bluuebunny/crossref_metadata_2025 huggingface dataset:
Progression-free survival (PFS) with maintenance treatment with bevacizumab (B) in patients with responding mCRC after first-line chemotherapy (CT) plus B.
Authors: Fabbri Maria Agnese , Nelli Fabrizio , Moscetti Luca , Cortesi Enrico , Gamucci Teresa , Sperduti Isabella , Franco Daniela , Pavese Ida , Grande Roberta , Alesini Daniele , Ruggeri Enzo
Published: February 2017

612

Background: Maintenance treatment with B is considered an option for mCRC pts in responding pts after a first line CT + B, but few data are available on its real benefit on PFS.

Methods: We collected data from a cohort of mCRC pts consecutively treated in five oncologic centers of Lazio. One-hundred-ninety-nine mCRC pts treated with first line CT + B achieving a response [partial (PR) or complete (CR)] or a stable disease (SD) were considered eligible, 117 pts had received B maintenance (BM) whereas 82 did not (noBM). The two groups were homogeneous for main characteristics. First-line therapy in the BM vs noBM group included FOLFIRI regimen (96 vs 59 pts), FOLFOX (18 vs 22 pts) and FUFA (3 vs 1 pts). K-ras status was analyzed in 115 pts with an higher percentage of wild-type (wt) in the BM group (65 vs 50 pts, p= 0.04). A CR or PR have been achieved in 65% of pts in the BM group and 61% of noBM group, while a SD was observed in 35% and 39% of pts respectively for the BM and noBM group. The median number of BM cycles administered was 7 (range 3-25). Effectiveness measures included the PFS duration. A multivariate Cox proportional hazard model was developed using stepwise regression (forward selection)

Results: At a median follow-up of 18 months (1-109), the median PFS was 13 months (C.I.95%: 11-15) vs 8 months (C.I.95%: 7-10; p<0.0001, and the 1-year PFS 53% vs 28% for BM and noBM respectively. Pts with CR/PR had a mPFS of 15 months (CI 95% 12-19) vs 10 months (CI 95% 10-12) p=0.004 and a 1-year PFS of 62.6% vs 33.7% for the BM vs noBM group respectively. No difference in the 1-year PFS was observed in pts showing SD to chemotherapy and bevacizumab. The mPFS in these patients was 12 (CI 95% 10-13) vs 8 months (CI 95% 7-10, p=0.11) for the BM and noBM group respectively. The multivariate analysis did not show any difference in PFS comparing age, sex, number and site of metastasis, ECOG PS and k ras status. A significant difference in PFS was observed for response to first-line CT (CR/PR vs SD, p=0.002) and for BM vs noBM (p=0.003).

Conclusions: The maintenance strategy with B shows a longer PFS in pts responding to the first line chemotherapy + B whereas for pts who achieving an SD no difference was observed.
Survival investigation in patients with colorectal liver metastasis: A single-institution analysis.
Authors: Xu Jianmin , Zhu Dexiang , Ren Li , Wei Ye
Published: February 2017

617

Background: To investigate survival in patients with colorectal liver metastasis (CRLM) and identify risk factors associated with survival.

Methods: Clinical, pathologic, treatment and complete follow-up data were retrospectively collected from 1613 consecutive patients with CRLM in Zhongshan Hospital between 2000 and 2010. The prognostic value of different factors was studied through univariate and multivariate analyses.

Results: The median survival was 22.0 mo and 5-yr survival rate was 16%. Survival of synchronous liver metastases (SLM) (21.2 mo and 16%) was lower than that of metachronous liver metastases (MLM) (30.1 mo and 23%, p<0.01). Survival after resection of liver metastases was 49.8 mo and 37%, higher than that after chemotherapy (22.2 mo and 0%), that after intervention(19.0 mo and 11%), that after chemotherapy combined with intervention(22.8 mo and 10%)and that after local regional treatment (28.5 mo and 0%). Expansion of the indications for liver resection (38.0 vs 48.0 mo, 32% vs 40%), simultaneous or staged resection of primary colorectal tumor and liver metastases (47.0 vs 44.0 mo, 33% vs 35%) and preoperative neoadjuvant therapy (44.0 vs 48.0 mo, 38% vs 36%) had no significant effect on survival. 64 initially irresectable patients could undergo surgery after convertible therapy, with the median survival 36.9 mo and 5-yr survival 30%, better than that of unresectable patients (18.2 mo and 8%). Five factors were found to be significant and independent predictors of poor survival by multivariate analysis: SLM, poorly differentiated primary, number of liver metastases >= 4, largest liver metastases >= 5 cm, and no surgical treatment of liver metastases. Giving one point to each above factor, the population was divided into six groups with 5-yr survival rates: 0 (64%), 1 (44%), 2 (29%), 3 (4%), 4 (4%) and 5 (1%) (p<0.01).

Conclusions: Survival of SLM was lower than that of MLM. Resection of liver metastases provides good long-term survival benifit for patients with resectable and initially irresectable liver metastases. Expansion of the indications for liver resection is acceptable. Long-term survival outcome can be predicted from a risk factor scoring system.
Cetuximab in first-line treatment of metastatic colorectal cancer in a real-life setting: Preliminary results of the EREBUS cohort.
Authors: Smith Denis , Rouyer Magali , Mitry Emmanuel , Monnereau Alain , Sa Cunha Antonio , Bignon Emmanuelle , Le Monies Alise , Jove Jeremy , Noize P. , Moore Nicholas , Fourrier-Réglat Annie
Published: February 2017

621

Background: Cetuximab (CTX) has demonstrated to improve survival outcomes in metastatic colorectal cancer (mCRC), but little data for real-life use is available.

Methods: EREBUS is a French multicentre (n=92) hospital-based cohort. Patients initiating CTX in 2009 and 2010 were identified retrospectively from registries of nominative drug dispensations. Those with wild-type KRAS gene receiving 1st-line treatment for mCRC were followed-up for 12 months. Data were collected from patient medical records and response based on physician assessments (CT-Scan). Presented here are preliminary results of the EREBUS cohort about administration regimen and according response rates for patients included in 2009.

Results: Of the 190 patients included in the cohort, data has been collected for 160 (84.2%): median age at baseline 65.5 years, 70.6% male. Regarding cancer characteristics, 79.4% of patients had a colon cancer and 53.8% a primary tumor resection. Metastatic sites were liver in 73.1% of patients, peritoneum in 29.4%, lymph nodes in 26.3%, and lung in 25.6%. For patients for which the ECOG status was available (54.4%): 79.3% have an ECOG score between 0 and 1, 20.7% ≥2. Half the patients (48.8%) had only one metastatic site. CTX was given every three weeks to 2 patients (1.3%), every two weeks to 113 of patients (70.6%), and weekly to 45 (28.1%). For those receiving CTX every two weeks: 64.9% had irinotecan-based regimens (vs. 45.5% of those receiving CTX weekly, p=0.03), 31.5% had oxaliplatin-based regimens (vs. 47.7%, p=0.06), median duration of CTX use was 3.8 months (vs. 5.3 months, p=0.69) and that of 1st-line therapy 6.3 months (vs. 7.5 months, p=0.97), 69.0% discontinued 1st-line treatment (vs. 82.2%, p=0.09) – mainly for progression (71.8 vs. 75.7%, p=0.66) or toxicity (20.5 vs. 10.8%, p=0.20). Overall response evaluated for 100 patients receiving CTX every two weeks out of 113 was 46.0% (vs. 52.6%, p=0.49, evaluated for 38 receiving CTX weekly).

Conclusions: CTX administration every two weeks was the most frequent regimen. In this preliminary analysis, patients receiving weekly or every two weeks regimens had similar duration of treatment and response rate.
Rates of pathologic complete response and sphincter-sparing surgery after neoadjuvant radiochemotherapy with or without regional pelvic hyperthermia for locally advanced rectal cancer.
Authors: Gani Cihan , Schroeder Christopher , Lamprecht Ulf , Bamberg Michael , Berger Bernhard
Published: February 2017

622

Background: Regional pelvic hyperthermia is frequently added to neoadjuvant radiochemotherapy for locally advanced rectal cancer. The present retrospective study is the first to evaluate the impact of hyperthermia on rates of complete pathologic response and sphincter-sparing surgery in the context of a standard up-to-date neoadjuvant radiochemotherapy scheme.

Methods: Between 2007 and 2010, 85 consecutive patients with locally advanced cancer (cT3, cT4, cN+) of the middle and lower rectum received neoadjuvant radiochemotherapy at our institution. 45 of 85 patients (“RCT group”) received standard treatment consisting of radiotherapy to the pelvis with 5040 cGy in 28 fractions of 180 cGy and 5-fluorouracil as a continuous infusion with 1000 mg/m² over 120 hours during the first and fifth week of treatment. 40 of 85 patients (“HRCT group”) received the same treatment with at least four treatments of weekly regional hyperthermia. Target temperature was 40.5°C for at least 60 minutes. Total mesorectal excision was routinely performed.

Results: No significant difference in the distribution of age, gender, clinical stage and tumor grade was observed between both groups. Complete pathologic response was seen in 6.7% of patients in the RCT group and 22% of patients in the HRCT group (p=0.034). Overall rates of sphincter-sparing surgery were 64% in the RCT group and 65% in HRCT. However for deep seated tumors located within 4 cm of the anal verge (based on initial staging), sphincter sparing surgery was achieved in only 11.1% of patients in the RCT group but 35.7% of patients in the HRCT group (p = 0.19).

Conclusions: The addition of regional hyperthermia to neoadjuvant radiochemotherapy significantly increases the rate of complete pathologic response, with a tendency towards higher rates of sphincter-sparing surgery for deep seated tumors.
Validation study of a prognostic classification system in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy.
Authors: Yamazaki Kentaro , Naito Yoichi , Yuki Satoshi , Kawamoto Yasuyuki , Yasui Hirofumi , Takano Toshimi , Komatsu Yoshito , Muro Kei , Shitara Kohei
Published: February 2017

624

Background:Previously, five prognostic factors (ECOG PS 2, pathologically poorly differentiated adenocarcinoma, peritoneal metastasis, PFS of 1st-line therapy <6 months, and LDH >400 IU/L) were identified in 124 patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy (Shitara K, et al. ASCO-GI 2009). Patients were categorized into three prognostic groups (low-risk = no factors, intermediate-risk = 1 factor, high-risk = 2 or more factors), with significant differences in median overall survival (23.5, 14.6, and 5.5 months, respectively). The purpose of this study was to validate this prognostic classification in an external validation cohort.

Methods: We retrospectively analyzed 198 patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy in 3 institutions. This was our validation cohort.

Results: The median overall survival of this validation cohort was not significantly different from that of the generating cohort (12.1 vs. 14.6 months; P=0.47). The distribution of the three prognostic groups in the validation cohort was as follows: low-risk (n=68; 35%), intermediate-risk (n=80; 41%), high-risk (n=45; 23%), with a higher proportion of intermediate-risk patients in comparison with the generating cohort. The median overall survival of each prognostic group in the validation cohort was 19.8, 11.0, and 7.9 months, respectively, with significant differences among groups (P<0.01), as was shown for the generating cohort. A similar tendency was observed for progression-free survival.

Conclusions: Our results validated the previously defined prognostic classifications in patients with metastatic colorectal cancer who received irinotecan-based second-line chemotherapy. This classification may be useful as a stratification factor in clinical trials or in considering treatment strategies for individual patients.
Fast-track surgery in colorectal surgery: When laparoscopy is not an option.
Authors: Silva José Pedro Carvalho Moreira da
Published: February 2017

642

Background: “Fast-track” protocols are multimodal programs that when applied to colorectal surgery, permit a reduction in morbidity, hospital stay and a faster recovery after the surgery. Most of these protocols are associated to laparoscopic surgery. However it is possible to reproduce these results with open surgery, when laparoscopy is not an option (lack of material or medical experience or in low-resource scenario).

Methods: Main objective: 1) Apply a fast-track protocol, designed to our patients that have colon malignancies and are submitted to colon resections through an open procedure 2) To study the peri-operative morbidity in the first 30 days after surgery. We conducted a pilot study with 30 patients in 2007. After assuring the feasibility of this protocol we started to apply it regularly in 2009; 177 patients underwent to fast track open colorectal surgery until July 2011. Main studied outcomes were duration of the surgical procedure, pain control, postoperative complications, and length of hospital stay. Other variables included patient (demographic characteristics, BMI, ASA and POSSUM scores), tumour (TNM status) and surgery (type) related variables.

Results: 54,8% of the patients were male. Median age was 63 years old (Min.: 36; Máx.: 79). 53,7% had sigmoid or rectosigmoid tumors. Most were classified as pT3N0 tumors. In 89% of the patients, epidural catheter was placed. 92,7% had a vertical median abdominal incision with a median of 19 cm (Min.: 10; Máx.: 30). The most performed surgery was the sigmoid colectomy and the anterior rectosigmoid resection. 89,3% tolerated oral clear liquids, 2 hours after surgery. 31,6% of the patients referred nauseas or vomits in the post-operative period. 83,6% didn't refer pain after the surgery. 2,83% had an anastomotic fistula and had to be reoperated (similarly to historical data). 36,7% were discharged at day three after surgery and 87% have been discharged by the 5th day.

Conclusions: The “Fast-track” protocol applied to open colon surgery is feasible, doesn’t increase the morbidity or mortality and permits shorter hospital stays and is not expensive. To its success contribute the detailed information to the patient, the formation and the motivation of the health care people involved.
The management of patients with T1 adenocarcinoma of the low rectum: An updated decision analysis.
Authors: Johnston Calvin F. , Tomlinson George A. , Temple Larissa K. F. , Baxter Nancy N.
Published: February 2017

645

Background: Patients with T1 adenocarcinoma of the low rectum are faced with a choice between Transanal Local Excision (TLE) and Abdonimoperineal Resection (APR). Fundamentally a tradeoff between quantity and quality of life, this problem is well-suited to decision analysis. A previous decision analysis examined this issue in 1999, but subsequent case series have reported TLE recurrence rates higher than that study considered plausible. Decision analytic techniques have also evolved by incorporating Markov modeling, which better accounts for the temporal aspects of the problem, and microsimulation, which allows for greater flexibility.

Methods: We developed a Markov-type microsimulation to evaluate the decision between APR and TLE in T1 adenocarcinoma of the low rectum. We used the software package 'R' and have made all computer code freely available for full transparency. Critical parameters such as transition rates and utilities were elicited by systematic literature reviews and expert opinion. Conflicting values were resolved by weighted averaging and sensitivity analyses.

Results: On average, selecting TLE over APR for T1 rectal cancer resulted in a loss of 0.53 years of life expectancy but a gain of 0.97 quality-adjusted life years; hence, TLE was considered the preferable option in the majority of patients. APR was preferred if and only if the patient was unwilling to yield 7% of his or her life expectancy to avoid a permanent stoma. This transition point shifted depending on the anticipated risk of recurrence after TLE. Sensitivity analysis indicated robustness of our findings.

Conclusions: Though performing an APR for T1 adenocarcinoma of the low rectum does provide an extra six months of life expectancy, a TLE is the preferable approach for the majority of patients when quality-of-life is taken into consideration. The decision in an individual patient's case can be facilitated by tumour risk-stratification and by ascertaining the patient's willingness to yield life expectancy to avoid a permanent stoma.
First-line treatment of advanced colorectal cancer with bevacizumab in France: The ThInDiT observational cohort study.
Authors: Doat Solene , Samson Solene , Ricordeau Philippe , Guillemot Didier , Mitry Emmanuel
Published: February 2017

655

Background: ThInDiT (Therapeutic Innovations in Digestive Tumors) is an ambispective observational cohort study based on the database of the French national health insurance system. Using this database, we analysed the use of bevacizumab in the front-line treatment of metastatic colorectal cancer.

Methods: Patients and treatment characteristics were collected for 4 273 incident cases of colorectal cancer with synchronous metastases diagnosed between April 1st and September 30th 2009. A logistic regression was used to identify factors predictive of non-prescription of bevacizumab among patients receiving chemotherapy within the first three months.

Results: 2 757 (64.5%) received chemotherapy, in combination with bevacizumab in 827 patients (30% of the treated patients). Median age was 64 years in the bevacizumab group against 70 years in the no bevacizumab group (p<0.0001). Major factors significantly associated with the non-prescription of bevacizumab in multivariate analysis were: age ≥ 75 years (OR= 2.47, IC95% 1.9-3.1), unresected primary tumour (OR=1.44, IC95% 1.2-1.8), rectal site (OR= 1.37, IC95% 1.1-1.8), peritoneal carcinosis (OR=1.37, IC95% 1.1-1.7), radiotherapy within the last month (OR=3.59, IC95% 2.1-6.1), arterial (OR= 1.72, IC95% 1.1-2.6) or venous (OR=2.04, IC95% 1.3-3.1) thromboembolic event within 6 months, arterial hypertension (OR=1.37, IC95% 1.1-1.7), wound (OR=3.35, IC95% 1.3-8.7), chronic bronchopneumopathy (OR=1.66, IC95%: 1.0-2.7), nephropathy (OR=2.69, IC95% 1.5-4.7). Brain metastasis and colonic endoprothesis were not associated. 1-year overall survival rate was 81% in the bevacizumab group and 76% in the no bevacizumab group.

Conclusions: Based on the database of the national health insurance system, this analysis reports data on the use of chemotherapy in combination with bevacizumab in the French population, reflecting the real life practice among non-selected patients. About 2/3 of the patients with synchronous metastatic colorectal cancer are treated with chemotherapy, in combination with bevacizumab in 30% of the cases. Patients receiving bevacizumab are younger with less comorbidities.
Treatment patterns and outcomes of acneiform eruptions from anti-epidermal growth factor receptor (EGFR) therapies for metastatic colorectal cancer (MCRC).
Authors: Dascalu Bogdan , Kennecke Hagen F. , Lim Howard John , Cheung Winson Y.
Published: February 2017

668

Background: Use of anti-EGFR therapies, such as cetuximab (cmab) and panitumumab (pmab), is associated with acneiform eruptions. Because prior research suggests a possible correlation between rash severity and outcomes in unselected patients, concerns remain that prophylactic treatment of rash may interfere with anti-tumor activities of these drugs. Our aims were to: 1) characterize the treatment patterns for rashes due to cmab and pmab; and 2) evaluate if a prophylactic vs. reactive approach to rash management modifies outcomes.

Methods: All patients diagnosed with wild-type K-ras MCRC from July 2009 to June 2011 in British Columbia, Canada and prescribed either cmab or pmab were identified. We conducted a detailed retrospective review to describe prophylactic (before rash) and reactive (after rash) use of antibiotics and steroid creams. Using Cox regression, the relationship between rash management and overall survival was characterized.

Results: In total, 78 eligible patients were analyzed: median age was 62 years, 65% were male, 27% received cmab and 73% pmab, and median number of anti-EGFR treatment was 9 cycles. Rash occurred in 88% of patients. Among them, reactive treatment was favored over prophylactic treatment (74% vs. 26%). There were no differences in rash management based on any patient or tumor characteristics (all p>0.05). Median overall survival was 7.2 months. The number of treatment cycles and overall survival were similar in both prophylactic and reactive groups. In Cox regression, ECOG 2+ correlated with worse overall survival (HR for death 5.95, 95% CI 1.68- 21.13). However, outcomes were statistically similar between patients prescribed antibiotics prophylactically vs. reactively (HR=1.47, 95% CI 0.37-5.90) and between patients given steroid creams prophylactically vs. reactively (HR=0.75, 95% CI 0.11-4.88).

Conclusions: Prophylactic treatment of anti-EGFR related rash is associated with similar outcomes as reactive rash treatment in wild-type K-ras MCRC patients. Because rash can lead to decreased quality of life, pre-emptive skin treatment represents a reasonable strategy for patients on anti-EGFR therapies.
Phase II trial of bevacizumab, irinotecan, cisplatin, and radiation as preoperative therapy in esophageal adenocarcinoma.
Authors: Ilson David , Goodman Karyn A. , Janjigian Yelena Yuriy , Shah Manish A. , Kelsen David Paul , Rizk Nabil P. , Rusch Valerie W. , Wu Abraham Jing-Ching , Campbell Jenny , Capanu Marinela , Bains Manjit S.
Published: February 2017

67

Background: Preop chemo and radiotherapy (RT) with weekly irinotecan (I), cisplatin (C) and 5040 cGy is tolerable and active [Cancer, in press]. Bevacizumab (B) + weekly I/C in advanced esophagogastric cancer increased response rate and PFS without an increase in toxicity [JCO 24: 5201; 2006]. In a phase II trial in esophageal adenocarcinoma (EA) we combined B + I/C + RT as preop therapy. A toxicity analysis after 10 patients (pts) undergoing surgery indicated no unexpected toxicity with B [JCO 27: Abstract 4573; 2009]. We completed a planned accrual of 33 pts.

Methods: Pts had resectable Siewert’s I or II EA, T2-3 or N1 staged by EUS, PET, and CT scan. Induction chemo: I 50-65 mg/m2 + C 30 mg/m2 weeks 1,2,4,5, B 7.5 mg/kg weeks 1 and 4; Chemort: 180 cGy daily fractions to 5040 cGy, I/C weeks 7,8,10,11+ B weeks 7,10. Esophagectomy was planned 6-8 weeks after RT. Postop: B 7.5 mg/kg every 3 weeks for 8 cycles.

Results: 33 pts were enrolled. 26 male: 7 female; 13 Siewert I (39%): 20 Siewert II (61%); 21 T3N1 (64%); 10 T3N0 (30%); 2 T2N0-1 (6%). 25/33 pts went to surgery (76%), 24 had R0 resection (73%). Pathologic CR 4/33 pts (12%). 8 pts did not go to surgery: 2 for adverse events (9%, 1 CVA due to patent foramen ovale, 1 esophageal perforation due to endoscopic biopsy), 5 for progressive disease (15%). 21/24 pts (88%) received adjuvant B, 20 (95%) completed all cycles. Grade 3/4 toxicity in 30 evaluable pts during chemort: 27% neutropenia, 3% neutropenic fever, 23% esophagitis, 13% dehydration, 13% thrombocytopenia, 7% pulmonary embolism, 3% nausea/vomiting. Surgical complications: 3 anastamotic leaks (12%), 4 respiratory failure (16%), 1 pulmonary embolism (4%), 2 post op deaths (8%). At a median follow up of 20 months, PFS was 14 months and OS was 30 months.

Conclusions: The addition of B to preop chemoRT in EA was tolerable without increase in treatment toxicity or surgical complications. There was no suggestion of improved pathologic CR, PFS, or OS with the addition of B to I/C/RT. Evaluation of B in phase III trials of chemort does not appear warranted. Supported by a grant from Genentech.
Retrospective cohort study on the safety and efficacy of bevacizumab for metastatic colorectal cancer patients: The HGCSG0801 study—Efficacy of KRAS mutational status.
Authors: Sogabe Susumu , Yuki Satoshi , Hayashi Hideyuki , Naruse Hirohito , Nakamura Michio , Iwanaga Ichiro , Kato Takashi , Takagi Tomofumi , Okuda Hiroyuki , Komatsu Yoshito
Published: February 2017

680

Background: Mutations of the KRAS gene were identified as a prognostic marker in metastatic colorectal cancer(mCRC). Previously reported data suggests that the longer overall survival (OS) observed with bevacizumab(BV) treatment in mCRC is independent of alterations in the KRAS mutation status. So we analyzed efficacy of bevacizumab combined chemotherapy in mCRC relative to KRAS mutation status.

Methods: In the retrospective analysis(n=212) of patients treated with BV(HGCSG0801), additional statistical analyses were done with data from KRAS mutation analyses. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival(PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRAS in terms of PFS and OS. All statistical tests were performed using SPSS.

Results: KRAS status was assessed in 88 patients (41.5%). Response rate was 58.9% with wild-type and 62.5% with mutant KRAS, that was not significant(p=0.823). The median Progression-free survival was 11.5 months with wild-type and 11.5 months with mutant KRAS, that was not significant(p=0.222). And median OS was 31.8 months with wild-type and 27.5 months with mutant KRAS, that was not significant(p=0.760) as well. Similar results were seen among patients with first-line therapy.

Conclusions: Bevacizumab provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS.
Retrospective cohort study on the safety and efficacy of cetuximab for metastatic colorectal cancer patients: HGCSG0901—Analysis of predictive markers.
Authors: Hatanaka Kazuteru , Yuki Satoshi , Nakatsumi Hiroshi , Kogawa Takahiro , Fukushima Hiraku , Fujikawa Koshi , Sato Yasushi , Saito Mayuko , Munakata Masaki , Komatsu Yoshito
Published: February 2017

683

Background: The anti-EGFR antibody Cetuximab (Cmab) do not provide therapeutic effect to patients with KRAS mutations. It has been reported that there is no correlation between the staining intensity of EGFR and efficacy of Cmab. Moreover, the previous studies have suggested that the intensity of skin toxicity that occurs after the administration is a predictive marker of Cmab.

Methods: Of 269 cases registered in the multi-institutional retrospective study (HGCSG0901) treated with Cmab, 252 patients for 3rd line or after treatment line were analyzed. Each degree of skin toxicity, KRAS mutation status and EGFR expression status, respectively, were analyzed for response rates, progression-free survival (PFS) and overall survival (OS). The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine PFS and OS. Log-rank test was used to compare each regimen in terms of PFS and OS. All statistical tests were performed using SPSS.

Results: KRAS status: wild type (WT)/mutant type (MT): 135/32, EGFR status: positive/negative: 210/38, Skin toxicity: Grade 0/1/2/3: 31/50/128/43. Analysis of KRAS status: Response rate: WT 23.7%/MT 6.3% (p=0.028), Progression-free survival: WT 4.8 months /MT 2.1 months (p<0.001), Overall survival: WT 9.9 months/MT 5.3 months (p=0.003). There was a significant correlation between the degree of skin toxicity and efficacy. However, EGFR expression status showed no differences in efficacy.

Conclusions: Here, we reported the results of efficacy analysis for each predictive marker of Cmab. As with previous reports, patients with KRAS mutations did not benefit from Cmab. Degree of skin toxicity was a useful indicator of effectiveness after starting treatment, whereas EGFR status was not effective predictor in daily practice setting.
Retrospective cohort study on the safety and efficacy of bevacizumab for metastatic colorectal cancer patients: The HGCSG0801 study—Analysis of bevacizumab beyond progression (BBP).
Authors: Fukushima Hiraku , Yuki Satoshi , Kobayashi Yoshimitsu , Hatanaka Kazuteru , Kusumi Takaya , Hosokawa Ayumu , Miyagishima Takuto , Takeuchi Satoshi , Kudo Mineo , Komatsu Yoshito
Published: February 2017

684

Background: Bevacizumab (BV) is widely used in first-line chemotherapy for metastatic colorectal cancer in Japan, but the use of beyond bevacizumab first progression (BBP) has been controversial yet.

Methods: Of patients treated with first-line BV in our retrospective cohort study (HGCSG0801), patients treated with BBP (n=22) and those without BBP ( n=19) in second-line setting were analyzed. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to assess adverse events. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine PFS and OS. Log-rank test was used to compare each group in terms of PFS and OS. All statistical tests were performed using SPSS.

Results: PS (0/1/2) before second line chemotherapy was 18/3/1 in BBP and 10/8/1 in NBBP, respectively. In the safety analysis, five patients in BBP showed a worsening/newer hypertension, which wasn’t a clinical problem. In the efficacy analysis, the response rate was 22.8% in BBP and 0% in NBBP. The median PFS was better in BBP (6.7 months in BBP and 2.7 months in NBBP), but there was no significant difference in median OS from first BV administration between two groups (27.3 months in BBP and 22.2 months in NBBP).

Conclusions: We analyzed BBP in daily practice in Japan. Adverse events were well tolerated, but survival advantage of BBP was not suggested. About the efficacy of BBP, we are waiting the results of ongoing Phase III trials.
Efficacy and tolerability of bevacizumab (BEV) plus capecitabine and cisplatin (XP) in Chinese patients (pts) with locally advanced or metastatic gastric/gastroesophageal junction cancer (AGC): Results from the AVATAR study.
Authors: Shen Lin , Li Jin , Xu Jian-Ming , Pan Hong-Ming , Dai Guanghai , Qin Shukui , Wang Liwei , Wang Jinwan , Yang Zhenzhou , Yongqian Shu
Published: February 2017

73

Background: In the AVAGAST study, chemotherapy (fluoropyrimidine and cisplatin) + BEV did not significantly improve overall survival (OS) vs. chemotherapy + placebo. Geographic differences in efficacy were observed, but only 12 Chinese pts were included. AVATAR, a study similar in design to AVAGAST, is a randomized double-blind study conducted exclusively in China in pts with AGC.

Methods: Pts aged >18 years with gastric adenocarcinoma were randomized 1:1 to XP + BEV 7.5 mg/kg or placebo + XP. The primary objective was OS; secondary objectives included progression-free survival (PFS) and safety.

Results: Baseline characteristics of the 202 pts were well balanced. The primary efficacy endpoint of improved OS in the BEV arm was not met (HR 1.11, 95% CI 0.79–1.56; p=0.5567; see table ). BEV + XP was well tolerated. Grade 3–5 adverse events (AEs) and serious AEs were 60% and 19% for BEV and 68% vs. 21% for placebo, respectively. Grade 3–5 AEs of special interest with BEV occurred in 8% of BEV pts and 15% of placebo pts; the difference was mainly due to grade 3–5 haemorrhage (BEV 4%, placebo 12%).

Conclusions: Addition of BEV to XP in Chinese pts with AGC did not significantly improve outcomes in AVATAR. The results from AVATAR are consistent with the findings seen in the Asian sub-population of the previous AVAGAST study.

[Table: see text]
Effect of increased time from chemoradiation to surgery on the pathologic complete response rate in patients with esophageal cancer.
Authors: Shaikh Talha , Ruth Karen , Scott Walter Joseph , Burtness Barbara , Cohen Steven J. , Konski Andre A. , Cooper Harry S , Astsaturov Igor A. , Meyer Joshua E.
Published: February 2017

84

Background: Studies have demonstrated that pathologic complete response (pCR) in patients undergoing tri-modality treatment for esophageal cancer predicts for decreased local and distant recurrence, as well as increased survival. Increased time from chemoradiation (CRT) to surgery has been shown to increase pCR rates in rectal cancer. This study assessed the effect of the time between the end of CRT and surgery on pCR rates in esophageal cancer.

Methods: Clinical records identified 231 patients with resectable esophageal cancer who were treated with CRT from 2000 to 2011, of which 89 underwent subsequent surgery. The records were analyzed for predictors of pCR. Univariate and multivariable analyses were used to determine the significance of all predictors of pCR.

Results: Of 89 patients completing trimodality therapy, 76 were male, and the median age was 61 years (range=36-80). Adenocarcinomas comprised 75 patients, and 14 were squamous cell carcinomas. Nine patients had T1/T2 lesions and 80 patients had T3/T4 lesions; 68 patients had node positive tumors. 72 patients received 5FU-based therapy and 17 patients received carboplatin-based therapy. The median radiation dose was 5040 cGy (720-6000) and median follow-up was 24 months. Overall, pCR was seen in 21 patients (24%). The median time from CRT to surgery for a pCR was 102 days vs. 87 days for less than a pCR (p=0.06). By quartile of time from CRT to surgery, pCRs were 18% for <81 days, 13% for 81-88 days, 18% for 89-102 days, and 45% for 103+ days (p=0.05). Multivariable logistic regression showed a trend towards a difference in pCR rates by interval quartile (p=0.06); OR for the highest vs lowest quartile was 5.3 (95% CI=1.1 to 25.6). T stage, N stage, histology, radiation dose and type of chemotherapy were not predictive of a pCR.

Conclusions: In this retrospective study, increased time between CRT and surgery was associated with a trend toward increased pCR rates; patients in the longest interval quartile (103+ days) had more pCRs than patients in the shortest interval quartile (<81 days). These data suggest further evaluation of time from CRT to surgery is warranted.
Infectious complication and recurrence after surgery for gastric cancer.
Authors: Hayashi Tsutomu , Tsuburaya Akira , Yoshikawa Takaki , Cho Haruhiko , Ogata Takashi , Aoyama Toru
Published: February 2017

85

Background: There are many known prognostic indicators following surgery for gastric cancer. However, the impact of infectious complication on prognosis is less clear. The aim of the present study was to evaluate the relationship between infectious complication and relapse-free survival in patients undergoing potentially curative resection of gastric cancer.

Methods: A consecutive series of 657 patients who underwent macroscopically curative resection between 2000 and 2005 in Kanagawa Cancer Center were retrospectively studied. Five-year relapse-free survival rates in each stages (TNM7th) were calculated. Infectious complications (≥Grage2 by Clavien-Dindo classification) were classified as pneumonia, anastomotic leakage, intra-abdominal abscess, septicaemia, colitis, pancreatic-fistula, and wound infection.

Results: Mean age was 61 years; male-female ration was 4:1; the number of patients in TNM7th stages were I :389, II :93, III :116, and IV :59. Infectious complications occurred in 57 patients (8.7%) including 8.5% in stage I, 3.2% in stage II, 12.1% in stage III, and 11.9% in stage IV, respectively. Five-year relapse-free survival rates in patients without infectious complications and with infectious complications were 93.1% vs 81.6% in stage I, 84.4% and 100% in stage II, 55.8% and 28.6% in stage III, and 9% and 0% in stage IV, respectively. In stage III, patients with infectious complication had significantly poorer outcome in relapse-free survival compared with those without one (p<0.05).

Conclusions: This study indicates a correlation between infectious complications and cancer recurrence in advanced but localized gastric cancer. Immunologic response of the host against postoperative infection could influence the viability of microscopic residual disease. Further clinical and basic study are needed to improve outcome for this category of patients.
Post-radiation metabolic tumor volume (MTV) and survival in esophageal cancer.
Authors: Cruz Alex , Chuong Michael D. , Weber Jill M. , Eikman Edward , Lomas Harry , Pimiento Jose Mario , Almhanna Khaldoun , Shridhar Ravi , Hoffe Sarah E. , Meredith Ken
Published: February 2017

9

Background: PET-CT is an important tool for staging and evaluating treatment response in esophageal cancer. Metabolic tumor volume (MTV) has been reported as a prognostic factor in other malignancies. We evaluated the utility of post-radiation MTV in esophageal cancer patients treated with chemoradiotherapy (CRT).

Methods: We evaluated pre- and post-treatment PET/CT scans in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) treated with neoadjuvant/definitive intent. We measured the significance of the post-treatment MTV2.0-5.0 which was defined as the metabolic volume above a threshold SUV of x. Cox regression models were used to determine any significance between MTV2.0 -5.0 and disease free survival (DFS) or overall survival (OS). Multivariate analysis was performed.

Results: We identified 63 patients (13 SCC, 50 AC) with a median follow-up of 12.0 months (range, 1.9-38.6). The median time to post-radiation PET/CT scan after completion of CRT was 40.1 days (range, 20-93). Thirty-seven (58.7%) patients underwent surgical resection. Univariate analysis revealed no significant correlation between post-treatment MTV and OS (MTV2.0 p = 0.968; MTV3.0 p = 0.945; MTV4.0 p = 0.890; MTV5.0 p = 0.316). There was also no significant correlation with respect to DFS (MTV2.0 p = 0.956; MTV3.0 p = 0.658; MTV4.0 p = 0.695; MTV5.0 p = 0.690). Multivariate analysis revealed that SCC histology and surgical resection were associated with improved OS while age, gender, post-radiation MTV2.0-5.0, and stage were not. Earlier stage and surgical resection were associated with improved DFS while post-radiation MTV2.0-5.0, age, gender, and histology were not.

Conclusions: Although other studies have shown post-radiation MTV to be a significant prognostic factor, our data demonstrate no significant correlation with MTV and survival among esophageal cancer patients.
Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1.
Authors: Van Cutsem Eric , Yeh Kun-Huei , Bang Yung-Jue , Shen Lin , Ajani Jaffer A. , Bai Yu-Xian , Chung Hyun Cheol , Pan Hong-Ming , Chin Keisho , Muro Kei , Kim Yeul Hong , Smith Heind , Costantini Chiara , Musalli Sara , Rizvi Syed , Sahmoud Tarek , Ohtsu Atsushi
Published: February 2017

LBA3

Background: The prognosis for patients with AGC after failure of first-line chemotherapy is poor. Currently, there is no level 1 evidence established for second-line treatment. EVE inhibits the PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, metabolism, and angiogenesis, and has shown efficacy against AGC in preclinical and phase I/II studies.

Methods: In a randomized, double-blind, multicenter, phase III study, patients age ≥18 years with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to oral EVE 10 mg/d plus best supportive care (BSC) or placebo (PBO) plus BSC. Randomization was stratified by region (Asia vs rest of world) and previous lines of chemotherapy (1 vs 2). Study drug was discontinued upon progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. The final analysis was performed when 526 deaths occurred.

Results: A total of 656 patients from 23 countries were enrolled from Jul 2009 to Dec 2010; 439 were randomized to EVE, 217 to PBO. Baseline characteristics were well balanced between arms; 73.6% were men, 55.3% were enrolled in Asia, 47.7% received 1 previous line of chemotherapy, and 50.6% had a gastrectomy. Median OS was 5.39 months with EVE vs 4.34 months with PBO (HR, 0.90; 95% CI, 0.75-1.08; P=0.1244). Median PFS per local investigator assessment was 1.68 months with EVE vs 1.41 months with PBO (HR, 0.66; 95% CI, 0.56-0.78; p<0.0001). Six-month PFS estimates were 12.0% with EVE and 4.3% with PBO. OS and PFS results were consistent across the various subgroups. ORR (95% CI) was 4.5% (2.6%-7.1%) with EVE vs 2.1% (0.6%-5.3%) with PBO. The most common grade 3/4 adverse events were anemia (16.0% with EVE vs 12.6% with PBO), decreased appetite (11.0% vs 5.6%), and fatigue (7.8% vs 5.1%).

Conclusions: EVE monotherapy did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. EVE did improve PFS. Results for OS and PFS were consistent across the various subgroups. The safety profile was consistent with that previously observed with EVE.
Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.
Authors: Grothey Axel , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Lenz Heinz-Josef , Yoshino Takayuki , Cihon Frank , Wagner Andrea , Van Cutsem Eric
Published: February 2017

LBA385

Background: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in pts with mCRC who had progressed after all approved standard therapies.

Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life.

Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented.

Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.
Prospective analysis of prostate cancer (PC) circulating tumor cells (CTCs) to predict response to docetaxel (DOC) chemotherapy.
Authors: Nanus David M. , Loftus Matthew , Akhtar Naveed Hassan , Tagawa Scott T. , Beltran Himisha , Goodman Oscar B. , Zhou Xi Kathy , Bander Neil Harrison , Giannakakou Paraskevi
Published: February 2017

100

Background: Taxane chemotherapy induces cellular microtubule stabilization (bundling) leading to mitotic arrest and apoptotic cell death. We recently reported that in castration-resistant PC, stabilizing of microtubules by taxanes inhibits ligand-induced androgen receptor (AR) nuclear translocation and activation of ARE-gene transcription (Cancer Res 2011;71:6019). This suggests the clinical activity of DOC results from inhibition of AR signaling. A pilot analysis of CTCs from 14 CRPC pts receiving taxanes revealed that predominant cytoplasmic AR and decreased total AR intensity each was associated with increased odds of response (P<0.001). We initiated a prospective trial to determine if CTC analysis could predict DOC response.

Methods: Eligibility: Patients (pts) receiving DOC q21 days for CRPC with >5 CTCs determined by CellSearch. On cycle 1 d1 + d8, CTCs are isolated by ficoll tube separation and by CellSearch enrichment. Cells are stained for expression of prostate specific membrane antigen (PSMA), CD45, AR and acetylated tubulin (AcTub) as a marker of microtubule stabilization. AR localization and total fluorescence intensity, and AcTub intensity are quantitated by confocal microscopy and correlated with response to DOC using PCWG2 criteria. 72 pts are planned to provide 80% power to detect an association.

Results: 28 of 72 pts have been prospectively enrolled to assess AR and AcTub as a biomarker of response. 20 pts have discontinued DOC. Day 1 samples were obtained from 27 pts and day 8 on 22 (5 pts on days 9 to 21). Immunofluorescence staining and evaluation of PSMA, CD45, and acetylated tubulin was performed successfully in 8 pts analyzed to date. CTCs can be identified in all pts. Cells are scored for AR and AcTub intensity (scale 1- 4) and AR nuclear vs cytoplasmic localization.

Conclusions: Our results to date indicate that PC CTCs can be readily isolated from men receiving DOC chemotherapy in a multicenter fashion and assayed for AR localization and AcTub. Preliminary results suggest that monitoring AR subcellular localization and microtubule bundling in CTCs may predict clinical responses to DOC chemotherapy, warranting further study, including our prospective trial.