bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of venting percutaneous endoscopic gastrostomy (VPEG) tube placement in patients with malignant obstruction.
Authors: Keswani Rajesh N. , Issaka Rachel B , Shapiro David M , Mulcahy Mary Frances , Komanduri Srinadh , Martin John A. , Parikh Neehar
Published: February 2017

538

Background: Refractory nausea and vomiting are common in patients with advanced malignancy. A venting percutaneous endoscopic gastrostomy (VPEG) tube can be placed to eliminate the need for a nasogastric tube and palliate obstructive symptoms. The aim of this study was to determine the outcomes of VPEG placement in patients with advanced malignancy. Methods: We retrospectively reviewed all patients in whom a VPEG tube was attempted for a malignant indication over a 13-year period (1998-2010). Demographic and clinical information, procedure details, and immediate & delayed complications were recorded. Results: Endoscopic VPEG placement was attempted in 96 patients (95% inpatient) with a median age of 57y. Colorectal (27%), pancreas (18.8%), and gynecologic (17.7%) malignancies were most common. Ascites was present in 46.9% of patients with drainage performed in a minority of patients (35.6%). VPEG was successfully placed by endoscopy in 89 patients (92.7%). Relief of obstructive symptoms was observed in 91.7% of patients. Eight patients had refractory obstructive symptoms despite functioning VPEG tube. Ten post-procedural complications were noted in 9 patients, with 1 death. Patients with ascites were more likely to have infectious complications (12.2%) than those without ascites (0%, p=0.02) with a trend towards decreased infectious complication when ascites was drained prior to VPEG placement (14.8% vs. 7.1%, p=NS). We observed decreased survival when complications occurred (73 days) compared to when they did not (141 days, p = NS). Conclusions: VPEG tubes can be safely placed in patients with inoperable malignancy and obstructive symptoms with complete relief of symptoms in the majority of patients. The presence of ascites was a risk factor for post-procedural infectious complications. Drainage of ascites prior to VPEG tube placement may minimize this risk, though this warrants further study.
A multicenter phase II trial of mFOLFOX6 plus bevacizumab as treatment for liver-only metastases from colorectal cancer unsuitable for upfront resection (TRICC 0808).
Authors: Uetake Hiroyuki , Yasuno Masamichi , Ishiguro Megumi , Kameoka Shingo , Shimada Yasuhiro , Takahashi Keiichi , Watanabe Toshiaki , Muro Kei , Baba Hideo , Yamamoto Junji , Mizunuma Nobuyuki , Tamagawa Hiroshi , Mochizuki Izumi , Kinugasa Yusuke , Matsubara Yoshihiro , Sugihara Kenichi
Published: February 2017

543

Background: Liver resection is a standard treatment for resectable liver metastases (mets) from colorectal cancer. In patients (pts) with multiple or large liver mets, liver tumors may not be resected completely or recurrence after complete resection are frequently observed. Methods: This prospective single arm phase II trial assessed R0 liver resection rate after mFOLFOX6 + bevacizumab (BV) in pts with liver mets considered unsuitable for upfront resection. Pts with liver-only mets, those were larger than 5cm in diameter or more than 4 in number, were treated with 6 cycles of mFOLFOX6 + BV (without BV in the 6th cycle). After chemotherapy, resectability of liver mets was assessed by CT or MRI. Secondary endpoints included liver resection rate, conversion rate from unresectable to resectable, safety of liver resection, recurrence rate, and survival. Results: Between May 2009 to October 2011, 46 pts were registered (one was excluded after registration due to ineligibility). Among the 19 pts with resectable mets at entry, 18, except one who refused the continuation of chemotherapy after the first cycle, underwent liver resection after 6 cycles of chemotherapy. In 16 of the 18 pts, R0 resection was performed. Among the 26 pts with unresectable mets at entry, 6 underwent liver resection and 4 had R0 resection. Overall R0 resection rate, liver resection rate and conversion rate were 44.4% (20/45), 53.3% (24/45) and 23.1% (6/26), respectively. The grade 3/4 adverse effects (AEs) by mFOLFOX6 + BV included fatigue (6.5%), stomatitis and nausea (2.2%), neutropenia (16.3%) and increase of serum total bilirubin (2.2%). As to BV related grade 3/4 AEs, hypertension (6.5%) and thromboembolism (2.2%) were observed. After liver resection, grade 3 wound infection, intra-abdominal abscess and delayed wound healing were complicated in two, in one and in one, respectively. Conclusions: In pts considered unsuitable for upfront resection of liver-only mets, mFOLFOX6 + BV was associated with high R0 resection rate, liver resection rate and conversion rate without severe toxicities and surgical complications. Updated results including survival will be presented. Clinical trial information: UMIN000002101.
Tumor size as a prognostic factor for patients with colon cancer undergoing sentinel lymph node mapping and conventional surgery.
Authors: Saha Sukamal , Kanaan Mohammed Nawaf , Shaik Mohammed , Abadeer Benjamin , Korant Alpesh , Krishnamoorthy Madhumitha , Kaushal Sunil , Singh T. Trevor , Arora Madan L. , Wiese David
Published: February 2017

546

Background: Unlike other solid tumors, tumor size (TS) is not a part of the TNM staging for colon cancer (CC). Our goal is to correlate TS with TNM staging, nodal positivity(NP), and 5-year overall survival (OS) for patients (pts) with invasive CC undergoing sentinel lymph node mapping (SLNM) vs. conventional surgery (CS). Methods: A retrospective review of 681 pts with invasive CC were reviewed and divided into two groups of pts (SLNM and CS). The pts in these two groups were subdivided according to the TS in four groups (0-2, 2-4, 4-6 and more than 6 cm). 461 pts underwent SLNM between 1996-2010 compared to 220 pts who underwent CS between 1996-2006. The pathology reports reviewed for TS (the maximum diameter of the primary tumor), T staging, and NP. The OS was calculated from the social security database and our hospital cancer registry. Then all data was compared between both groups. Results: Pts with TS <2cm were mainly T1+T2 (72%, 70%), whereas tumors >6 cm, majority of pts wereT3+T4 (94%, 85%). T1+T2 percentage consistently decreased as TS increased, and T3+T4 percentage was increasing consistently with increased TS (Table 1A). NP according to TS for SLNM pts were (16%, 53%, 56%, 48%) NP and for CS pts were (15%, 32%, 34%, 39%). In both groups, NP increased as TS increased compared to 0-2 cm group. The overall NP in both groups was 47% and 31% (Table 1B). OS for SLNM and CS pts were calculated in each group according to TS. Overall SLNM pts had better OS when compared to CS pts (65 %, 54%). Conclusions: Increasing TS was consistent with increasing T staging for both SLNM and CS pts. NP and OS were worse with increased TS for SLNM and CS pts. SLNM pts had higher NP and better outcome in OS when compared to CS pts, hence TS should be considered as a prognostic factor in pts with adenocarcinoma of the colon. [Table: see text]
Treatment of colorectal cancers with minimally invasive surgical techniques at a dedicated cancer center.
Authors: Reddy Sanjay S. , Sigurdson Elin R. , Farma Jeffrey M.
Published: February 2017

549

Background: Laparoscopic (LS) and robotic surgery (RS) for colorectal cancer provides a new perspective of the deep pelvis. Our goal was to identify the role of LS and RS for patients with sigmoid and rectal cancer. Methods: We retrospectively analyzed 53 patients treated from 2007-2012. Resection type, previous surgery, neoadjuvant and adjuvant therapy, timing of surgery, lymph nodes (LN) harvested, estimated blood loss (EBL), operative time (OT), complications, and pathology were reviewed. Results: Of 53 patients, 32 underwent LS, and 18 RS. There were 47 patients with adenocarcinoma, 5 with unresectable polyps and 1 with anal melanoma. 62% of patients underwent a recto-sigmoid resection, 23% rectal, and 8% sigmoid. 32% had prior surgery. Neoadjuvant treatment (NAT) was initiated in 31 patients; 3 received chemotherapy without radiation, and 1 short course radiation. An average of 12.8 and 8.4 LN were harvested in the LS and RS groups respectively, with a mean of 9.9 LN after NAT, and 13.9 without. EBL was 155ml (20-650) with LS and 178ml (25-600) with RS. 3 LS cases were converted to an open procedure. Median OT was 270 and 302 minutes for LS and RS groups. Using the Clavien grading system, 12 patients had grade 1-2 complications, 5 grade 3, and 2 grade 4’s within 30 days. Radial margins were positive in 2 patients; one received NAT for a fungating anal adenocarcinoma, and the other had chemotherapy alone. One patient had a positive proximal margin with no prior therapy. Rate of complete pathological response (pCR) was 35%, and 71% were down staged. The mean interval between completion of NAT and resection was 8 weeks (range 4-12), and surgery to adjuvant therapy was 8 weeks (range 4-22). Conclusions: LS and RS surgery for colorectal cancer can be safely performed in conjunction with neoadjuvant and/or adjuvant chemotherapy. NAT should not preclude adoption of these techniques, as we achieved a 35% pCR with minimal operative morbidity allowing patients to proceed to adjuvant chemotherapy in a timely fashion. [Table: see text]
A phase II study on third-line chemotherapy combined bevacizumab with S-1 for metastatic colorectal cancer with mutated KRAS: SAVIOR study.
Authors: Takagane Akinori , Miyake Yasuhiro , Kobayashi Kouji , Nagata Naoki , Sato Atsushi , Ogata Yutaka , Fukunaga Mutsumi , Otsuka Koki , Takahashi Takao , Matsumoto Hidetomo , Negoro Yuji , Matsubara Yoshihiro , Yoshida Motoki
Published: February 2017

552

Background: Anti-Epidermal growth factor receptor (EGFR) antibody therapy is expected to be effective in treatment for metastatic colorectal cancer (mCRC) with wild-type KRAS, but for mCRC with mutated KRAS, no salvage treatment has been established. We performed a phase II clinical study on 3rd-line chemotherapy combined bevacizumab with S-1, an oral fluorinated pyrimidine preparation containing a dihydropyrimidine dehydrogenase inhibitor, and bevacizumab for mCRC resistant to oxaliplatin and irinotecan. Methods: Subjects were mCRC patients with mutated KRAS, who showed aggravation even after 2 regimens with oxaliplatin and irinotecan. S-1 (80-120 mg/body) was administered for 4 weeks and withdrawn for 2 weeks. The dose of S-1 was decided according to the subjects’ body surface area. Bevacizumab (5 mg/kg) was administered on Days 1, 15, and 29. This treatment was provided until progression. The primary endpoint was disease control rate (DCR), and secondary endpoints were response rate (RR), median progression free survival (mPFS), overall survival (OS), and adverse event (AE). Results: A total of 31 subjects mutated KRAS were enrolled between August 2009 and July 2011. An independent review committee evaluated antitumor effects in eligible 29 of the 31 subjects in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). Two subjects in whom antitumor effects could not be evaluated were excluded. The DCR was 69% (95% confidence interval [CI], 49.2-84.7%), RR 0% (95% CI, 0-12.3%), mPFS 3.7 months (95% CI, 2.7-6.5 months), OS 9.0 months (95% CI, 7.5-12.0 months), and the median observation period 9.0 months. In 30 subjects for safety evaluation, the incidence of Grade 3 or greater adverse events was 50%. There was no treatment-related death. Major adverse events were anorexia (Grade 3 or greater, 20%), diarrhea (Grade 3, 10%), and decreased hemoglobin (Grade 3 or greater, 16.7%). Conclusions: The results suggest that 3rd-line chemotherapy combined bevacizumab with S-1 is safe and may delay the progression of mCRC resistant to oxaliplatin and irinotecan with mutated KRAS. Clinical trial information: NCT00974389.
Algorithm for identifying various second- and third-line chemotherapy regimens in elderly U.S. Medicare patients with metastatic colon cancer.
Authors: Bikov Kaloyan A , Mullins C. Daniel , Onukwugha Ebere , Seal Brian S. , Hanna Nader
Published: February 2017

553

Background: Patients with metastatic colon cancer (mCC) often receive multiple lines of chemotherapy treatment (TX) in response to disease progression or toxicities. A claims-based algorithm that identifies TX lines can provide information on “real world” clinical practice patterns that may not be captured by clinical trials. Methods: Our claims-based algorithm was applied to SEER-Medicare data of elderly mCC patients diagnosed in ‘03-‘07 and followed through ‘09. The algorithm included 17 clinical rules for identifying the beginning and end TX lines. The face validity of the algorithm was assessed by 1) examining the output against a TX map for a random sample of patients; 2) evaluating the overall results; and 3) conducting a sensitivity analysis, which evaluated the variability in the number of detected TX lines as a function of key algorithm parameters. Results: Of 7,951 mCC patients, 3,266 (41%) received TX; 1,440 (18% of all, 44% of TX) and 274 (3% of all, 8% of TX) received 2nd and 3rd line TX, respectively. Fewer than 1% of treated patients had a 4th TX line. The utilization patterns in terms of number and type of TX lines were robust to changes in the algorithm parameters. OX±BEV (45%), 5FU/LV±BEV (33%) and IRI±BEV (16%) were the three most common initial TXs. 2nd line TX most commonly consisted of IRI±BIOLOGIC (62%) and OX±BIOLOGIC (26%), but 6% of patients received only BIOLOGICS. CETUX (19%), PANIT (15%), IRI alone (17%) and OX alone (12%) were the most common 3rd line TXs. OX to IRI (49%), IRI to OX (14%), 5FU/LV to OX (12%), and 5FU/LV to IRI (12%) were the most frequent TX progressions for those with 2nd line TX. 5FU/LV to OX to IRI (26%), OX to IRI to BIOLOGICS alone (25%), 5FU/LV to IRI to OX (14%) and IRI to OX to BIOLOGICS alone (6%) were the most frequent TX progressions for those with 3rd line TX. Conclusions: Our claims-based algorithm suggests that during 2003-2009 relatively few elderly mCC patients received 2nd and 3rd line TX. Sensitivity analysis confirmed the robustness of the algorithm. Future observational studies should address the “real world” benefits and risks of 2nd and 3rd line TX among elderly mCC patients.
Uptake of recommendations for adequate nodal removal in colorectal cancer resection.
Authors: Becker Daniel Jacob , Hanna Mina Samir Erian , Carter Eileen , Henderson Joy , Grossbard Michael L.
Published: February 2017

557

Background: The number of lymph nodes removed during colorectal cancer (CRC) resection is associated with overall survival. The National Cancer Institute published recommendations to remove at least 12 lymph nodes in 2001. Previous analyses noted that as of 2001 the majority of patients in the US had inadequate lymph node resection (<12); geographic location is strongly associated with adequacy of lymph node resection. In this study, we examined the association between the year of cancer diagnosis and the number of lymph nodes removed between 2000 and 2008. Methods: We used the Surveillance Epidemiology and End Results (SEER) New Jersey cancer registry to identify patients diagnosed with stage I- III colon cancer from 2000 to 2008 who underwent resection and had lymph nodes removed. We used multiple linear regression to test for the independent association of year of diagnosis and the number of lymph nodes resected. We controlled for age at diagnosis, gender, race, tumor grade, tumor stage, and tumor location. Results: Our inclusion and exclusion criteria yielded 25,407 cases. The patients were 51% male, and 49% female; 48% had right–sided colon cancer, 29% had left–sided colon cancer and 23% had rectal cancer. The majority of the patients were white (87%); 25% had stage 1 CRC, 28% had stage 2 CRC, and 37% had stage 3 CRC. The mean number of lymph nodes removed was suboptimal in the year 2000 (11.4) but gradually rose to the recommended cut-off of 12 in 2002 and was 15.6 in 2008 (p<0.0001 for comparison of 2000 and 2008). The regression confirmed the independent association of year of diagnosis and number of lymph nodes removed. For every 1 year increase in the year of diagnosis, keeping all covariates constant, there is an increase of 0.55 lymph nodes removed (p < 0.0001). Higher grade, higher stage, female gender, and right colon tumors were also associated with increased lymph node removal. Conclusions: Between 2000 and 2008 in the New Jersey, there was a steady increase in the number of lymph nodes removed with CRC resection, reflecting an increased adherence to evidence-based guidelines and an improvement of cancer care.
Survival outcomes in U.S. patients with metastatic colorectal cancer (mCRC).
Authors: Knopf Kevin , Iqbal Sheikh Usman , Thompson Stephen F , Malangone Elisabetta , Gorritz-Kindu Magdaliz , Stern Lee , Sherman Steven A , Naoshy Sarah , Wooten Michael , Andria Michael L.
Published: February 2017

559

Background: The increase in survival seen in recent years in patients with mCRC has been attributed to improvements in treatments, including the introduction of targeted biologic agents. The objectives of this retrospective, observational study are to investigate recent treatment patterns in US mCRC patients and examine real-world survival outcomes. Methods: Data were obtained from a large U.S. database (SDI/IMS Health) of mCRC patients diagnosed from January 1, 2004 to June 30, 2011, ≥18 y at diagnosis, and who received chemotherapy and/or biologic treatment. Complete follow-up was defined as those who either died before June 2011 or who had at least 1 claim within 30 days of June 30, 2011. Kaplan-Meier curves were generated to determine overall survival (OS) from the date of mCRC diagnosis. Results: 1,066 stage IV mCRC patients with complete follow-up were identified (57.5% male; mean age, 61.6 y). Approximately 80% were diagnosed with mCRC after 2006; 51.7% had liver metastases. The most common 1L, 2L, and 3L regimens were FOLFOX plus bevacizumab (34.52%), FOLFIRI plus bevacizumab (21.83%), and irinotecan plus cetuximab (15.83%), respectively. A total of 445 patients died during the study period, yielding a mortality rate of 41.74%. Mean time from diagnosis to first treatment was 3.31 months (SD=7.13). All patients received 1L therapy; OS from diagnosis was 35.77 months (95% CI: 32.57-38.10); 5-year survival was approximately 28%. After 1L, 591/1066 (55%) patients went on to receive 2L therapy; for these patients, median survival from diagnosis was 37.13 months (95% CI: 34.07-40.43) and 5-year survival was approximately 25%. After 2L, 278/591 (47%) patients received 3L therapy; for these patients, median survival from diagnosis was 38.10 months (95% CI: 34.83-43.13); 5-year survival was approximately 25%. Conclusions: In this study, OS (35.77 months) was longer than for other mCRC observational studies that have reported survival from start of treatment, but is more comparable when the ~3 months from diagnosis to start of treatment are not included. Addition of targeted agents and novel chemotherapy has prolonged OS in mCRC patients. Because of poor 5-year survival rates, the need for additional agents in later lines of therapy still exists.
The utility of PET scanning in colorectal cancer liver metastases being considered for surgery.
Authors: Kelly Ciara Marie , McCarthy Lauragh , O'Reilly Aine , McEneaney Peter , Bennett Michael William , O'Regan Kevin N. , Mulvihill Erica , O'Sullivan Adrian , O Suilleabhain Criostoir , O'Reilly Seamus , Power Derek G.
Published: February 2017

561

Background: Liver resection remains the only potentially curative option for a subset of patients with metastatic colorectal cancer (CRC) to liver. Preoperative imaging used to determine resectability includes contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). The objective of this study was to determine the utility of PET scanning for potentially resectable metastatic CRC to liver. Methods: We retrospectively reviewed a prospectively maintained database for all patients considered for liver resection of metastatic CRC from July 2010 to July 2012 in a specialist colorectal/hepatobiliary cancer centre. We extracted and analysed data with respect to preoperative staging imaging and definitive treatment performed on completion of staging. Results: We identified 50 patients who underwent preoperative staging investigations for potentially resectable metastatic CRC to liver. The imaging techniques performed included: CT (n=50, 100%), MRI liver (n=45, 90%), PET (n= 47, 94%). In 9 (9/47, 19%) patients PET scanning added to the preoperative cross sectional staging information, identifying local recurrence (n=1, 2%), confirming liver metastases following an inconclusive CT/MRI (n=1, 2%), and identifying extrahepatic sites suspicious for disease (n=7, 15%). The extrahepatic sites included either lung (n=4) or bone (n=1) or lymph nodes (n=2). One patient with FDG-avid mediastinal lymph nodes had no cancer on endobronchial biopsy. PET scanning definitively changed the therapeutic strategy in 6 patients (6/47, 12.8%): precluding liver resection in 2 patients (2/47, 4.3%), leading to resection of extrahepatic disease in 3 patients (3/47, 6.4%) and resection of hepatic metastases in one patient (1/47, 2.1%). Conclusions: In this small retrospective cohort the addition of metabolic imaging changed the management in 12.8% of patients with potentially resectable liver confined metastatic CRC. We plan to include data from other cancer centres in Ireland to confirm our findings.
Can grade 2 neutropenia predict the risk of grade 3 neutropenia in metastatic colorectal cancer patients treated with chemotherapy?
Authors: Yoshida Yoichiro , Hoshino Seiichiro , Aisu Naoya , Naito Masayasu , Tanimura Syu , Yamashita Yuichi
Published: February 2017

562

Background: Neutropenia is a major factor affecting the continuation of chemotherapy for colorectal cancer. In many clinical trials, a neutrophil count of more than 1500 is targeted for the continuation of chemotherapy; for a count of less than 1500, medication is commonly discontinued. However, there is no definite evidence for setting the targeted neutrophil count at 1500. In our department, chemotherapy is discontinued when the neutrophil count is less than 1000 (Grade 3); for a count of 1000 to 1500 (Grade 2), chemotherapy is continued. We examined the neutrophil count during continuation of chemotherapy in patients with a count of 1000 to 1500, and verified whether these neutrophil counts warrant discontinuation of medication. Moreover, we examined the neutrophil count during the previous course of chemotherapy when it fell below 1000. Methods: The study included 104 patients who received XELOX + bevacizumab (BV) therapy, XELOX therapy, and XELIRI + BV therapy for advanced or recurrent colorectal cancer. Results: The patients with a neutrophil count of 1000 to 1500 were 26 (23.1%) of the total. Two (7.7%) of 26 patients had a neutrophil count of less than 1000 during the following course of chemotherapy. Moreover, among the patients with a neutrophil count of less than 1000, 25% had a count of 1000 to 1500 during the previous course of chemotherapy and 75% had a count of more than 1500. Conclusions: According to these results, Grade 2 neutropenia cannot predict the risk of the Grade 3 neutropenia. Continuation of chemotherapy in patients with a neutrophil count of 1000 to 1500 may be appropriate, and discontinuation of therapy is not always required.
Colorectal carcinoma (CRC) management approach in octogenarians and over a single institute experience.
Authors: Jordan Emmet , Murphy Amy , Coyle Seamus , O Connor Miriam , Calvert Paula , Horgan Anne M
Published: February 2017

575

Background: The incidence of CRC increases with age. Future numbers are projected to rise due to an ageing population. Little data exists on chemotherapy in those ≥80 years (yrs) with CRC, a subgroup rarely included in clinical trials. The purpose of this study was to evaluate chemotherapy use, feasibility and tolerability in patients ≥80 yrs with CRC in a single institution. Methods: CRC diagnosed in those ≥80 yrs in a single institution in Ireland , from 2004 -2009, was determined. Clinicopathological data collected included age, gender, morphology, stage, and treatment including surgery, radiation or chemotherapy. In those receiving chemotherapy tolerance was determined by dose delays, reductions and number of completed cycles. Results: 83 cases of CRC were identified; 80-89 yrs (n=78), 90-100 yrs (n=5). Median age was 84 yrs (range 80-102), 38/83 (45.8%) were female. 59 cases of colon and 24 cases of rectal cancer were seen. Stage at diagnosis included IV (n=18), III (n=21), II (n=38) and I (n=6). For stage IV disease 4/18 (22%) received chemotherapy. Median overall survival for those with stage IV disease who received chemotherapy was 317 days (range 64-487) versus 169 days (range 30-473) for supportive care. 3/21(14%) stage III patients received chemotherapy. Median survival for stage III disease who received chemotherapy was 1193 days (range 432-1640) compared to 641 days who did not (range 0-1640). All patients with stage IV disease received single agent (SA) treatment (capecitabine n=3, cetuximab n=1). Treatment of stage III disease included: XELOX n=1, 5Fluorouracil/Leucovorin n=1, capecitabine n=1). 3/6 (50%) had dose reductions (n=4) and delays (n=7) in treatment. 1 patient completed scheduled adjuvant treatment. 1 patient with metastatic disease received second and third line treatment (SA irinotecan, cetuximab). Data including performance status, co morbidity will be presented. Conclusions: The uptake of chemotherapy in this cohort is low. Although the rates of treatment modifications are high, those treated appear to benefit. Better clinical tools are needed to differentiate those older patients likely to benefit from systemic therapy and those better served by supportive measures alone.
Dose escalation using dose-painted IMRT in locally advanced rectal cancer.
Authors: Ghaly Maged , Vijeh Lili , Marrero Mihaela , Vinciguerra Vincent , Angel Luz Paulina , Nasim Mansoor , Bloom Beatrice
Published: February 2017

582

Background: After preoperative chemo-radiation, clinical response and tumor pathologic downstaging showed a close correlation with improved outcomes. We report our initial experience in dose escalation using dose-painted intensity-modulated radiation therapy (DP-IMRT) in patients with locally advanced rectal cancer. Methods: Fifteen patients with locally advanced rectal cancer (T3-4,N0-1) were prospectively identified. Tumors were staged using the cTNM classification by PET/CT, EUS & MRI. All received preoperative 5-FU and DP-IMRT. Doses were prescribed as follows:56 Gy/2.0 Gy fractions (fxn) to the planning target volume (PTV) and 47.6Gy/1.7Gyfxn to elective nodal PTV. Surgery was performed 6-8 weeks after chemo-radiation. The surgical procedure was tailored to tumor downstaging. The choice of sphincter-preserving surgery was based on the distance between the lower tumor pole and the anorectal ring “ after” chemoradiation. All were reevaluated for tumor response, preoperatively by imaging studies (ycTNM) and by pathological staging (ypTN) following surgery. Acute and late toxicities were monitored by the treating physician. Results: All patients completed therapy. Tumors were in the lower 1/3 in 3 patients, middle 1/3 in 7, and upper 1/3 in 5. With preoperative endorectal US, PET/CT and MRI, the clinical staging of the tumors was: 13 (T3N0) and 2 (T4N0). Acute toxicity was limited to a moderate proctitis (RTOG acute toxicity scoring system, G1 ) in all patients, with two patients with tumors extending into the anal canal having G 3 dermatitis. Complete clinical response was obtained in 10 of 15 patients.All 15 underwent surgery; 6 had pathological pT0N0, 4 had residual micro foci of carcinoma (pT1N0), and 5 had residual disease limited to the muscularis propria (pT2N0). No difference in perioperative complications was seen. Conclusions: Preoperative dose-escalation using dose-painted radiation therapy (DP-IMRT) seems to be safe. Moderate local acute toxicity was seen with very low-lying tumors. This modality provides a high rate of tumor downsizing especially for patients with lesions in the lower 2/3 of the rectum with a possible potential for an increased ability to perform sphincter-preserving surgery.
Does gap-free intensity modulated chemoradiation therapy provide a greater clinical benefit than 3D conformal chemoradiation in patients with anal cancer?
Authors: Dewas-Vautravers Claire , Maingon Philippe , Dalban Cecile , Petitfils Aurelie , Peignaux-Casasnovas Karine , Truc Gilles , Martin Etienne , Khoury Cedric , Dewas Sylvain , Crehange Gilles
Published: February 2017

584

Background: Chemoradiation is the standard treatment for anal cancer. The purpose of this study was to compare outcomes and toxicities in patients treated with either intensity-modulated radiation therapy (IMRT) or 3D conformal radiotherapy (3D-CRT). Methods: Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Thirty-nine patients (76.5%) had concomitant chemotherapy: capecitabine alone (1), MMC combined with 5FU or capecitabine (36), MMC and CDDP (4). Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6]. Results: Median duration of the treatment was 56 days [22-103] (59 versus 47 days with 3D-CRT and IMRT respectively, p= 0.0007). A gap was planned in 29 patients (57%), 23 with 3D-CRT and 6 with IMRT (p< 0.0001). Treatment was stopped for toxicity in 9 patients (17.6%), 4 with 3D-CRT and 5 with IMRT (p= 0.48). There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival (OS), locoregional relapse-free survival (LRS) and colostomy-free survival (CFS) rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 (G3) acute toxicity. No grade 4 (G4) toxicity occurred. Conclusions: Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to reduce treatment time, notably by abandoning the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT.
Secondary resection in a general mCRC population with cetuximab-based first-line treatment: Interim analysis of the German noninterventional study ERBITAG.
Authors: Overkamp Friedrich , Goehler Thomas , Reich Gernot , Schwerdtfeger Michael , Stuebs Patrick , Stenzel Karsten G , Neumann Ulf P
Published: February 2017

590

Background: Resection of liver and/or lung metastases (LM) are a potentially curative option for patients with mCRC. Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase the resection rate of primarily unresectable LM in mCRC patients. After approval of cetuximab in Germany for first-line treatment of pts with unresectable mCRC, this noninterventional study was initiated to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in patients with unresectable mCRC. Methods: We conducted an interim analysis of the first 124 fully documented pts to evaluate the response rate (RR) and resection rate of LM. Enrolment was restricted to pts with mCRC with proven KRAS wildtype mutation status without prior systemic treatment in the metastatic stage. Predefined endpoints were amongst others RR, LM resection rate, TTF, PFS, OS, and safety. Results: From May 2010 to May 2012 360 eligible pts were enrolled at 109 sites (75% office-based physicians), documentation for 124 was finalised (data cut-off for this analysis 03 May 2012) and evaluated. The median age was 68 [range 34-84] years, ECOG performance status was 0, 1, 2 in 29%, 60%, and 9% of pts, respectively, in 2% of pts ECOG performance status was missing. Resection rate was 18.5% (n=23) performed at 18 sites with 16.9% R0 resections (n=21). 42% of pts (n=52) had liver-limited disease (LLD). Resection rate in pts with LLD was 34.6% (n=18) with a 30.6% R0-resection rate (n=16). Median treatment duration from start of cetuximab-based therapy to resection of LM was 3.7 months [0.7-12.0]. Objective response rate was 46.8% (CR 4.8%, PR 41.9%) and 59.6% (CR 5.8%, PR 53.8%) for pts with LLD. Conclusions: In a clinical practice setting cetuximab-based first-line treatment of an unselected population with KRAS wildtype mCRC resulted in an R0-resection rate of 16.9% overall, and 30.6% for LLD pts. These data compare fairly well with data from clinical trials: CRYSTAL, OPUS, and CELIM.
A phase (Ph) Ib study of irinotecan (IRI), levofolinate (LV), and 5-fluorouracil (5-FU) (FOLFIRI) plus ramucirumab (RAM; IMC-1121B) drug product in Japanese (JP) patients (pts) with metastatic colorectal carcinoma (mCRC) progressive during or following first-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and a fluoropyrimidine (FP) (CP12-1029/NCT01286818).
Authors: Yoshino Takayuki , Yamazaki Kentaro , Yoshida Motoki , Rutstein Mark Daniel , Yoshizuka Naoto , Ohtsu Atsushi
Published: February 2017

591

Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We assessed the safety of RAM + FOLFIRI among JP mCRC pts. Methods: Eligible pts had measurable or nonmeasurable disease, ECOG PS 0-1 with disease progression during or within 6 mos following 1st-line therapy with BEV, OXALI, and a FP. Pts received 8 mg/kg RAM IV every 2 wks + FOLFIRI (IRI: 180 mg/m2, LV: 200 mg/m2, 5-FU: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hrs). Dose-limiting toxicities (DLTs) were assessed Cycle 1 Day 1 to Cycle 3 Day 1. We assessed the safety of RAM + FOLFIRI among JP mCRC pts to support the participation of Japan in a global Ph 3 mCRC study. Results: 6 pts were treated; all pts completed study as of 3/19/2012. Median age was 62 yrs (range 48-71). 4 pts had colon cancer and 2 pts had rectal cancer . 1 of 6 pts experienced a DLT (Grade [G] 2 proteinuria and G4 neutropenia resulting in dose delay >2 wks). All 6 pts (100%) experienced at least one G3 adverse event (AE): neutropenia (5 pts; 83%), proteinuria (2 pts; 33%), anemia, thrombocytopenia, hypertension (1 pt each, 17%). 3 pts (50%) experienced G4 neutropenia. 2 pts discontinued (D/C) RAM due to G2 and G3 proteinuria, respectively; 1 pt D/C FOLFIRI due to G3 neutropenia. There were no serious AEs or deaths. Best overall response: 1 PR (17%), 4 SD (67%), 1 PD (17%). Median PFS: 7.3m (range: 1.25-10.91m; 95% CI: 1.2 – 10.9). As of 9/24/2012, 57 JP pts have been enrolled into ongoing P3 study I4T-MC-JVBB. Conclusions: RAM + FOLFIRI were reasonably tolerated and demonstrated anti-tumor activity in JP mCRC pts previously treated with BEV, OXALI, and a FP. The incidence of proteinuria in this small cohort of JP pts appears higher than that observed in other studies evaluating RAM to date. These safety data supported the enrollment of JP pts into an ongoing global P3 mCRC study. Clinical trial information: NCT01286818.
Pharmacokinetics (PK) of panitumumab in a single patient with metastatic colorectal cancer (mCRC) and liver dysfunction.
Authors: Krens Lisanne , Baas Jara , de Jong Floris A. , Guchelaar Henk-jan , Gelderblom Hans
Published: February 2017

594

Background: Panitumumab is used for the treatment of metastatic KRAS wild type (WT) colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment are unknown and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction. Methods: A heavily pre-treated KRAS WT mCRC patient with liver disease Child-Pugh class B was treated with two-weekly 6 mg/kg panitumumab. The patient received 2 doses of 490 mg iv panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected and panitumumab concentrations were determined using a validated immunoassay. PK parameters after the first dose, including dose-normalized AUC from time zero–day 14, clearance (CL), and elimination half-life (T1/2), were estimated via trapezoidal non compartmental methods. Data was compared to historical data from a normal population as reported by Stephenson (Clin Colorectal Cancer 2009). Values within the range of the mean ± 1 standard deviation (SD) were considered not deviant. Results: Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg*day/mL (Stephenson’s cohort 1: 744 ± 195 μg*day/mL). Estimated T1/2was 3.58 days (5.28 ± 1.90 days) and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ± 1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment, particularly, no diarrhea and skin toxicity. Conclusions: The pharmacokinetics of panitumumab in this patient suffering from colorectal cancer with liver dysfunction Child-Pugh class B was similar when compared to patients with adequate liver functions. Moreover, no substantial toxicity was detected. The here presented data may help clinical decision making in real life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS WT mCRC and hepatic dysfunction without the need for dose adjustments.
The impact of the peak (day 2) C-reactive protein (CRP) on the day 3 and day 4 CRP thresholds associated with infective complications following curative surgery in colorectal cancer.
Authors: Ramanathan Michelle Leana , Horgan Paul G. , Mcmillan Donald C.
Published: February 2017

595

Background: The postoperative systemic inflammatory response, as evidenced by C-reactive protein (CRP) on day 3 (threshold ~170 mg/L) and day 4 (threshold ~130mg/L), have been reported to be associated with the development of infective complications following surgery for colorectal cancer. The aim of the present study was to assess the impact of the peak, day 2 CRP, on CRP concentrations at day 3 and day 4. Methods: Patients with colorectal cancer who were considered to have undergone elective curative resection were recorded in a prospective database (n=396). CRP was measured preoperatively and on days 1 to 4 postoperatively. Correlations between day 2 CRP and other perioperative CRP concentrations were examined. Results: The majority of patients were 65 or older (67%), male (55%), had colonic tumours (66%), had node negative disease (57%) and were from a deprived area (55%). Day 2 CRP was not associated not with age (p=0.055), sex (p=0.185), deprivation (p=0.103), tumour site (p=0.529) or stage (p=0.395). Day 2 CRP was directly associated with day 1 (r2=0.421, p<0.001), day 3 (r2=0.617, p<0.001) and day 4 (r2=0.315, p<0.001) CRP, but not preoperative CRP (r2=0.008, p=0.084). The median day 2 CRP that corresponded with the previously described thresholds (~170mg/L and ~130mg/L at day 3 and 4 respectively) for predicting infective complications was 190mg/L. Similarly, the median day 2 CRP corresponding to the previously described thresholds (~190mg/L and ~140mg/L at day 3 and 4 respectively) for predicting an anastomotic leak was 200mg/L. Conclusions: A day 2 CRP concentration >190 - 200mg/L, was associated with day 3 and 4 CRP concentrations above established CRP thresholds for the development of infective complications. It remains to be determined whether reduction in day 2 CRP concentrations will reduce infective complications following surgery for colorectal cancer.
Randomized phase III trial of irinotecan plus cisplatin versus irinotecan alone after S-1 based chemotherapy failure for patients with advanced and recurrent gastric cancer (AGC) (TCOG GI-0801).
Authors: Shimada Ken , Higuchi Katsuhiko , Hosaka Naoshi , Sasaki Eisaku , Nakayama Norisuke , Amagai Kenji , Takeda Yuiti , Moriwaki Toshikazu , Sekikawa Takashi , Sakuyama Toshikazu , Yajima Kazuhito , Tanabe Satoshi , Saito Yusuke , Maeda Yoshiharu , Nishimura Ken , Sasaki Tohru , Kobayashi Kouji , Shimoyama Tatsu , Hyodo Ichinosuke , Koizumi Wasaburo
Published: February 2017

61

Background: S-1based chemotherapy is the standard first-line chemotherapy for AGC in Japan. Currently, there is no high level evidence established for second-line treatment. Irinotecan (CPT-11) plus cisplatin (CDDP) are active in AGC. The combination of these 2 agents is synergistic effect in preclinical and clinical studies. We conducted a phase III study of CPT-11 plus CDDP (CP) compared with CPT-11 alone (C) in patients with AGC refractory to S-1 based chemotherapy. Methods: Patients with previously treated with S-1-based chemotherapy for AGC, an ECOG PS of 0-1 and adequate organ functions were randomly assigned to receive either CPT-11 60 mg/m2 plus CDDP 30 mg/m2 on day 1 every 2 weeks or CPT-11 150mg/m2on day 1 every 2 weeks. The primary endpoint is progression free survival (PFS). The statistical design is based on superiority hypothesis; PFS is 110days in CP, 65days in C; two-sided α=0.05, 1-β=0.8; and planed accrual is 130 pts. Secondary endpoints include Overall Survival (OS), Time to Treatment Failure (TTF), Response Rate (RR), and safety. Results: From April 2008 to July 2011, 130 patients from 21 sites in Japan were randomized to CP (n=64) or C (n=66). Patient demographics were well balanced between the two groups. At the final analysis, total of 117 PFS events were observed. The primary endpoint was met. PFS for CP was superiority to C (median PFS, 4.17(95%CI 3.03-4.80) vs. 3.03(95%CI 2.20-3.33) months, respectively; HR=1.490(1.029-2.155), p=0.0324,). There were no significant differences in the TTF and RR (TTF was 3.4(95%CI 2.7-4.2) vs. 2.9(95%CI 2.2-3.3) months, RR was 21.9(95%CI 12.5-34.0) % vs. 16.4(95%CI 7.9-27.3) % with CP and C. OS is analyzing now. The most common grade 3/4 toxicities in CP/C (%) were neutropenia, 40.6/38.7; diarrhea, 1.6/7.9; anorexia, 4.7/11.1. Related adverse events were comparable with CP and C.Conclusions: CP has promising efficacy for the second-line chemotherapy compared with C for AGC.CP suggested to be one of the standard second-line chemotherapy regimen for AGC. Clinical trial information: 000001028.
Prediction of gastric cancer survival after gastrectomy using nomogram from 10,621 patients: Developed and validated using international databases.
Authors: Woo Yanghee , Hyung Woo Jin , Song Ki Jun , Hu Yanfeng , Okumura Naoki , Cho Gyu Seok , Noh Sung Hoon
Published: February 2017

66

Background: Patient-specific prognosis for gastric cancer is difficult to determine. Internationally accepted AJCC TNM staging system currently provides the best framework for predicting a patient’s prognosis. However, a major weakness of the TNM system is that significant survival differences exist even within its subgroups. The objective of this study was to create a simple tool to accurately predict patient survival from gastric cancer after gastrectomy. Methods: Between December 1986 to March 2007, 10,621 patients were surgically treated for gastric cancer at a single institution and observed until death. A nomogram was determined using Cox proportional hazard regression for multivariate analysis and the Kaplan-Meier method for estimation of 5-year overall survival. Overall survival was the endpoint. The predicted probability of the nomogram for actual overall survival was compared to the 7th edition AJCC TNM staging system. Then, the nomogram was validated using external data sets from four different institutions from Korea, Japan, and China. The number of patients in each data set was 1573 (A), 297 (B), 78 (C) and 767 patients (D). Results: Variables selected for the prediction model included age, gender, depth of invasion, number of metastatic lymph nodes (LN), total number of LN retrieved, and the presence of distant metastasis. The newly developed nomogram more accurately predicted a gastric cancer patient’s overall 5-year survival than the 7th Edition AJCC TNM system (p=0.0024) with area under the curve 0.8023 (our nomogram) and 0.7869 (AJCC TNM staging system). The concordance indexes of the different validation sets were 0.824 (A), 0.835 (B), 0.916 (C), and 0.767 (D). Conclusions: Our simple nomogram requires minimal patient and tumor information. It accurately predicts the 5-year overall survival for a patient with gastric cancer after surgical resection. Already internationally validated with data sets of various sample sizes and from different countries, our new nomogram provides a useful tool for prognostication after gastrectomy with wide applicability in different patient populations and institutions.
Randomized phase II study of S-1/CDDP plus TSU-68 versus S-1/CDDP in patients with advanced gastric cancer.
Authors: Yamaguchi Kensei , Koizumi Wasaburo , Hosaka Hisashi , Takinishi Yasutaka , Nakayama Norisuke , Hara Takuo , Muro Kei , Baba Hideo , Sasaki Yasutsuna , Nishina Tomohiro , Fuse Nozomu , Esaki Taito , Takagi Masakazu , Gotoh Masahiro , Kitamura Ryuichi , Matsumoto Hideki , Sasaki Tsuneo
Published: February 2017

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Background: Gastric cancer (GC) is the second leading cause of cancer death in Japan as well as globally. Effective treatment of GC remains a therapeutic challenge. Although in the AVAGAST trial, bevacizumab was found to offer no survival benefit. Angiogenesis continues to be the standard treatment for GC, and thus, clinical trials on many anti-angiogenic drugs have been conducted. TSU-68 (orantinib) is an oral, angiokinase inhibitor targeting the vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor β, and fibroblast growth factor receptor 1. The present study evaluated the progression-free survival (PFS) and pharmacokinetics (PK) of TSU-68 in combination with Japanese standard S-1 and cisplatin (S-1/CDDP) in patients with advanced GC. Methods: In this open-label, multicenter, randomized, controlled, parallel-group, phase II trial, patients were randomized to Arm A (S-1/CDDP) or Arm B (TSU-68 plus S-1/CDDP). All patients received oral S-1 (40-60 mg/m2) twice daily for 21 days followed by a 14 day rest plus intravenous CDDP (60 mg/m2) on Day 8, repeated every 35 days. In Arm B pts received oral TSU-68 (400 mg/dose) alone, twice daily by addition 35 days. The primary endpoint was PFS. Results: In total, 93 patients were enrolled. For Arm A [male:female ratio], n=47 [35:11]; Arm B, n=45 [30:15]; the respective median age was 63.5 and 62.0 years. The median PFS was 7.0 and 6.8 months in Arms A and B, respectively (HR, 1.23; 95%CI, 0.74 to 2.05; P=0.425); the respective response rates were 56.5% and 62.2%. The most common grade 3/4 toxicities were neutropenia (Arms A and B, 34.8% and 31.1%) and hemoglobin (Arms A and B, 26.1% and 48.9%). There were no differences in other toxicities between the 2 arms, both treatments were tolerated, and no treatment-related deaths were observed. In the PK study, although Arm B had a significantly lower plasma exposure to FT, CDHP, and Oxo compared to Arm A, the exposure to 5-FU was not different between the 2 arms. The exposure to CDDP in Arm B was significantly but slightly lower than that in arm A. Conclusions: Thus,TSU-68 plus S-1/CDDP therapy did not prolong PFS of patients with advanced GC as compared with S-1/CDDP. Clinical trial information: JapicCTI-101327.