bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of cetuximab (cet) and mFOLFOX6 in metastatic colorectal cancer (mCRC) (JACCRO CC-05).
Authors: Yamaguchi Tatsuro , Tsuji Akihito , Sunakawa Yu , Nakamura Masato , Kochi Mitsugu , Denda Tadamichi , Shimada Ken , Tani Satoshi , Takagane Akinori , Kotaka Masahito , Kuramochi Hidekazu , Koike Junichi , Furushima Kaoru , Yonemura Yutaka , Negoro Yuji , Takinishi Yasutaka , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Nakajima Toshifusa
Published: February 2017

611

Background: FOLFOX4 combined with cet for mCRC patients (pts) with KRAS wild tumor demonstrated the prolonged progression-free survival (PFS) with higher response rate (RR) in the OPUS study. To evaluate the clinical efficacy and safety of the cet plus mFOLFOX6, we conducted a multi-center phase II study of Japanese pts. Methods: In this trial, pts with KRAS wild type tumor and receiving no prior chemotherapy for mCRC were treated with cet (initial dose 400, and 250 mg/m2 weekly) followed by mFOLFOX6 (oxaliplatin 85mg/m2, l-leucovorin 200 mg/m2, fluorouracil, as 400mg/m2 intravenous bolus then 2,400mg/m246-hour continuous infusion). The treatment was repeated every 2 weeks. The primary endpoint was RR evaluated by the external review board according to RECIST v1.1. Secondary endpoints included PFS, OS, % chronological change at the base line and safety. Results: A total of 57 pts were enrolled from August 2010 to September 2011. The median age was 60 years, 65% of pts were male, and ECOG PS 0 was observed in 91% of pts. All pts had EGFR-expressing disease. The median treatment courses were 21 (cet) and 10 (FOLFOX). The RR was 66.7% (95%CI, 53.4 to 77.7). Complete remission was observed in 5 cases (9.3%). The median PFS was 11.1 months (95%CI, 8.0 to 14.7). The early tumor shrinkage (ETS; over 20% regression at 8 weeks) was observed in 80% of pts, and the PFS for pts with ETS was statistically significantly prolonged as compared with pts without ETS (median PFS, 11.5 vs. 3.7 months, respectively; p = 0.0002). The OS was not reached at the time of median follow-up (19.2 months). Grade 3 or worse adverse events were neutropenia (48.2%), leucopenia (22.2%), rash acneform (20.4%), and peripheral neuropathy (18.5%). Conclusions: The first-line cet+mFOLFOX6 has an acceptable safety profile and demonstrates advantages in response rate for pts with KRAS wild tumor. The first-line cet+mFOLFOX6 should be considered as one of the recommended treatment regimens for pts with KRAS wild tumor. Update survival data will be presented. Clinical trial information: UMIN000004197.
Surgical management of synchronous colorectal liver metastases: Simultaneous versus staged resections.
Authors: Shchepotin Igor , Lukashenko Andrii , Kolesnik Olena , Burlaka Anton
Published: February 2017

616

Background: Surgical treatment of metastatic colorectal cancer remains the only method that improves overall 5-year survival. This study aimed to compare the surgical outcome and survival benefit between synchronous and staged resection of liver metastases from colorectal cancer. Methods: Clinicopathologic data, treatments, and postoperative outcomes from 110 patients who underwent simultaneous (48 patients, group A) or staged (62 patients, group B) colorectal and hepatic resections at clinic of National cancer institute in period of 2008-2013 were reviewed. Results: Postoperative complications in patients with simultaneous resections (group A) were observed in 13 cases (27.1%), including 5, 1, 4, 2, 0, and 1 of grades I, II, IIIa, IIIb, IV, and V, respectively. Similar results have been reported in group B after staged resections, where overall postoperative complications registered in 16 patients (25.8 %), including 4, 3, 6, 3, 0 of grades I, II, IIIa, IIIb, and IV respectively. Overall level of post-operative complications in the groups A and B after surgical stages finishing did not differ statistically (p=0.96). Shorter operative intervention duration was registered in the group A – (311±10.1) min, whereas in the group B it was (496.6±16.2) min (р<0.001). Patients after staged resection stayed in clinic for a longer time – 23.9±0.8 bed-days, when simultaneous resections provided with shorter recovery terms in post-operative period – 9.8±0.5 bed-days (p<0.001). Overall 3-year survival in the group of patients with simultaneous resections (group А) was 42 % and in the group B 55 % (р=0.22). Conclusions: Analysis of our research indicated necessity of the development of differentiated approach in management of synchronous colorectal liver metastatic cancer. Simultaneous resections of colorectal cancer primary lesions and hepatic metastases were safe and could serve as a primary option for selected patients. Subsequent research should be directed towards study of prognosis factors and criteria for patients’ selection for surgical treatment groups, assessment of economic effect, and patients life quality.
Combination of 5FU-based chemoradiation with EGFR inhibitor cetuximab and effect on PCR rate in patients undergoing neoadjuvant treatment in advanced rectal cancer.
Authors: Semrau Robert , Kocher Martin , Vallbohmer Daniel , Hoelscher Arnulf
Published: February 2017

623

Background: Neoadjuvant chemoradiation is a standard treatment for advanced rectal cancer patients. Here, we investigate whether treatment combined with the EGFR inhibitor cetuximab could enhance prognosis. Safety and efficacy (pathohistological regression rate, pCR) of chemoradiation in combination with cetuximab were evaluated. Methods: In a single-center phase I/II study patients with adenocarcinoma of the rectum (up to 16 cm above the anal verge) in stage cT3-4, cN0-1, were treated with cetuximab (weekly 250mg/m2, loading dose 400mg/m2) combined with radiotherapy (50,4Gy in 28 fractions) and 5-FU. Maximal tolerated dose of 5FU in combination with cetuximab and radiotherapy was determined in a phase I part (3+3 design; dose level 1: 750 mg/m2 5FU days 1-5 and 29-33; dose level 2: 1000 mg/m2 5FU days 1-5 and 29-33. Surgery was performed between 4 to 6 weeks after combined treatment. pCR rate of tumor cells was determined after surgery. Results: 20 patients were included into the trial, 19 patients received treatment: In the phase I part 2 out of 6 patients in level 2 experienced dose limiting toxicities (thrombocytopenia and diarrhea grade 3). Therefore, dose level 1 was considered safe for further enrollment. All 19 patients received the complete course of radiotherapy (50,4Gy). 15 patients received the complete cetuximab schedule, one patient discontinued after an allergic reaction at the first infusion, 3 patients missed 1 cycle of cetuximab in week 3 or 6. 18 patients continued to surgery. Sphincter preservation surgery was performed in 12 patients (63.2%), R0-resection rate was 100%. pCR grade IV (pCR) was documented in 1 patient (5,5%), grade III in 4 patients and grade I and II in 13 patients. So far no local recurrences occurred, 4 patients died (3 patients due to metastatic disease progression). Conclusions: The MTD of 5FU in combination with radiotherapy and cetuximab was 750mg/m2. Treatment was well tolerated and did not alter surgical management. However, pCR-rate was not elevated compared to standard 5FU-based preoperative chemoradiation. Whether the addition of cetuximab improves prognosis in this group of patient remains unclear. Clinical trial information: 2005-004139-23.
A preoperative clinical staging and metabolic imaging model to predict prognosis in early-stage esophageal adenocarcinoma.
Authors: Turkington Richard Calvin , Blayney Jaine K. , Jalil Awais , Goody Rebecca Barbara , Papafili Anastasia , Henderson Chloe , McManus Damian , Johnston Patrick , Kennedy Richard D. , Eatock Martin McKinlay
Published: February 2017

63

Background: Accurate prediction of outcome for neo-adjuvant therapy in early stage esophageal adenocarcinoma (EAC) is essential for clinical trial design, patient counseling and treatment decisions. The use of 18F-fluorodeoxyglucose positron emission tomography (PET) has improved the staging of EAC and can predict pathological response and survival. Our aim was to develop a pre-operative prognostic model based on metabolic imaging and clinical parameters. Methods: Between April 2004 and December 2010, 118 patients with early stage adenocarcinoma of the distal esophagus or gastro-esophageal junction were treated with platinum and fluorouracil-based combination chemotherapy prior to surgical resection. Patients were staged by endoscopic ultrasound and PET/CT was performed prior to, and upon completion of, chemotherapy. A metabolic response was defined as a >35% reduction in the maximum standard uptake variable (SUVmax). The final prognostic model was selected by multivariate Cox regression analyses and the concordance-index (c-index) was used to assess the fit of the final multivariate model. Results: In both the univariate and multivariate analysis of patient prognosis post-surgery, five pre-surgery factors were included: clinical T and N staging, PET response, neutrophil-lymphocyte ratio and albumin levels. The majority of the patients were T3 (82.1%) and N1 (73.7%) and 69.8% of patients demonstrated a PET response. In the univariate analysis PET response was the only significant prognostic factor with a median overall survival (OS) of 60.4 months for responders compared to 23.3 months for non-responders (p=0.0241). The final multivariate model of T staging and PET response had a c-index of 0.624 with T3/PET non-response resulting in a poorer prognosis compared to T3/PET response and T2/PET responder or non-responder (median OS 11.5 vs 44.5 vs undefined months; p=0.0284). We seek to validate our model in an independent patient dataset to assess its predictive capability. Conclusions: Metabolic imaging and clinical staging can be combined in a prognostic model in early stage EAC. Our model can inform patient counseling and the development of clinical trial strategies.
Effect of intensity-modulated radiation therapy with SIB technique on local control and toxicity for neoadjuvant pelvic radiation with concurrent 5-fluorouracil based chemotherapy for rectal cancer compared with three-dimensional conformal radiation therapies.
Authors: Thawani Nitika , Shilpa Vyas , Hasan Shaakir , Axelrud Gabriel , Niloyjyoti Deb , Mutyala Subhakar
Published: February 2017

632

Background: To compare the areas of residual disease after neoadjuvant pelvic radiation with 5-FU based chemotherapy for rectal cancer using Intensity Modulated Radiation Therapy (IMRT) with simultaneous integrated boost (SIB) technique compared to 3D Conformal Radiation Therapy (3DCRT) Methods: Fourty nine (49) consecutive rectal cancer patients treated with pelvic radiation and concurrent 5-FU based chemotherapy were analyzed. We compared twenty-eight (28) patients treated on an institutional IMRT protocol versus twenty-one (21) patients treated with 3DCRT. All patients received 45-50.4 Gy to the pelvis in 3DCRT group. All patients with IMRT received 45 Gy in 25 fractions to the pelvic no des. The primary rectal tumor recieved a simultaneous integrated boost to a dose of 50 Gy in 25 fractions. IMRT planning was done with dose constraints for bladder, rectum, and small bowel and bone marrow. All patients in both groups received 5-FU based chemotherapy during radiation. Evaluation of toxicity was based on RTOG criteria. 2 patients in the 3DCRT group and 2 in IMRT group received either growth factors or blood-products transfusion and needed hospitalization during treatment secondary to acute toxicities. Results: All patients completed their prescribed course of radiation. CR rates were 5/21(23%) in 3DCRT and 4/28(25%) in the IMRT-SIB (p-value 0.74). 9/21(42%) in 3D and 19/29(65%) in the IMRT group underwent Low anterior resection according to the location of the tumor. There was no grade 4 toxicity in the IMRT-SIB group. Overall grade 2 toxicity in 3D Vs IMRT-SIB group was - GI -52% Vs 19%, GU- 8% Vs 8%, skin 42 Vs 4%, hematologic 33 Vs 47%. Overall Grade 1 toxicity in 3DCRT Vs IMRT group was- GI- 33% Vs 52%, GU 23% vs 28%, Skin 52% Vs 38%, hematologic 4% Vs 33%. Conclusions: Neoadjuvant pelvic radiation with 5 FU for rectal cancer has similar local control rates. There is less GI, skin and hematologic toxicity when delivered via IMRT-SIB versus 3DCRT. IMRT is safe and may allow dose escalation with potential probability of increased tumor response.
The correlation of neutrophil/lymphocyte ratio and tumor reduction ratio in preoperative chermoradiotherapy for advanced rectal cancer.
Authors: Yasuda Koji
Published: February 2017

633

Background: Preoperative chemoradiotherapy (CRT) is widely used for the treatment of advanced lower rectal cancer and is considered to reduce the local recurrence rate and improve the anus preservation rate. However, the tumor reduction effect varies among patients, and thus far, no factor has yet been found to be effective in the prediction of therapeutic efficacy. Recent studies have shown tumor immunity in the tumor microenvironment to be involved in the anti-tumor effect of radiation and anti-cancer drugs. Among these studies, some show that the neutrophil/lymphocyte (NL) ratio in blood test results correlates with the therapeutic efficacy. We examined the correlation between the NL ratio based on blood test results and tumor-reducing effect of preoperative CRT on advanced lower rectal cancers. Methods: We included 30 advanced lower rectal cancer patients who underwent preoperative CRT during the period ranging from January 2008 to June 2013.For advanced lower rectal cancers classified as cT3orT4NXM0, preoperative CRT was conducted according to the following regimen: 50.4 Gy (1.8 Gy × 28 fr) + UFT (300 mg/day, LV [75 mg/day]) × 28 days. The neutrophil count and lymphocyte count were determined based on the blood tests conducted before and after CRT; the NL ratio was calculated, and the correlation between the value of the ratio and tumor reduction rate was examined. Results: Radical surgery was performed on 28 of the 30 patients who underwent preoperative CRT. One of the 28 patients showed local recurrence (rate, 3.6%). In addition, down stage tumors were found in 16 of the 28 patients, and the down stage rate was 57.1%. Significant differences (p < 0.0001) were found between the tumor reduction effect and NL ratio from blood tests before CRT, as well as between the tumor reduction effect and the ratio from blood tests after CRT. Conclusions: The above findings suggest anti-tumor immunity in the tumor microenvironment, particularly that lymphocytes might be involved in the antitumor effectiveness of preoperative CRT in advanced lower rectal cancers. In addition, NL ratio from blood tests could be a predictive factor of the tumor reduction effect.
Analysis of Kohne's prognostic index in KRAS wild-type patients with metastatic colorectal cancer (mCRC) treated with salvage-line cetuximab-based regimen: HGCSG0901.
Authors: Doi Ayako , Yuki Satoshi , Tsuji Yasushi , Sasaki Takahide , Fukushima Hiraku , Hatanaka Kazuteru , Naruse Hirohito , Okuda Hiroyuki , Kusumi Takaya , Fujikawa Koshi , Takahashi Yasuo , Saitoh Soh , Kajiura Shinya , Hosokawa Ayumu , Watanabe Yutaka , Yamamoto Fumiyasu , Kudo Mineo , Akakura Nobuaki , Sakata Yuh , Komatsu Yoshito
Published: February 2017

634

Background: In the treatment for mCRC, it is essential for understanding the prognosis of each individual patient. Köhne’s index (KI) based on performance status, white blood cell count, alkaline phosphatase and number of metastatic sites has been previously proposed. However, in the salvage setting, the validity of KI has not been reported in patients treated by cetuximab-based chemotherapy. Methods: 269 patients with mCRC treated by cetuximab contained chemotherapy were retrospectively registered from 27 centers in Japan. This analysis was included in the KRAS wild-type patients who were refractory to or intolerant for 5-FU/irinotecan/oxaliplatin and were never administered anti-EGFR-antibody. Univariate and multivariate analysis for overall survival were performed using patient characteristics. Survival analyses were performed with Kaplan-Meier method, log-rank test and Cox proportional hazards model. The analysis was also designed to determine whether the Köhne’s classification could be extended to other endpoints such as progression-free survival. Results: All data were available for prognostic categorization in 127 patients. Median overall and progression-free survival was 9.8 and 4.2 months. The distribution and median survival / progression-free survival for KI were as follows: low risk (L) (n = 40; 13.1/5.1 months), intermediate risk (I) (n = 17; 9.6/3.5 months), and high risk (H) (n = 70; 7.6/4.1 months). For overall survival, there was significant difference between L and H (p = 0.004), but not between L and I (p = 0.213), and between I and H (p = 0.321). For progression-free survival, there was tended to difference between L and H (p = 0.083), but not between L and I (p = 0.392), and between I and H (p = 0.630). In Cox multivariate analysis, KI showed an independent prognostic impact (HR 1.370, p = 0.010), but not predictive impact (HR 1.147, p = 0.212). Conclusions: In this analysis, KI might be a prognostic factor in salvage treatment with cetuximab-based regimen, but no effect predicted impact. Moreover, the prospective evaluation is needed for the further validation.
Timing of adjuvant chemotherapy in stage III colon cancer as a measure of quality: Reasons for noncompliance.
Authors: Rashid Omar M. , Coyne Karen A. , Ross Thomas W. , Shibata David
Published: February 2017

640

Background: The Institute of Medicine's report on improving cancer care, along with the evolution of ASCO's Quality Oncology Practice Initiative, has helped to develop process measures into critical quality of cancer care indicators. One such measure relates to "receipt of chemotherapy for stage III colon cancer (CC) within 120 days of diagnosis" and is now being incorporated into processes including hospital accreditation (American College of Surgeons; ACS), managed care contracts and Center for Medicare and Medicaid Services (CMS) quality monitoring. To better understand potential pitfalls related to the strict guidelines of this measure, we sought to evaluate institutional adherence at a tertiary care cancer center and to examine the reasons for non-compliance. Methods: A retrospective review was performed of all cases of stage III colon cancer reported at a single institution from 2008 – 2012. Coding for compliance was performed using standard ACS guidelines. Results: A total of 122 eligible cases were identified and consisted of 49 (40.2%) women and 73 (59.8%) men with a median age of 58 (range 32 - 77). Overall, 15 (12.3%) cases were non-compliant with 2 (1.6%) lost to follow up. Of the non-compliant cases, 14 (93.3%) cases did go on to receive chemotherapy while 1 (6.7%) never received adjuvant treatment. Of those receiving delayed treatment, 7 were due to patient-centered factors [e.g. patient timing preference (n=4), request for chemotherapy closer to home (n=2) and lost to follow up (n=1)]. Other reasons included delays at outside facilities (n=4), postoperative complications (n=1) and insurance approval (n=1). In 2 cases, designation of date of diagnosis based on suspicion rather than definitive biopsy contributed to non-compliant status. Conclusions: Our center averaged an annual compliance with the CC adjuvant therapy measure of approximately 90%. Larger scale studies are indicated to determine whether refinements in coding guides that account for patient preferences, clear diagnosis dates and cross-facility care could better reflect quality of care, and also promote improved patient-centered multidisciplinary management.
Panitumumab or cetuximab combined with irinotecan in patients with KRAS wild-type metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens.
Authors: Ikezawa Nobuaki , Iwasa Satoru , Shoji Hirokazu , Honma Yoshitaka , Takashima Atsuo , Okita Natsuko T. , Kato Ken , Shimada Yasuhiro
Published: February 2017

642

Background: Panitumumab and cetuximab are known to be effective in KRAS wild-type metastatic colorectal cancer (mCRC). However, it is not clear whether panitumumab and irinotecan confers benefit that are comparable to those of cetuximab and irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimes. Methods: We analyzed 139 patients who had received panitumumab or cetuximabu combined with irinotecan for KRAS wild-type mCRC previously treated with fluor opyrimidine-, oxaliplatin-, and irinotecan-based regimes.We evaluated and compared efficacy and safety of panitumumab plus irinotecan and cetuximab plus irinotecan. Results: Baseline characteristics were similar for the two groups receving cetuximab pulus irinotecan (n = 97) and panitumumab plus irinotecan (n = 42),respectively.In patients with measurable lesions,the response rate (unconfirmed complete or partial response) were 20% (18/92) in the group receving cetuximab plus irintecan and 34% (14/41) in that receving panitumumab plus irinotecan. Median progression-free survival was 5.7 months in the cetuximab plus irinotecan group versus 4.3 months in the panitumumab plus irinotecan group. Median overall survival was 11.2 months in the cetuximab plus irinotecan group versus 13.6 months in the panitumumab plus irinotecan group. The most common adverse events in the cetuximab plus irinotecan versus panitumumab plus irinotecan groups were all-grade rash acneiform (82% versus 90%), paronychia (61% versus 52%), and grade 3-4 neutropenia (26% versus 19%). Conclusions: Panitumumab or cetuximab plus irinotecan were well tolerated and produced similar response rate and survivals compared to those previous clinical traials.These combinations are cosidered as standard treatment in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimes.
Efficacy and safety of FOLFOX biweekly cetuximab as first-line therapy for patients with nonresectable metastatic colorectal cancer (CELINE trial): Multicenter phase II trial.
Authors: Kondo Ken , Kotake Masanori , Doden Kenji , Munemoto Yoshinori , Kobayashi Kenji , Nishimura Genichi , Omote Kazuhiko , Sakamoto Junichi
Published: February 2017

645

Background: Efficacy and safety of FOLFOX{Bi-weekly cetuximab as first-line therapy for patients with nonresectable metastatic colorectal cancer (mCRC) were examined. Methods: The multicentre phase II trial had began from September 2011. Inclusion criteria were an age of 20 years or older, adenocarcinoma of the colon or rectum, first occurrence of metastatic disease with KRAS wild type tumor that could not be resected, performance status score (ECOG) of 1 or less, and adequate hematologic, hepatic, and renal function. Patients received mFOLFOX6/Cetuximab 500 mg/‡u/biweekly 120min until PD, unacceptable adverse effects, or withdrawal of consent occurred. In the event of grade 2 adverse effects, suspension of Oxaliplatin only was permitted. Primary endpoint was Response Rate, secondary endpoint was anti-tumor effect at week 8, PFS, OS, safety, and efficacy of 5-FU{LV{Cetuximab therapy. Results: 60 patients were screened and 59 underwent the treatment by March 2013. Age 64.5 (38-82), male/female: 47/13, PS 0/1: 51/9, rectal/colon: 31/29 and metastasis in liver/lung/ lymph node/ the other: 51/15/19/7. Data had been analyzed to date showed high response rate, 64% with disese control in 96% -PR 38pts (64%), SD 19 pts (32%). Incident rate of grade 3 or 4 adverse events were neuropenia 19%, peripheral sensory neuropathy 4.8% and rash 8.1%. Conclusions: FOLFOX{Bi-weekly cetuximab therapy benefited in safety administration with high response rate. Therefore it can be considered as a beneficial treatment. Clinical trial information: UMIN000006402.
A retrospective analysis of the demographic profile and clinical outcomes of stage III colon cancer patients treated with adjuvant chemotherapy in a real-world perspective.
Authors: Ramakrishnan Geethakumari Praveen , Pomerantz Sherry , Leighton John Charles
Published: February 2017

648

Background: It is standard to use results of randomized controlled trials (RCT’s) for therapeutic decisions in community oncology. However participant selection in trial environments may not reflect real-world scenario. We aim to perform a retrospective analysis of patient profile and treatment outcomes in a community cancer center. Methods: Patients with stage III colon cancer offered adjuvant chemotherapy after curative resection from 2003-2010 (N=177) were reviewed. Eighty-seven patients with complete medical records were analyzed. Patient eligibility was assessed on criteria from the MOSAIC and NSABP C-07 trials. Eligible and ineligible patients were compared using Fisher’s exact test, Student’s t-test and Kaplan-Meier survival analysis. Results: The study group (females: 53%) with mean age of 65 years, was predominantly African American (60%). ECOG performance status was ≥ 2 in 13% patients. Only 29% satisfied all standard eligibility criteria. Ineligibility characteristics included age > 75 years (21%), non-malignant severe systemic disease (10%) and > 42 days from surgery to chemotherapy (39%). Seventy-five patients (86%) received chemotherapy. Chemotherapy regimens included FOLFOX (51%), FLOX (10%), FL (29%) and Capecitabine (8%). Total planned dose had to be modified in 64% patients with mean doses of 89% 5-fluorouracil and 79% oxaliplatin employed. The 3-year disease free survival (DFS) was 53% and 5-year overall survival (OS) was 56%. Age ≥ 69 years was significantly associated with poor 3-year DFS (P=0.013). On Kaplan-Meier survival analysis, the ineligible patient group had significantly reduced overall survival (hazard ratio, 2.88; 95% CI, 1.05-4.82; P= 0.037). Conclusions: This pilot venture studied adjuvant management of Stage III colon cancer in a real-world setting. Our results reveal that over 70% patients did not meet standard eligibility criteria and show decreased 5-year OS among these patients that needs to be addressed in future prospective RCT’s.
Survivin expression in circulating tumor cells of patients with gastric cancer.
Authors: Terashima Masanori , Hatakeyama Keiichi , Yamakawa Yushi , Sugisawa Norihiko , Miki Yuichiro , Makuuchi Rie , Goto Hironobu , Tokunaga Masanori , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Oshima Keiichi , Mochizuki Toru
Published: February 2017

65

Background: Detection of circulating tumor cells (CTC) in peripheral blood is thought to be a promising method to evaluate the extent of minimal residual disease that may be useful for predicting recurrence and for monitoring treatment efficacy. However, unlike breast or lung cancer, little information is available in patients with gastric cancer. Among them, evaluation of survivin, a member of the inhibitor of apoptosis (IAP) family, mRNA expression in peripheral blood appears to be a promising procedure with relative good performance for predicting recurrence after curative resection. In order to evaluate the clinical significance of surviving expression in peripheral blood, we performed real-time RT-PCR analysis using whole blood obtained from patients with gastric cancer. Methods: A total of 95 patients with gastric cancer treated at our cancer center between Nov. 2009 and Aug. 2012 were enrolled in this study. Peripheral blood samples were collected using PAX gene and RNA was isolated using Boom method. After cDNA synthesis, quantitative real-time PCR targeting survivin gene was performed. The relative expression level of survivin mRNA was calculated with actin beta as an internal standard. Correlation between survivin expression and clinicopathologic factors was investigated. Results: Survivin mRNA expression level in peripheral blood ranged from 34.8 to 1889.6, and the median level was 370.3. Survivin mRNA level tended to be higher in patients with T4, N3b, CY1, and Stage IV. There was no significant correlation with histological type, lympho-vascular invasion, or macroscopic type. If we set a cut-off value at 540, survivin was positive in 27 patients (28%). Disease-free survival was significantly worse in survivin positive patients than in negative patients (p=0.0216). Conclusions: Survivin expression in CTC was higher in advanced stage and appears to be a good prognostic marker in patients with gastric cancer. Validation with large sample size should be performed to confirm the significance of survivin in CTC.
Advantage of adjuvant radiation therapy in octogenarians undergoing surgical resection of rectal cancer.
Authors: Chauhan Dhaval , Burnett Atuhani S. , Rajab Taufiek Konrad , Cevasco Marisa , Ernst Philip , McCain Donald A. , Mokashi Suyog A.
Published: February 2017

650

Background: Radiation in patients with rectal cancer is an important adjuvant therapy. It can be given either pre-operative or post-operative phase or both. However the optimum timing of the radiation in terms of pre-operative or post-op phase remains a question of debate in octogenarian patients as there is lack of enough evidence. Methods: In this study we aim to find the optimum time of radiation therapy in octogenarians with rectal cancer undergoing surgical resection. Octogenarians with rectal cancer were selected from surveillance, Epidemiology and End Results (SEER) database collected between 1998 and 2009. The data set contained 4,026 patients with rectal cancer who underwent surgical resection and radiation therapy. They were divided into 3 groups. 1,586 (39%) patients had radiation before the surgery. 66 (2%) patients had radiation before and after the surgery, also called the combination group. 2,347(59%) patients had radiation after the surgery. Taking in the consideration of unequal sample sizes, Tukey-Kramer multiple comparison tests was used to compare the mean survival of the patients in each group. Results: The mean survival in pre-operative radiation group was 37.7 months, in combination group was 48.41 months and post-operative radiation group was 44.3 months. There was no statistically significant difference in survival time between the combination group and the radiation after surgery group (p-value=0.64). There was marginal statistical significance in survival time between the combination group and the before surgery group (p-value=.05). There was a statistically significant difference in survival time between the radiation after surgery group and the radiation before surgery group (p-value<0.0001). Conclusions: Octogenarian patients with rectal cancer undergoing adjuvant radiation therapy, with or without neoadjuvant radiation, have greater survival than compared to neoadjuvant only radiation. There appears to be survival advantage of postoperative radiation therapy in octogenarian patients with rectal cancer.
Prospective observational study on chemotherapy-induced nausea and vomiting (CINV) for colorectal cancer patients by the CINV study group of Japan.
Authors: Miyamoto Yuji , Baba Hideo , Tsuji Yasushi , Doi Ayako , Takeda Koji , Kobayashi Michiya , Maehara Yoshihiko , Gotoh Masahiro , Yoshida Kazuhiro , Kokudo Norihiro , Kakeji Yoshihiro , Aiba Keisuke
Published: February 2017

652

Background: The aim of this study is to investigate the incidence of Chemotherapy Induced Nausea and Vomiting (CINV) among moderately emetogenic chemotherapy-naive patients with colorectal cancer. We also assessed whether the medical staff accurately recognized the incidence of CINV in their own practices. Methods: A prospective observational study of patients receiving the first cycle of oxaliplatin or irinotecan-based chemotherapy was performed. A 7-day diary for CINV was provided to the patients prior to chemotherapy to record daily incidence of CINV. Observed incidence rates of acute (day1) and delayed (days 2-7) CINV were compared with medical staff's predictions. Results: A total of 191 patients (110 males and 81 females) were registered during the period from April 2011 to December 2012. All patients were treated with oxaliplatin-based (n = 175) or irinotecan-based chemotherapy (n = 16). Acute vomiting was observed in 4 patients (2.1%), while delayed vomiting was observed in 19 patients (10.0%). Acute nausea occurred in 14 patients (7.3%), while 63 patients (33%) were affected by delayed nausea. Irinotecan significantly induced acute nausea more frequently than oxaliplatin did (p = 0.019). The presence of motion sickness was significantly associated with the incidence of acute nausea (p < 0.001) and vomiting (p = 0.003). Antiemetics were given along the guideline to all patients. 58 patients were administered a neurokinin-1 (NK1) receptor antagonist. Patients with NK-1 receptor antagonist showed significantly less incidence of delayed vomiting than patients without one (3% vs 13%, p = 0.048). 30 patients (15.7%) required rescue antiemetics. The staff had estimated the incidence of acute CINV in 91 patients (47.6%). However, only 14 patients (7.3%) really experienced acute CINV. Conclusions: CINV seems to be controllable with appropriate management, but delayed CINV still remains an important problem to be targeted. The presence of motion sickness should be affected by efficient antiemetic management. The extent of CINV in this patient group seems to be overestimated.
Helical tomotherapy with concurrent chemotherapy in the treatment of anal canal carcinoma: A review of clinical outcomes at a tertiary referral center.
Authors: Longo John Maclou , Siker Malika Lisa , George Ben , Kosinski Lauren , Ludwig Kirk A. , Otterson Mary F. , Thomas James P. , Wiebe Lauren Allison , Erickson Beth
Published: February 2017

656

Background: We report the clinical outcomes of patients with anal carcinoma treated with helical tomotherapy (HT) IMRT and concurrent chemotherapy. Methods: From September 2005 to January 2013, 32 patients with squamous cell carcinoma of the anal canal received chemoradiation with HT planned in a consistent manner in parallel to the RTOG 0529 guidelines. Of the patients, 17 (53%) were T1-2, 13 (41%) were T3-T4, 15 (47%) were node positive, and 1 was M1 with para-aortic nodal metastases. There were 7 HIV positive and 3 renal transplant patients. All but 2 patients received 5-fluorouracil and mitomycin C. The median doses to the primary site, involved nodes, and uninvolved nodes were 54 Gy, 50.4 Gy, and 45 Gy, respectively. All acute and late toxicities were scored with the CTCAE v4.0. Results: Median follow-up was 31 months (range 10-97 months). Median length of treatment was 43 days. Twenty-two patients (69%) took a median of 3.5 break days. Acute grade 3-4 hematologic toxicity occurred in 27 patients (84%). There were no grade 4 gastrointestinal or dermatologic toxicities. Eight patients (25%) experienced grade 3 gastrointestinal and dermatologic toxicities. Twenty-one patients (66%) were hospitalized a total of 37 times during chemoradiation or within 90 days of therapy completion. Neutropenic fever was the most common reason for hospitalization, accounting for 30% of admissions. Thirty-one patients were followed for late toxicity with results as follows: 7 patients (23%) had grade 3 gastrointestinal toxicity, 1 patient (3%) had grade 3 dermatologic toxicity, and 3 patients (10%) had grade 3 sexual dysfunction. Nine patients (29%) developed pelvic insufficiency fractures, 5 requiring intervention. The 2-year progression-free and overall survivals were 97% and 97%, respectively. Two patients died; 1 from local progression and 1 from unrelated causes. Conclusions: HT delivering moderate radiation doses consistent with the RTOG 0529 guidelines and chemotherapy paired with aggressive, multidisciplinary management of acute and late toxicities effectively treat squamous cell carcinoma of the anal canal.
Is greater downstaging achieved if surgery is delayed beyond 8 weeks in patients with locally advanced (LA) rectal cancer?
Authors: Shrikhande Shailesh V. , Sirohi Bhawna , Gupta Alok , Sheth Vipul , Ramadvar Mukta , Goel Mahesh , Desouza Ashwin
Published: February 2017

660

Background: Neoadjuvant Chemoradiotherapy (NACTRT) improves local recurrence rate in LA rectal cancer with no survival benefit. Pathological complete response (pCR) and better tumour regression grade (TRG) is associated with improved outcome. Debate is ongoing as to what is the best time to operate—if greater downstaging can be achieved by a longer interval to surgery and have an impact on sphincter saving surgery rates. In this study, we have correlated the pCR rate and TRG post completion of NACTRT with timing of surgery (TD). Methods: This is a retrospective study of prospective database of patients with LA adenocarcinoma of rectum treated from Jan 2012 to May 2013. 89 pts who completed NACTRT (50Gy/25 fractions with capecitabine 825 mg/m2BD) followed by surgical resection were included. For response evaluation patients were divided into two groups, group 1 (TD < 60 days, n=34) and 2 (TD > 60 days, n=55). Results: Of 89 pts (median age 48 y (22-76), 64 M/25F; 16/89 (18%) had signet ring histology) 93% pts underwent R0 resection; 7% R1 resection. Response to NACTRT was CR in 8 pts, PR in 65 (73%) pts and 15 SD, 1 not assessed. Median time from completion of NACTRT to surgery was 64 d (32-141). Median number LN resected were 11 (1-50). Overall, 25 (28%) pts achieved pCR; 6/89 (7%) pts had positive circumferential resection margin. 25 (74%) patients in group 1 compared to 28 (51%) pts in group 2 underwent sphincter preserving surgery (P=0.045). Eight (24%) pts in group 1 and 17 (31%) in group 2 achieved pCR (P=0.479). The median TRG in group 1 was 2.5 and in group 2 was 2 (P=NS). In pts who achieved pCR, median TD was 67 d compared to 63 d in pts who did not achieve pCR. Of the 16 pts with signet histology 4(25%) had pCR compared to 21(29%) in those with non-signet histology (P=NS). Conclusions: We conclude that the timing of surgery is not an important variable post completion of NACTRT and our data suggests that it's possible that earlier surgery may be better for organ conservation. There is no incremental benefit of delaying the surgery though this needs to be confirmed in a prospective randomised trial.
Observational cohort study focused on treatment continuity of patients (pts) treated with XELOX plus bevacizumab (BV) for previously untreated metastatic colorectal cancer (mCRC).
Authors: Kotaka Masahito , Ikeda Husao , Ikumoto Taro , Tsuzie Masaki , Yoshioka Shinichi , Nakamoto Yoshihiko , Ishii Takaaki , Goto Saori , Itami Atsushi , Kato Takeshi
Published: February 2017

661

Background: Systemic chemotherapy for unresectable mCRC has remarkably progressed as a results of wide spread use of irinotecan, oxaliplatin, anti-VEGF antibody and anti-EGFR antibody. It is important to continue treatment combined with these drugs and prolong progression-free survival so as to improve overall survival. Methods: We planned and conducted the prospective observational cohort study of 40 pts treated with XELOX + BV for previously untreated mCRC to investigate the treatment continuity of XELOX + BV. Endpoints were time to treatment-failure (TTF), overall response rate, resection rate, liver resection rate, progression-free survival (PFS), overall survival (OS) and safety. Eligibility criteria were (1) histologically confirmed mCRC, (2) with lesions evaluable by imaging, (3) previously untreated (except for surgery), (4) with condition enough to receive XELOX + BV, (5) written informed consent. Forty pts were planned to be enrolled during 2 years and followed up to 2 years. Results: Between July 2010 and June 2012, 40 pts were enrolled. Baseline characteristics were the following; male/female 24/16, median age 63 yrs (range 35-84 yrs), ECOG PS 0/1/2 33/6/1, primary cite colon/rectum 24/16, primary resection prior XELOX+BV yes/no 35/5, metastatic cite liver/lung/paraaorta/peritoneal/local recurrence/others 23/16/4/7/3/4, the number of metastatic cite 1/2/3 26/9/5.The median TTF was 5.3 months (95%CI: 3.6 – 9.1 months), and the reasons for treatment discontinuation were the following; CR 4 pts, resection 10 pts, progression 12 pts, adverse events 7 pts and pts refusal 3 pts. Four pts continued their treatments.The overall response rate was 52.5% (CR 6 pts and PR 15 pts), resection rate was 25.0% (liver 6 pts, lung 2 pts and primary 2 pts), and liver resection rate was 15.0%. The median PFS was 13.3 months (95%CI: 9.8 months – NR) and the median OS was not reached. Conclusions: Although the median TTF was 5.3 months, the median PFS was prolonged to 13.6 months. This might result from chemo-free interval caused by 4 pts’ CR and 9 pts’ resections. We will further investigate 40 pts’ 2-year survival data. Clinical trial information: UMIN000003416.
Efficacy and safety of raltitrexed combinations with uracil-tegafur or Mitomycin C as salvage treatment in advanced colorectal cancer patients.
Authors: Ozkan Metin , Bozkurt Oktay , Karaca Halit , Ozaslan Ersin , Daloglu Osman Onur , Ciltas Aydin , Kaplan Mehmet Ali , Benekli Mustafa , Sevinc Alper , Demirci Umut , Eren Tulay , Kodaz Hilmi , Isikdogan Abdurrahman , Buyukberber Suleyman
Published: February 2017

662

Background: Oxaliplatin and irinotecan in combination with 5-fluorouracil and leucovorin for metastatic colorectal cancer (mCRC) accepted as the standard treatment. There is no standard treatment approach for patients after progression with these agents. In this study aimed to evaluate the efficacy and side effects of patients with previously treated metastatic colorectal cancer a salvage combination with oral 5-fluorouracil (tegafur-uracil UFT) or Mitomycin C and Raltitrexed. Methods: In the 7 centers, data of 62 patients who received Raltitrexed 2.6 mg/m2 (max. 5 mg) (day 1) and UFT 500 mg/day (1-14. days), or Mitomycin C 6mg/m2 (day 1) every 3 weeks, with a diagnosis of metastatic colorectal cancer, between December 2008 and June 2013 has been analyzed retrospectively. Overall survival (OS), progression-free survival (PFS), and toxicity profiles were evaluated. Results: The median age of patients was 51 (min-max: 18-76 years), and 35 (56%) were male and 27 (44%) were female. Thirty nine patients (63%) had ECOG performance status 0 and 1. Four patients (10%) received a combination of UFT and Raltitrexed at the second line and 38 patients (90%) had third, fourth, and fifth lines. Otherwise Mitomycin C plus Raltitrexed protocol used at the second and third lines. Twelve patients (19%) developed grade 3/4 toxicities as diarrhea and fatigue and 13 patients (21%) needed to dose reduction. In all patients the median PFS was 3 months (%95 CI, 2,65–3,34) and the median OS was 6 months (%95 CI, 2,09–9,90). Two groups were evaluated separately; the median PFS was 3 months (%95 CI, 2,60–3,39) and median OS was 6 months (%95 CI, 2,47–9,53) in UFT arm and, the median PFS was 3 months (%95 CI, 1,64–4,35) and median OS was 12 months (%95 CI, 2,83–21,1) in Mitomycin C arm. Statistical significance could not be determined (p>0.05). Conclusions: Thecombination of Raltitrexed with UFT and Mitomycin C showed an acceptable survival time and toxicity in the treatment of patients with previously treated mCRC. It could be considered as a salvage treatment option in mCRC.
The impact of KRAS mutation on radioembolization in the treatment of unresectable liver predominant metastatic colorectal cancer.
Authors: Schacht Michael , Coldwell Douglas M. , Sharma Vivek
Published: February 2017

664

Background: Radioembolization with either Yttrium-90 labeled resin or glass microspheres is an FDA approved treatment for hepatic metastases from primary colorectal cancer. Y-90 therapy is used almost exclusively in unresectable liver metastases. However, radioembolization is only an optional part of the treatment process along with first-line, second-line, and salvage chemotherapy. KRAS is a known proto-onco gene that has typically been studied as a negative prognostic factor in the chemotherapeutic treatment of metastatic colorectal cancer (mCRC). KRAS is a known marker for resistance to anti-EGFR antibodies and generally have a poorer prognosis. The aim of this study is to begin to shed light on the impact of KRAS status on the outcome of patients undergoing radioembolization for the treatment of unresectable liver predominant metastatic CRC, regardless of their chemotherapy regimens. Methods: This is a retrospective analysis of 18 subjects treated with radioembolization for liver predominant metastatic CRC. KRAS status and treatment outcomes were followed for each patient up to the study close date of 9/15/13. Statistical analysis was performed using the Mann-Whitney U test. Results: Of the 18 subjects included in the study, 5 were found to have KRAS mutant oncogene. The remaining 13 were found to have the KRAS wildtype. Overall, those subjects with KRAS mutant were found to have a statistically significant difference in median time to progression of intrahepatic metastatic disease burden when compared to KRAS wildtype even when liver-directed therapy was utilized (2.0 vs. 6.4 months). Differences in median time to progression of extrahepatic metastatic disease burden and overall survival were not found to be statistically significant at this time. Conclusions: KRAS mutant patients are exceedingly difficult to treat due to both intrahepatic and extrahepatic disease recurrence/progression.
Overexpression of melanoma-associated antigen D4 as an independent prognostic factor in squamous cell carcinoma of the esophagus.
Authors: Kanda Mitsuro , Oya Hisaharu , Hibino Soki , Takami Hideki , Shimizu Dai , Koike Masahiko , Nomoto Shuji , Yamada Suguru , Fujii Tsutomu , Nakayama Goro , Sugimoto Hiroyuki , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2017

71

Background: To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. Methods: MAGE-D4 mRNA expression was analyzed in nine EC cell lines using quantitative reverse transcription-polymerase chain reaction (RT-PCR). In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. Results: The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative RT-PCR. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P < 0.001). Patients with the highest MAGE-D4 mRNA expression in EC tissues (top quartile, n=17) had significantly shorter overall survival than patients with low expression (2-year survival: 44% and 73%, respectively, P = 0.006). Univariate analysis identified age (≥ 65 years), lymphatic involvement and high MAGE-D4 mRNA expression as significant prognostic factors; high MAGE-D4 mRNA expression was also an independent prognostic factor in multivariable analysis (hazard ratio: 2.194; P = 0.039), and was significantly associated with Brinkman index (P = 0.008) and preoperative carcinoembryonic antigen level (P = 0.002). Immunohistochemical MAGE-D4b expression was consistent with MAGE-D4mRNA profiling. Conclusions: Our results suggest that MAGE-D4 overexpression influences tumor progression and MADE-D4 can be a prognostic marker and a potential molecular target in squamous cell EC.