of celecoxib leading to better tolerance of radiation therapy and possible synergistic anti-tumor activity. Final results will be reported upon completion of the trial. Clinical trial information: NCT00250835.
Investigation of thrombospondin 1 (THBS1) as prognostic and predictive factor of neoadjuvant chemotherapy for advanced gastric cancer.
Authors: Matsumoto Noriko
Published: February 2017

49

Background: Curative R0 operation is the best treatment for patients with Stage II/III gastric cancer, but still there are recurrent cases. Although chemotherapy is an important treatment, there is no evidence of neoadjuvant chemotherapy (NAC) for both R0 operated advanced gastric cancer and inoperable cases. Thrombospondin 1 (THBS1) plays a role in angiogenesis in many cancers, and we reported that THBS1 could be prognostic factor of Stage IV gastric cancer and predictive factor of S-1+ paclitaxel chemotherapy. The aim of this study is to investigate THBS1 plays as prognostic and predictive factor of neoadjuvant chemotherapy for advanced gastric cancer. Methods: Study 1. Investigation of THBS1 as prognostic factor in R0 cases: 129 patients with R0 operated for stage II/III gastric cancer (II: 56, III: 73) were enrolled in this study. THBS1 expression was investigated by immunostaining with resected specimen. Relationship between THBS1 expression and disease free survival (DFS), and recurrence rate were evaluated. Study 2. Investigation of THBS1 as predictive factor in unresectable cases: Among 111 patients who had unresectable gastric cancer, 55 patients had NAC (NAC (+) group; S-1+PTX i.p.: 23, Docetaxel+CDDP+S-1 (DCS): 17, S-1+CDDP 6, Docetaxel{S-1 (DS): 5, S-1 alone: 4) were compared with NAC (-) group (n=56) by evaluation of relationship between immunohistological expression of THBS1 and overall survival. Results: Study 1: There were 39 (30%) gastric cancers with positive staining for THBS1, 19 patients (49%) recurred cancer and 5-year DFS was 20% in THBS (+) group. Among 90 patients of THBS (-) group, 19 patients (20%) recurred, and DFS was 73%. Study 2: there were 32 (29%) unresectable gastric cancers with THBS1 (+). NAC (+) group showed 30.4% of 2-year OS, whereas 13.1% of NAC (-) group. Among NAC (+) group, 24 (43.6%) patients showed response of NAC, and among responder group, 13 (54%) patients showed THBS1 (+), whereas 10 (28.6%) patients showed THBS (+) in non-responder group. Conclusions: THBS1 expression showed reverse correlation with prognosis and positive correlation with prediction of neoadjuvant chemotherapy for Stage II/III gastric cancer.
Preoperative chemotherapy prior to pulmonary metastatecomy in patients with prior surgically resected primary colorectal carcinoma.
Authors: Subbiah Ishwaria Mohan , Blackmon Shanda H. , Correa Arlene M. , Kee Bryan K. , Vaporciyan Ara A. , Swisher Stephen , Eng Cathy
Published: February 2017

490

Background: The exact benefit of preoperative chemotherapy prior to pulmonary metastasectomy for patients with metastatic colorectal carcinoma (CRC) is unknown. Here, we identify outcomes of preop chemo in pts w previously resected primary CRC who then had resectable pulmonary CRC metastases. Methods: We queried a prospectively collected database to identify pts who underwent pulmonary CRC metastasectomy and the specific chemo regimen given prior to but w/i 3 months of surgery. Two multivariate logistic analyses were performed to identify preop regimen as predictors of overall survival (OS) and progression free survival (PFS). Results: From Feb 2000 onwards, 229 pts underwent lung met resection (median age 61, range 24-82). Of those pts, 114 received preop chemo for a median duration of 4months (range 0.1-25.3mos). 41pts receiving 0-3 mos of preop chemo, 37 3-6mos, and 36 >6mos. 38pts received an oxaliplatin-based regimen (23 FOLFOX+bevacizumab [bev], 5 XELOX, 5 FOLFOX alone, 3 FOLFOX+cetuximab, 1 FOLFOX + novel TR-2/DR5 antibody, 1 oxali+irinotecan). 53 pts received an irinotecan-regimen. 29 received a capecitabine therapy. Pts on an oxali-based therapy had an improved OS vs alternate chemo regimen (mean OS 77.6 mos vs 54.2 mos, median OS not reached in oxali-group, p .001). However pts on an irinotecan-based regimen had a lower OS vs alternate chemo (median OS of 49.1mos vs 57.9mos, p .024). 5FU, capecitabine, or bev-based therapies did not significantly impact OS. The type of preop chemo regimen did not significantly affect PFS after lung met resection. Oxali-based regimen moved towards a favorable OS when compared to OS without any preop chemo but not of statistical significance (HR 0.69; 95% CI 0.287 to 1.663, p 0.409) while receiving a non-oxali-based preop regimen was associated with a shorter OS when compared to no preop chemo (HR 2.64; 95% CI 1.634 to 4.275, p <0.001). Conclusions: Preop chemo with an oxaliplatin regimen prior to pulm met resection may improve OS, providing long-term benefit, whereas a preop irinotecan-based therapy appears to result in a shorter OS. Prospective trials on specific preop regimens and criteria for patient selection are planned.
A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer.
Authors: Shin Sang Joon , Lee Jeeyun , Chung Ik-Joo , Kim Tae Won , Chun Hoo Geun , Shin Dongbok , Kim Yeul Hong , Song Hong-Suk , Han Sae-Won , Kim Jong Gwang , Kim Sun Young , Choi Young Jin , Chung Hyun Cheol
Published: February 2017

492

Background: Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Oxaliplatin-based treatment (FOLFOX, CapeOX) combined with bevacizumab is one of the standard chemotherapies for metastatic CRC. However, several clinical studies performed using S-1 plus oxaliplatin (SOX) indicate that SOX is a treatment option for metastatic CRC. TSU-68 (orantinib) is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor and has promising efficacy and high safety. The recommended phase II dose of TSU-68 plus SOX has been determined in a phase I study. This trial aimed to evaluate the efficacy of TSU-68 in combination with SOX. Methods: We performed an open-label multicenter randomized phase II trial in Korea. Treatment-naive metastatic CRC patients with a performance status 0 or 1 were randomized in a ratio of 1:1 to receive either TSU-68 plus SOX (group A) or SOX (group B). The primary endpoint was progression-free survival (PFS). Results: We randomized 105 patients (52 patients, group A and 53 patients, group B). Median PFS was 7.0 months in group A (hazard ratio [HR], 1.057) and 7.2 months in group B (P = 0.8401). The most frequent grade 3/4 events were thrombocytopenia (9.6% vs 26.4%), neutropenia (13.5% vs 15.1%), and anemia (3.8% vs 13.2%). We observed a difference between the 2 groups in all grades of anemia (15.4% vs 32.1%), diarrhea (30.8% vs 47.2%), vomiting (50.0% vs 26.4%), and chromaturia (23.1% vs 0.0%). Analysis using a COX proportional hazard model showed that baseline interleukin 6 (IL-6) level was associated with survival benefit of TSU-68 (P = 0.012). Conclusions: TSU-68 plus SOX showed a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. Baseline serum IL-6 levels could be prognostic factors for TSU-68 efficacy. Further biomarker analysis is being performed to determine the efficacy of this treatment. Clinical trial information: JapicCTI-111403.
Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 versus UFT to rectal cancer for personalized therapy (UMIN ID: 000001704).
Authors: Iwata Takashi
Published: February 2017

499

Background: Preoperative chemoradiotherapy (CRT) in rectal cancer reduces the local recurrence rate after operation and preserves the anus, but it is difficult to predict the effects of CRT. Multicenter randomized phase II clinical trial of preoperative chemoradiotherapy by S-1 vs UFT for rectal cancer was conducted to compare the toxicity and efficacy of CRT using oral DPD-inhibitory fluoropyrimidines (UFT versus S-1, (UMIN ID: 000001704)) in patients with locally advanced rectal cancer. Methods: In this randomized phase II study, during April 2008 to October 2010, rectal cancer patients (n=59) who underwent preoperative CRT were randomly divided into two groups; S-1 group (n=30, 80 mg/m2/day, 5 days/w x 4 w), and UFT (n=29, 300 mg/m2/day, 5 days/w x 4 w). Both groups were combined with 40Gy radiotherapy (2 Gy ×5 days/w × 4 weeks,total 40 Gy). The pathological response rate, clinical response rate by RECIST, and frequency of adverse events of CRT were compared between S-1 group and UFT group. Results: Response to CRT determined by histopathologic examination of surgically resected specimens and RECIST were as follows: responders (grade 2 or 3) were 60% (S-1) and 52% (UFT) (p=0.52). S-1 group showed 54% of response rate in pathological response, whereas UFT group showed 45% (p=0.43). In adverse events, frequence of Grade 2 and 3 diarrhea was significantly higher in S-1 group compared with UFT group. There was no difference between the two groups in compliance (S-1group: 83%, UFT group: 97%). Conclusions: Both S-1 and UFT were safely used for preoperative CRT. S-1 tended to show higher response rate than UFT, although diarrhea in S-1 was higher than in UFT. Clinical trial information: 000001704.
Phase II study to evaluate efficacy and safety of irinotecan, capecitabine, and bevacizumab in metastatic colorectal cancer (mCRC) patients.
Authors: Garcia Alfonso Pilar , Chaves-Conde Manuel , Munoz Andres , Salud Antonia , Garcia-Giron Carlos , Gravalos Castro Cristina , Massuti Bartomeu , González Flores Encarnación , Queralt Bernardo , Lopez Ladron Amelia , Losa Ferran , Oltra Ferrando Amparo , Gomez Reina Maria Jose , Garcia-Carbonero Rocio , Garcia-Escobar Ignacio , Aranda Enrique
Published: February 2017

501

Background: XELIRI regimen biweekly (combination of capecitabine and irinotecan) is an active and well tolerated treatment for mCRC. Bevacizumab provides significant clinical benefits in previously treated patients with mCRC. On this basis, the aim of this study is to evaluate the efficacy and safety of this combination. Methods: Multicentric, prospective, open-label phase II trial. Treatment scheme: irinotecan (iri) (175mg/m2 d1 q2w) + capecitabine (xel)(1,000mg/m2bid d 2-8) + bevacizumab (bev) (5mg/kg, d1 q2w). Results: 77 patients (p) were evaluated (66.2%, male) with a median age of 65.1 years (41.1-81.1). ECOG performance status was ≤1 in 96.1%. Primary tumor locations were: colon (53.2%), rectum (31.2%), and rectum/colon (15.6%). 27 p (35.1%) received adjuvant chemotherapy. Metastases were detected in liver (62.3%) and lung (54.5%). Mean time in treatment was: 7.1±4.9 months and median of cycles administered was 12(1-43). Median relative dose intensity was 89% for xel and bev and 85% for iri. Best response confirmed were: complete response (5.2%), partial response (32.5%), stable disease (46.8%). After a median of follow-up of 23.3 (0.4-39.6) months, median overall survival (OS) and progression free survival (PFS) was 24.8 and 11.8 months respectively. Analysis on Kras status was done in 71 p. There were no significant differences in OS or in PFS between WT and MUT p. 17 p (22.1%) underwent salvage surgery, 12 of whom had an R0 resection. The most frequent G3-4 toxicities were: diarrhea (18.2%), asthenia (16.9%), pulmonary embolism (13%; in eight of 10 p were asymptomatic), neutropenia (10.4%), febrile neutropenia (6.5%) and HFS (5.2%). Three treatment related deaths were reported (2 cases of multi-organ failure, and 1 case of intestinal perforation). Conclusions: Bevacizumab combined with biweekly XELIRI is an active first-line regimen for mCRC treatment with a feasible and manageable safety profile. Bevacizumab treatment efficacy was independent on Kras status. Clinical trial information: NCT00875771. [Table: see text]
Randomized clinical trial on accelerated hyperfractionated versus hypofractionated preoperative radiotherapy for rectal cancer: A report on perioperative complication rates.
Authors: Wzietek Iwona , Bialas Marcin , Kryj Mariusz , Chmielarz Andrzej , Widel Maciej , Idasiak Adam , Namysl-Kaletka Agnieszka , Stobiecka Ewa , Chmielik Ewa , Wydmanski Jerzy , Suwinski Rafal
Published: February 2017

506

Background: The aim of the study is to verify hypothesis that accelerated hyperfractionated preoperative radiotherapy for rectal cancer (HART) may provide a favorable long-term tolerance compared to treatment given in higher fraction (fx) doses (HYPO). This report focuses on early outcomes of the study. Comparison of late tissue reactions, evaluation of QLQ and long-term outcome in both trial arms is the ultimate goal. Methods: Between 2005 and 2011, 238 patients (pts) with cT3-4 resectable adenocarcinoma of the rectum were enrolled, which represents app. 70% of an overall trial size. The pts were randomly assigned to HART (n=122) or HYPO (n=116). The pelvis was irradiated 2x/day to the total dose of 42 Gy in 1.5 Gy/fx over 18 days (HART). Patients in HYPO received 39 Gy in 3.0 Gy/fx over 17 days. Postoperative chemotherapy (PCT) was given to ypN+ pts. Results: The actuarial perioperative complication rate at 1 year after treatment was 24.4% vs. 33.4% for HART and HYPO resp. (RR=0.69, p=0.13). The crude rate of pts with any surgical complication during the follow-up (median of 3.1 year) was 32/122 (26.2%) vs. 36/116 (31.0%) for HART and HYPO resp. (p= 0.41). If the values were expr. In terms of number of events (some pts had more than one complication) the rates were 55 events per 122 pts (HART) vs. 63 events per 116 pts (HYPO). Anastomotic leakage appeared in 11/122 HART pts (9.0%) vs. 16/116 in HYPO (13.8%). Anterior resection was performed in 48.8 % vs. 44.1% for HART and HYPO resp. PCT was given to 46.1% of the pts in HART and 45.4% in HYPO. There were no significant differences in 3-year loco-regional control (RR=1.08, p=0.44) and overall survival (RR=0.97, p=0.72) between HART and HYPO, with actuarial rates (for both arms) of 85% and 73% resp. Neither the rate of complicatons, nor type of surgery were influenced by duration of the interval RT-surgery (median 11, Std±18 days) Conclusions: The perioperative complication rate observed had the propensity to favor HART over HYPO, but the differences did not reach the level of statistical significance. Longer follow-up and the analysis encompassing all of the pts enrolled is required to fully address the study endpoints.
Assessment of macroscopic features in relation to tumor response to neoadjuvant chemoradiation therapy in rectal cancer.
Authors: Arrington Amanda Kathleen , Garcia-Aguilar Julio , Duldulao Marjun Philip , Luu Carrie , Sanchez Julian , Kim Joseph , Choy Kristi
Published: February 2017

507

Background: Several studies show locally advanced rectal cancer patients with clinical complete response (cCR) have comparable oncologic outcomes to pathologic complete response (pCR) to neoadjuvant chemoradiation therapy (NCRT). Thus, total mesorectal excision (TME) could potentially be avoided. Our objective was to validate macroscopic features of cCR. Methods: 164 patients with stage II/III rectal cancer were previously enrolled in a phase II trial and treated by NCRT and TME. Tumor response in the surgical specimens was assessed according to AJCC guidelines. A pCR was defined as absence of viable tumor cells. Gross macroscopic features by the pathologist were tabulated and our cohort was applied to previously published cCR criteria. Results: 25.0% (n = 41) had pCR; 75.0% (n = 123) had non-pCR. Descriptors were condensed into 14 macroscopic features by combining terms and excluding those rarely mentioned. Several reports affirm that scarring signifies cCR, while others suggest that fibrosis, edema, ulceration and nonpalpable tumor to be consistent with cCR. In our study, scarring was found in 6.1% of patients, 16.7% of which had pCR. We found that hyperemia, scarring, flat, smooth, and tan-pink mucosa were significantly associated with pCR (p < 0.05). In contrast, a firm lesion and ulceration were frequently observed in patients with non-pCR (p = 0.02 and 0.05 respectively). Conclusions: Our study suggests that macroscopic pathologic features do correlate with pCR. Although cCR has comparable oncologic outcomes as pCR with favorable outcomes, standard criteria of cCR should first be defined so NCRT patients can safely be selected for observation only. [Table: see text]
The impact of palliative resection (PR) of the primary tumor on overall survival (OS) in metastatic colorectal cancer (mCRC).
Authors: Gresham Gillian , Renouf Daniel John , Chan Matthew , Cheung Winson Y.
Published: February 2017

509

Background: The role of PR of the primary tumor in mCRC remains unclear. Using population-based data, we explored the impact of PR on OS. Methods: Patients (pts) with mCRC who were referred to 1 of 5 regional cancer centers in British Columbia between 2006 and 2008 were reviewed (n=802). Pts with prior early stage CRC who relapsed with mCRC were excluded (n=285). We conducted survival analysis using Kaplan Meier methods and determined adjusted hazard ratios (HR) for death using Cox proportional hazards models. A secondary propensity score matched analysis was performed to control for baseline differences between pts who underwent PR and those who did not. Results: A total of 517 pts with mCRC were identified: median age was 63 years (range 23-93), 54% were men, 55% had ECOG 0-1, 76% had a colon primary, and 31% had >1 metastatic site. The majority (n=378; 73%) underwent PR of the primary tumor and a significant proportion (n=327; 63%) received palliative chemotherapy (CT). Compared to pts without PR, those with PR were more likely to be men (62 vs 51%, p=0.03), aged <65 years (63 vs 52%, p=0.03), ECOG 0-1 (61 vs 38%, p<0.0001), and receive palliative CT (68 vs 50%, p=0.0004). PR was associated with improved median OS across groups (Table). The benefit of PR on prognosis persisted in multivariate analysis (HR for death 0.56, 95%CI 0.43-0.72, p<0.0001 for entire cohort; HR 0.51, 95%CI 0.37-0.70, p<0.0001 for individuals who were treated with CT; and HR 0.54, 95%CI 0.34-0.84, p=0.007 for those who did not receive CT). In a propensity score matched analysis that considered age, gender, ECOG, and receipt of palliative CT, prognosis continued to be more favorable in the PR group (HR 0.66, 95% CI 0.50-0.86, p=0.0019). Conclusions: In this population-based analysis, PR of the primary tumor in mCRC was associated with a significant OS benefit. [Table: see text]
A randomized phase II study of neoadjuvant chemoradiotherapy with 5-FU/leucovorin or irinotecan/S1 in patients with locally advanced rectal cancer.
Authors: Jung Minkyu , Shin Sang Joon , Lim Seungtaek , Park Ji Soo , Koom Woong Sub , Keum Ki Chang , Kim Nam Kyu , Back Seung Hyuk , Min Byung Soh , Hur Hyuk , Kim Ho Geun , Lim Jun Seok , Kim Tae IL , Roh Jae Kyung , Park Young Suk , Ahn Joong Bae
Published: February 2017

511

Background: The purpose of this study was to evaluate rate of pathologic complete response (pCR) in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy (CRT) with 5-FU/leucovorin (FL) versus Irinotecan/S-1 (IS) and surgery followed by fluoropyrimidine based adjuvant chemotherapy. Methods: Patients with resectable, locally advanced (cT3-4 and/or cN positive) adenocarcinoma of rectum were randomly assigned to receive preoperative radiation (45-50.4 Gy in 25-28 daily fractions) and concomitant chemotherapy with bolus injections of 5-FU 400 mg/m2/day and LV 20 mg/m2/day for 3 consecutive days every 4 weeks for 2 cycles (FL group), or with irinotecan 40 mg/m2 on days 1, 8, 15, 22, 29 and S-1 35mg/m2 twice on the day of irradiation (Monday-Friday) (IS group). Curative surgery was performed for about 4-8 weeks after the completion of chemoradiotherapy. Postoperative chemotherapy regimen is FL. The primary endpoint was pCR rate. Results: 142 eligible patients were randomly assigned. Of 142, 130 patients (91.5%) underwent total mesorectal excision. The pCR was achieved 11 (17.2 %) of 64 patients in the FL group and was 16 (24.2%) of 66 patients in the IS group (p=0.1). When pCR was combined with few residual cells, the rate was significantly higher in IS group compared to FL group (57.6 % vs. 39.1 %, p-value=0.035). Preoperative rate of grade 3-4 toxicity was 1.4% with FL and 7.0 % with IS group (p=0.095). Conclusions: The results have suggested that neoadjuvant CRT using IS is feasible and effective for patients with locally advanced rectal cancer. Longer follow-up is needed to assess survival. Clinical trial information: NCT01269216.
Prediction model for ypΝ status after preoperative chemoradiotherapy in patients with rectal cancer.
Authors: Jwa Eunjin , Kim Jong Hoon , Han Seungbong , Park Jin-hong , Kim Jin Cheon , Yu Chang Sik , Lim Seok-Byung , Kim Tae Won , Hong Yong Sang
Published: February 2017

513

Background: Pelvic lymph node status after preoperative chemoradiotherapy (CRT) is not only an important indicator for oncologic outcome but critical information to determine the type of a subsequent surgical resection (i.e. curative surgery or local excision) in patients with locally advanced rectal cancer. The purpose of this study is to develop a nomogram to predict the lymph node status after preoperative CRT in rectal cancer patients whose ypT information is available. Methods: Using logistic regression analyses, we constructed a prediction model to predict the probability of lymph node metastasis after preoperative CRT in a cohort of 1,099 patients with rectal cancer treated with preoperative CRT and total mesorectal excision (TME) from 2007 to 2011. The model was internally validated for discrimination and calibration using bootstrap resampling. Results: Pretreatment clinical nodal stage, distant metastasis, pre- and post-treatment tumor differentiation, and ypT stage were reliable predictors for lymph node metastasis after preoperative CRT. The nomogram developed using these parameters represents a valid and accurate method for predicting lymph node metastasis after preoperative CRT in rectal cancer patients. (c-index: 0.75) Patients with low pretreatment nodal stage, nonmetastatic, and well differentiated rectal adenocarcinoma downstaged to ypT0-1 after preoperative CRT will have low chance of pelvic lymph node involvement. Conclusions: Our model is expected to assist clinicians in quantifying the benefit of radical resection and finding out the patient group who can be treated with local excision after preoperative CRT for rectal cancer.
FOLFOXIRI plus bevacizumab (BEV) in patients (pts) with previously untreated metastatic colorectal cancer (mCRC): Preliminary safety results from the OPAL study.
Authors: Stein Alexander , Atanackovic Djordje , Hildebrandt Bert , Stuebs Patrick , Steffens Claus-Christoph , Brugger Wolfram , Hapke Gunnar , Illerhaus Gerald , Bluemner Ernst , Bokemeyer Carsten
Published: February 2017

515

Background: The addition of BEV to standard doublet chemotherapy (CT) improves outcomes vs CT alone in pts with mCRC. Use of more intensive triplet CT may prolong overall survival (OS), progression-free survival (PFS), increase response rates and improve resectability rates but at the expense of greater toxicity. The OPAL study examined the effect of BEV + FOLFOXIRI on PFS in pts with previously untreated unresectable mCRC. Here we report preliminary safety findings. Methods: Eligible pts had histologically confirmed mCRC, ECOG PS ≤1 and were 18–70 years old. Pts received ≤12 cycles of FOLFOXIRI (infusional 5-fluorouracil [FU] 3200 mg/m2, folinic acid [FA] 200 mg/m2, oxaliplatin 85 mg/m2, irinotecan 165 mg/m2) + BEV 5 mg/kg q2w (induction phase) followed by ≤40 cycles of 5-FU/FA + BEV q2w (maintenance phase). PFS was the primary endpoint; secondary endpoints included OS, proportion of pts achieving resectability and safety. Results: 96 pts were enrolled. Of these, 90 received study medication and formed the safety population: 64 male, 26 female; median age 58 (range 28–71) years; ECOG performance status 0/1 in 49/41 pts. All pts have completed induction treatment and the study is ongoing. In total, 61 serious AEs occurred in 34 pts (38%). AEs resulting in death occurred in 3 pts (3%); these were not considered treatment-related by the investigators. The incidence of AEs of special interest with BEV was low. Main AEs reported during the induction phase are summarised in the table. Conclusions: BEV + FOLFOXIRI was generally well tolerated in this mCRC pt population. The incidence of AEs was as previously reported [Falcone et al. ASCO 2010] and there were no new safety signals. Clinical trial information: NCT00940303. [Table: see text]
Randomized, controlled trial comparing S-1 with UFT/LV as adjuvant therapy for curatively resected stage III colorectal cancer (BCOG-CC02 study).
Authors: Koda Keiji , Miyauchi Hideaki , Yokoi Kimiyoshi , Kosugi Chihiro , Kaiho Takashi , Kobayashi Susumu , Ochiai Takenori , Matsubara Hisahiro
Published: February 2017

520

Background: Oral anticancer drug, UFT/LV, has recently been reported to improve both overall survival (OS) and relapse free survival (RFS) for patients with Stage III colorectal cancer in Japan. We conducted a randomized clinical trial to compare S-1 with UFT/LV for adjuvant therapy in patients with Stage III colorectal cancer. Methods: Patients with Stage III colorectal cancer (PS, 0 to 1; age, 20 to 80 years) were randomized to take either UFT / LV (28 days per 5 weeks) for 6 months. or S-1 (28 days per 6 weeks) for 12 months started within 6 weeks following curative resection. We investigated the correlations between disease- free survival (DFS) and tissue mRNA levels of 5-FU and folate metabolism-related enzymes. In addition, we investigated overall survival (OS) and safety. Results: Between April 2008 and August 2010, a total of 145 patients were registered from 22 centers. There were no clear intergroup differences in background factors. The patients who relapsed during protocol duration of treatment were excluded, the percentages of patients who took expected dosage of medicine were 67.1% (47/70) and 87.3% (62/71) in S-1 and UFT/LV groups, respectively. Grade3 to 4 myelosuppression(4%), bilirubin(3%) and diarrhea(8%) were occurred in S-1 group whereas, grade 3 liver dysfunction (5%) and diarrhea (5%) occurred in UFT/LV group, but all of them were reversible. The median follow-up period was 934 days, 3-years’ DFS in patients of S-1 and UFT/LV groups were 65.9% and 72.7%, respectively (p=0.88). In a univariate analysis, topoisomerase-1 (TOPO-1) mRNA level was shown as a factor of the recurrences. A poor-prognosis patient population was observed in the S-1 group such as with low gamma-glutamyl hydrolase (GGH) mRNA level. Conclusions: Oral anticancer drug, S-1 showed an equivalent effect for UFT/LV in Stage III colorectal cancer as adjuvant therapy. Tissue levels of mRNA of 5-FU/ folate metabolism-related enzymes were important parameters for postoperative prognosis in patients with stage III colorectal cancer who take oral 5-FU derivatives for adjuvant therapy. Clinical trial information: UMIN000001560.
Course of calcium and magnesium serum levels in cetuximab-treated patients: Relation to concurrent chemotherapy and possible predictive value.
Authors: Stintzing Sebastian , Fischhaber Doris , Modest Dominik Paul , Giessen Clemens Albrecht , Hendrich Saskia , Aubele Phillip , Heinemann Volker
Published: February 2017

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Background: Hypomagnesaemia and hypocalcaemia are well known adverse events of cetuximab treated patients. Whether these side effects are of predictive value remains unclear. Methods: Patients receiving cetuximab for antitumoral treatment in the day clinic were investigated. Calcium and magnesium serum levels were analysed weekly during therapy, and tumor response and adverse events were followed. Serum levels were noted in relation to baseline measurements. Evaluable patients should at least be treated over a period of 6 weeks. Results: Between 2008 and 2011, a total of 97 patients were treated with cetuximab and were evaluable for serum levels. 38 patients had metastatic colorectal cancer, 27 suffered from SCCHN, 14 had other neoplastic diseases. During therapy, calcium serum levels decreased to a level of about 97% of baseline measurement and stayed there for the duration of treatment. Magnesium levels, however, showed a time dependent decrease during the whole observation time. When calculating the serum levels in relation to the chemotherapeutic combination partner, serum levels of magnesium were significantly lower when cetuximab was combined to a platin-derivative (oxali-, cis- or carboplatin). After a treatment duration of 12 weeks, magnesium levels dropped to 70% in platinum-treated pts, while they decreased to only 90% of baseline in pts without platinum therapy. In patients treated for metastatic colorectal cancer (mCRC) a decline of serum magnesium below 95% of baseline levels 14 days after initiating treatment separated patients with good outcome from those with poor outcome. While, a significant correlation between lower magnesium serum levels and the occurrence of acneiform exanthema was shown, no correlation of hypomagnesemia with clinical symptoms such as e.g. muscle cramps were documented. Conclusions: Magnesium levels decline in a time dependent manner during cetuximab therapy without occurrence of clinical symptoms. Hypomagnesaemia was more prominent in patients receiving platinum agents and was associated with better outcome.
Induction chemotherapy followed by chemoradiotherapy and total mesenteric excision for locally advanced rectal cancer with resectable metastases.
Authors: Hajj Carla , Cercek Andrea , Saltz Leonard , Segal Neil Howard , Reidy Diane Lauren , Stadler Zsofia Kinga , Kemeny Nancy E. , Wu Abraham Jing-Ching , Weiser Martin R. , Paty Philip , Guillem Jose G. , Nash Garrett Michael , Temple Larissa K. F. , Garcia-Aguilar Julio , Goodman Karyn A.
Published: February 2017

526

Background: Optimal management of patients with locally advanced rectal cancer (LARC) and synchronous, resectable metastases remains controversial and treatment decisions benefit from a multidisciplinary approach. To better characterize the role of induction chemotherapy followed by chemoradiation and surgery, we evaluated patterns of distal progression and overall survival in this subset of patients. Methods: We reviewed records of 25 LARC patients with synchronous resectable metastases treated with induction chemotherapy (ICT) followed by 5-fluorouracil-based concurrent chemoradiation (CRT) at our institution between December 2006 and December 2010. Radiation was delivered using a standardized three-field technique or IMRT. The incidence and sites of failure were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated from the completion of CRT using the Kaplan-Meier method. Results: Of the 25 patients who received ICT followed by CRT, 21 (84%) underwent total mesorectal excision and metastectomy. Eleven patients (44%) had liver metastases. The median ICT duration was 2.4 months. Twenty patients (80%) received a FOLFOX-based ICT regimen and 5 patients (20%) received irinotecan-based chemotherapy. Two patients had unresectable disease, one was medically inoperable, and surgery was aborted due to intra-operative complications in one patient. Eighteen of the 21 were NED after surgery and metastatectomy (86%) with 24% pathologic complete response rate in the primary tumor; 10 (56%) received adjuvant chemotherapy. None of the patients recurred locally. Six of the 18 (33%) progressed distally, four of whom had received adjuvant chemotherapy. Four distal recurrences were in the lungs. With a median follow-up of 29.6 months, the 3-year OS was 50.4%. Median OS and PFS were 25.1 months and 13.5 months, respectively. Conclusions: ICT prior to CRT is associated with acceptable toxicity, substantial primary tumor regression, and promising clinical outcomes in patients with high-risk LARC with synchronous, resectable metastatic disease.