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2114 Chemotherapy tolerance and oncologic outcomes in patients with inflammatory bowel disease and gastrointestinal malignancy: The Mount Sinai Hospital experience
Abstracts
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2112 POSTER Association between early tumour shrinkage and outcomes in RAS-wild type patients with metastatic colorectal cancer receiving first-line FOLFOX or FOLFIRI + cetuximab once every 2 weeks in the APEC study A.L. Cheng1 , G.H. Cornelio2 , L. Shen3 , T.J. Price4 , T.S. Yang5 , I.J. Chung6 , G. Dai7 , J.K. Lin8 , A. Sharma9 , K.H. Yeh1 , B. Ma10 , A. Zaatar11 , Z. Guan12 , N. Masood13 , V. Srimuninnimit14 , T.C. Yau15 , F. Beier16 , S. Chatterjee17 , R.S.C. Lim18 . 1 National Taiwan University Hospital, Department of Medical Oncology, Taipei, Taiwan; 2 San Juan de Dios Hospital, Department of Oncology, Pasay City, Philippines; 3 Peking University Cancer Hospital & Institute, Department of Gastrointestinal Oncology, Beijing, China; 4 The Queen Elizabeth Hospital, Department of Haematology and Oncology, Woodville, Australia; 5 Chang Gung Memorial Hospital, Division of Medical Oncology, Linkou, Taoyuan, Taiwan; 6 Chonnam National University Hwasun Hospital, Department of Hematology-Oncology, Hwasun-eup, South Korea; 7 The General Hospital of the People’s Liberation Army, Department of Comprehensive Treatment Oncology, Beijing, China; 8 Taipei Veterans General Hospital, Division on Colon and Rectal Surgery, Taipei, Taiwan; 9 All India Institute of Medical Sciences, Department of Medical Oncology, New Delhi, India; 10 Chinese University of Hong Kong, Prince of Wales Hospital, Department of Clinical Oncology, Sha Tin, New Territories, Hong Kong, China; 11 Mount Miriam Cancer Hospital, Department of Radiotherapy & Oncology, Penang, Malaysia; 12 Sun Yat-sen University Cancer Center, Department of Medical Oncology, Guangzhou, China; 13 The Aga Khan University & Hospital, Department of Medical Oncology, Karachi, Pakistan; 14 Siriraj Hospital, Division of Oncology, Bangkok, Thailand; 15 Queen Mary Hospital, Department of Medicine, Hong Kong, China; 16 Merck KGaA, Global Biostatistics, Darmstadt, Germany; 17 Merck Serono, Regional Medical Affairs, Mumbai, India; 18 National University Cancer Institute, Department of Haematology-Oncology, Singapore, Singapore Background: Early tumour shrinkage (ETS) has been correlated with improved long-term outcome in patients with KRAS/RAS-wild type (WT) metastatic colorectal cancer (mCRC) treated with weekly cetuximab in the CRYSTAL and OPUS (at 8 weeks), as well as FIRE-3 (at 6 weeks), studies. The present analysis evaluated the association between ETS at 8 weeks and progression-free survival (PFS) and overall survival (OS) in the RASWT population from the Asia-Pacific, multicentre, nonrandomized, phase 2 APEC study that enrolled 289 patients with KRAS-WT tumours. Materials and Methods: Eligible patients received cetuximab once every 2 weeks + FOLFOX or FOLFIRI (investigator’s choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. RAS status was assessed retrospectively by ion torrent nextgeneration sequencing on evaluable samples. ETS was categorized as 20% decrease in the sum of longest diameters of target lesions between baseline and 8 weeks after start of treatment. Results: Median PFS and OS in the RAS-WT population (n = 167) were 13.0 and 28.4 months, respectively. ETS, as defined above, occurred in 81.8% (130/159) of evaluable patients and was associated with longer PFS and OS (Table); there were no major differences between patients receiving FOLFOX vs FOLFIRI. There were no unexpected safety findings. RAS-WT, ETS-Evaluable Patients (n = 159)
OS
PFS
n # of events (%) HR (95% CI) Median, mo (95% CI) n # of events (%) HR (95% CI) Median, mo (95% CI)
ETS 20%
ETS <20%
Total
130 81 (62.3%) 0.584 (0.357–0.954) 30.3(26.3–33.2) 130 90 (69.2%) 0.721 (0.438–1.186) 14.0 (11.2–14.9)
29 20 (69.0%)
159 101 (63.5%) − 28.5 (24.5–32.3) 159 109 (68.6%) − 13.3 (11.1–14.8)
16.4 (10.3–31.2) 29 19 (65.5%) 7.5 (3.6–16.6)
Conclusions: ETS at 8 weeks appears to be associated with longer PFS and OS in RAS-WT patients receiving FOLFOX or FOLFIRI + cetuximab once every 2 weeks in the phase 2 APEC study. These findings are comparable to earlier subgroup analyses of analogous pivotal studies involving weekly cetuximab. Conflict of interest: Advisory Board: Eisai, Exelixis Inc., Daiichi Sankyo.
2113 POSTER Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC) K. Muro1 , H. Uetake2 , N. Fujita3 , T. Furuta4 , N. Hara5 , J. Katori5 , T. Yoshino6 . 1 Aichi Cancer Center Hospital, Department of Clinical Oncology and Outpatient Treatment Center, Aichi, Japan; 2 Graduate School, Tokyo Medical and Dental University, Department of Surgical Specialties, Tokyo, Japan; 3 Taiho Pharmaceutical CO., LTD., Medical Affairs Department, Tokyo, Japan; 4 Taiho Pharmaceutical CO., LTD., Medical Affairs Project Management Office, Tokyo, Japan; 5 Taiho Pharmaceutical CO., LTD., Pharmacovigilance Department, Tokyo, Japan; 6 National Cancer Center Hospital East, Department of Gastroenterology and Gastrointestinal Oncology, Chiba, Japan Background: Pharmaceuticals and Medical Devices Agency in Japan requires Marketing Authorization Holder (MAH) to survey EPPV for new drugs approved in Japan. MAH takes safety assurance activities within a period of 6 months after a product launch in order to promote proper use of new drug in clinical practice, and to ensure early detection of serious Adverse Drug Reactions (SADRs). TAS-102 is comprised of an active component, trifluridine (FTD) and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that prevents degradation of FTD. Based on the results of a phase 2 trial, TAS-102 was approved first in Japan in March, 2014. The global phase 3 RECOURSE trial demonstrated a significant improvement in overall survival and progression-free survival with TAS102 over placebo with hazard ratio of 0.68 and 0.48, respectively (both P < 0.0001). Material and Methods: All mCRC patients (pts) who would intend to receive TAS-102 were pre-registered via FAX from the institutes to Taiho Pharmaceutical Patient Registration Center, on which survey was conducted to capture occurrence of any ADR from May 26th to November 25th 2014. Definition of “serious” and “ADR” are based on ICH-E2D and ICH-E2A guidelines, respectively. Results: During the 6-month period of EPPV, a total of 370 ADRs were reported in 219 pts that included 89 SADRs in 51 pts and 281 non-SADRs in 183 pts (a patient was counted twice if one experienced both SADR and non-SADR), out of 3373 pts from 1209 institutes. Out of 370 ADRs, a total of 185 ADRs of myelosuppression and related infection were reported in 125 pts, of which 58 ADRs in 31 pts were SADRs and 127 ADRs in 98 pts were non-SADRs. The most common ADRs were myelosuppression, consisting of neutropenia in 77 pts, leukopenia in 28 pts, thrombocytopenia in 23 pts, anemia in 20 pts, and febrile neutropenia (FN) was observed in 19 pts. A total of 162 ADRs of the 167 ADRs (97%) were confirmed to have resolved or been resolving. Half of non-serious neutropenia tends to occur from day 19 to day 25 in the first cycle, while most of serious neutropenia and FN tend to occur around day 15 in the first cycle. Treatment-related death due to infection induced by neutropenia was reported in 2 pts, of whom the patient experienced FN on day 15, and the other patient had neutropenia and thrombocytopenia on day 14 and FN on day 18. Interstitial pneumonia was noted in 7 pts, diarrhea in 25 pts, nausea/vomiting in 38 pts, anorexia in 31 pts, fatigue in 17 pts and cardiac events in 2 pts. There were no unexpected safety signals. Conclusions: This is the first to show mild safety profile of TAS-102 in clinical practice which is consistent with those from TAS-102 clinical trials. Careful monitoring of myelosuppression should be taken, especially for pts showing serious neutropenia around on day 15 in the first cycle, to prevent from FN. No conflict of interest.
2114 POSTER Chemotherapy tolerance and oncologic outcomes in patients with inflammatory bowel disease and gastrointestinal malignancy: The Mount Sinai Hospital experience J. Axelrad1 , S. Itzkowitz1 , J.F. Colombel1 , N. Harpaz1 , R. Holcombe1 , U. Ozbek1 , C. Ang1 . 1 Icahn School of Medicine at Mount Sinai, Medicine, New York City, USA Background: Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is an established risk factor for the development of gastrointestinal (GI) malignancies. Chemotherapy (CTX) toxicities may compound existing chronic GI tract inflammation and vice versa, raising concerns about the ability of patients with IBD and cancer to tolerate CTX. We sought to review CTX tolerance and oncologic outcomes in patients with IBD who developed GI malignancies. Material and Methods: We reviewed the medical records of patients with IBD who were treated for a GI malignancy between 2008–2013 at The
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Mount Sinai Hospital, NY. We examined IBD and cancer demographics, CTX treatments and tolerance, cancer recurrence, and survival. Results: We identified 109 patients with IBD [n = 46 (42%) CD; n = 63 (58%) UC] who developed a GI malignancy: 69 (63%) colon adenocarcinoma (adenoCa); 18 (17%) rectal adenoCa, 10 (9%) small bowel adenoCa; 9 (8%) anal squamous cell carcinoma (SCC); 2 (2%) appendiceal carcinoid; and 1 (1%) rectal SCC. At cancer diagnosis, median age was 57 years (range 24−92) and median duration of IBD was 25 years (range 1−59). Of patients with known pathology, cancer stage at diagnosis was 1, 2, 3, 4 in 31 (32%), 26 (27%) 26 (27%), 14(14%). Sixty-nine patients (73%) had active IBD on pathology at the time of cancer diagnosis, 52 (75%) of whom had colorectal cancer. Of patients with known cancer treatment plans, 87 (90%) underwent surgery, 62 (71%) received CTX [Table 1], and 24 (38%) received radiotherapy. Among patients who received CTX, 7 (11%) required dose modifications, 8 (12%) experienced treatment delays; 9 (15%) required treatment discontinuation for an overall treatment modification rate of 13%. Eight (13%) were hospitalized for treatmentrelated toxicities. Of patients with treatment modification or hospitalization for treatment-related toxicities, 67% had active IBD. Median follow up after cancer diagnosis was 21 months (range 1–121 months) and 21 (27%) developed cancer recurrence. There was no difference in overall survival between patients with stage 1 (88%) versus stage 2/3 (78%) cancers (p > 0.05). The difference in 5-year recurrence-free survival in patients with stage 1 (89%) compared to stage 2/3 (54%) cancers was borderline significant (p = 0.05). Conclusions: In this series, most IBD patients with GI malignancies received and completed CTX uneventfully. The incidence of cancer treatment discontinuations and complications resulting in hospitalization is comparable to that reported in the literature. Prospective studies are needed to further assess the relationship between IBD, CTX tolerance, and overall survival. Table 1 Chemotherapy
Number exposed
FOLFOX/CAPOX FOLFIRI 5FU/LV Bevacizumab 5FU/MMC Cetuximab Docetaxel/cisplatin/5FU/LV Regorafenib Panitumumab Carboplatin/paclitaxel >1 line of CTX
36 8 7 6 5 3 1 1 1 1 7
No conflict of interest. 2115 POSTER The role of adjuvant chemotherapy in patients with stage II/III upper-rectal cancer P. Barata1 , D.A. Costa2 , F. Filipe1 , J. Barreira1 , S. Oliveira1 , J. Penedo1 , L. Batarda1 , C. Almeida1 . 1 Centro Hospitalar Lisboa Central, Medical ˆ de Oncologia de Lisboa, Oncology, Lisbon, Portugal; 2 Instituto Portugues Medical Oncology, Lisbon, Portugal Background: Despite the advances in the treatment of rectal cancer, about one third of all patients treated with curative intent will recur. No clear benefit was found with the addition of adjuvant chemotherapy (AC) after preoperative chemo-radiation (CR) and surgery. However, in subgroup analysis, AC might benefit patients with a tumor 10−15 cm from anal verge, according to recent prospective studies and meta-analysis. In this study, we explore the effect of adjuvant fluoropyrimidine-based chemotherapy in patients with stage II/III upper-rectal cancer treated with preoperative CR followed by surgery. Material and Methods: We retrospectively analyzed data of 200 consecutive patients admitted at Central Lisbon Hospital Center, with clinical stage II/III rectal cancer at diagnosis, between 01/2008 and 06/2014. We analyzed the cohort of patients with histologically confirmed rectal cancer between 10 and 15 cm from anal verge, treated with preoperative concomitant long-course radiotherapy and fluorouracil-based chemotherapy, and submitted to R0 resection. The cohort was organized in two groups: patients who received AC and patients who did not receive any adjuvant treatment and underwent observation (O). Patient characteristics and outcomes were evaluated with univariate analysis. Kaplan–Meier curves were used to study the effect of selected variables on survival free
from invasive disease and overall survival; curves were compared with logrank test. Results: Forty-four patients, 70% men, median age 69 (range, 43−83), were identified. Median time between end of CR and surgery was 8.1 weeks (4.9−44). Pathologic complete responses were observed in 30% of the cases. The majority (95%) was submitted to anterior resection. Twentynine patients (66%) received fluorouracil-based chemotherapy, median length of 4 months (2−6). Twenty-seven patients completed planned AC, with no major toxicities. Fifteen patients (34%) underwent observation (O) (mainly to physician’s choice. No significant difference was found in relative proportion of clinical stage II-III disease in these 2 groups. The variables gender, age, time between AC and surgery, histologic regression and staging were not associated with different outcomes, in univariate analysis. The median follow-up period was 2.0 years. Among the 6 relapses seen, all of them occurred in patients treated with AC, mainly after 1 year of follow-up. The lung was the most common site of relapse, in 67% of the cases. The 2-year mortality of the cohort was 20%; among the 9 deaths observed, only 3 were cancer-related no toxic deaths were reported. Conclusions: Despite the limitations of this retrospective analysis, our data does not suggest a benefit with the addition of AC in patients with stage II-III upper-rectal cancer treated with CR and surgery. Prospective studies for this subgroup of patients are warranted. No conflict of interest. 2116 POSTER A multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE) K. Yamazaki1 , Y. Kuboki2 , T. Nishina3 , E. Shinozaki4 , K. Shitara2 , W. Okamoto2 , T. Kajiwara3 , T. Matsumoto3 , T. Tsushima1 , N. Mochizuki5 , M. Fukutani6 , M. Nakamoto6 , Y. Hasegawa6 , A. Sugama6 , S. Nomura6 , A. Sato6 , A. Ohtsu7 , T. Yoshino2 . 1 Shizuoka Cancer Center, Division of Gastrointestinal Oncology, Shizuoka-pref., Japan; 2 National Cancer Center Hospital East, Department of GI oncology, Chiba-pref., Japan; 3 Shikoku Cancer Center, Department of Gastrointestinal Medical Oncology, Ehime-pref., Japan; 4 Cancer Institute Hospital of Japanese Foundation for Cancer Research, Department of Gastroenterology, Tokyo, Japan; 5 National Cancer Center Hospital East, Department of pharmacy, Chiba-pref., Japan; 6 National Cancer Center, Center for Research Administration and Support, Chiba-pref., Japan; 7 National Cancer Center, Exploratory Oncology Research & Clinical Trial Center, Chiba-pref., Japan Background: In global phase III RECOURSE trial, TAS-102 significantly improved overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) over placebo for metastatic colorectal cancer (mCRC) patients (pts) refractory to standard therapies. In preclinical models, TAS102 with bevacizumab (BEV) demonstrated enhanced activity against CRC cells compared with either drug alone. This phase I/II study was conducted to determine the recommended phase II dose (RP2D) and evaluate the efficacy, safety and pharmacokinetics of this combination in pts with mCRC refractory to standard therapies. Methods: Eligibility criteria were: mCRC pts who were refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, anti-angiogenesis therapy and anti-EGFR antibody (if KRAS wild-type) and had no prior regorafenib treatment. Phase I was designed to determine RP2D in the dose de-escalation design of TAS-102 (35 mg/m2 BID on days 1−5 and 8−12 q4w for level 1 and 30 mg/m2 BID for level −1) with a fixed BEV dose (5 mg/kg q2w). Primary endpoint was centrally assessed PFS rate at 16 weeks in pts treated with RP2D. Using a single stage binomial design, this study required 21 pts, with a centrally assessed PFS rate at 16 weeks of 50% deemed promising and 25% unacceptable (alpha=0.1; beta=0.2). Results: From February to July 2014, 25 pts were enrolled. In phase I, dose-limiting toxicity was not observed in 6 pts at level 1, which was determined as the RP2D. Centrally assessed PFS rate at 16 weeks (n = 21) was 42.9% (80% confidence interval: 27.8–59.0%). Median PFS and DCR by central assessment were 3.7 months and 64.0%, and by investigator assessment were 5.4 months and 72.0%, respectively (n = 25). Median OS was not reach. The median number of treatment cycles was 4 (range: 2−8). The median relative dose intensity of TAS-102 and BEV were 100% (range: 83.3–100%) and 100% (range: 75.0%-100%), respectively. In patients with KRAS exon 2 wild-type tumors (n = 10), median PFS and DCR by central assessment were 3.7 months and 70.0%, and by investigator assessment were 5.4 months and 80.0%, respectively. In patients with KRAS exon 2 mutant-type tumors (n = 15), median PFS and DCR by central assessment were 3.8 months and 60.0%, and by investigator assessment were 3.9 months and 66.7%, respectively. There was no significant difference in PFS or DCR between the KRAS exon 2 mutation status. The most common grade 3 or worse adverse events were neutropenia (68%), anemia (12%),
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2112 POSTER Association between early tumour shrinkage and outcomes in RAS-wild type patients with metastatic colorectal cancer receiving first-line FOLFOX or FOLFIRI + cetuximab once every 2 weeks in the APEC study A.L. Cheng1 , G.H. Cornelio2 , L. Shen3 , T.J. Price4 , T.S. Yang5 , I.J. Chung6 , G. Dai7 , J.K. Lin8 , A. Sharma9 , K.H. Yeh1 , B. Ma10 , A. Zaatar11 , Z. Guan12 , N. Masood13 , V. Srimuninnimit14 , T.C. Yau15 , F. Beier16 , S. Chatterjee17 , R.S.C. Lim18 . 1 National Taiwan University Hospital, Department of Medical Oncology, Taipei, Taiwan; 2 San Juan de Dios Hospital, Department of Oncology, Pasay City, Philippines; 3 Peking University Cancer Hospital & Institute, Department of Gastrointestinal Oncology, Beijing, China; 4 The Queen Elizabeth Hospital, Department of Haematology and Oncology, Woodville, Australia; 5 Chang Gung Memorial Hospital, Division of Medical Oncology, Linkou, Taoyuan, Taiwan; 6 Chonnam National University Hwasun Hospital, Department of Hematology-Oncology, Hwasun-eup, South Korea; 7 The General Hospital of the People’s Liberation Army, Department of Comprehensive Treatment Oncology, Beijing, China; 8 Taipei Veterans General Hospital, Division on Colon and Rectal Surgery, Taipei, Taiwan; 9 All India Institute of Medical Sciences, Department of Medical Oncology, New Delhi, India; 10 Chinese University of Hong Kong, Prince of Wales Hospital, Department of Clinical Oncology, Sha Tin, New Territories, Hong Kong, China; 11 Mount Miriam Cancer Hospital, Department of Radiotherapy & Oncology, Penang, Malaysia; 12 Sun Yat-sen University Cancer Center, Department of Medical Oncology, Guangzhou, China; 13 The Aga Khan University & Hospital, Department of Medical Oncology, Karachi, Pakistan; 14 Siriraj Hospital, Division of Oncology, Bangkok, Thailand; 15 Queen Mary Hospital, Department of Medicine, Hong Kong, China; 16 Merck KGaA, Global Biostatistics, Darmstadt, Germany; 17 Merck Serono, Regional Medical Affairs, Mumbai, India; 18 National University Cancer Institute, Department of Haematology-Oncology, Singapore, Singapore Background: Early tumour shrinkage (ETS) has been correlated with improved long-term outcome in patients with KRAS/RAS-wild type (WT) metastatic colorectal cancer (mCRC) treated with weekly cetuximab in the CRYSTAL and OPUS (at 8 weeks), as well as FIRE-3 (at 6 weeks), studies. The present analysis evaluated the association between ETS at 8 weeks and progression-free survival (PFS) and overall survival (OS) in the RASWT population from the Asia-Pacific, multicentre, nonrandomized, phase 2 APEC study that enrolled 289 patients with KRAS-WT tumours. Materials and Methods: Eligible patients received cetuximab once every 2 weeks + FOLFOX or FOLFIRI (investigator’s choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. RAS status was assessed retrospectively by ion torrent nextgeneration sequencing on evaluable samples. ETS was categorized as 20% decrease in the sum of longest diameters of target lesions between baseline and 8 weeks after start of treatment. Results: Median PFS and OS in the RAS-WT population (n = 167) were 13.0 and 28.4 months, respectively. ETS, as defined above, occurred in 81.8% (130/159) of evaluable patients and was associated with longer PFS and OS (Table); there were no major differences between patients receiving FOLFOX vs FOLFIRI. There were no unexpected safety findings. RAS-WT, ETS-Evaluable Patients (n = 159)
OS
PFS
n # of events (%) HR (95% CI) Median, mo (95% CI) n # of events (%) HR (95% CI) Median, mo (95% CI)
ETS 20%
ETS <20%
Total
130 81 (62.3%) 0.584 (0.357–0.954) 30.3(26.3–33.2) 130 90 (69.2%) 0.721 (0.438–1.186) 14.0 (11.2–14.9)
29 20 (69.0%)
159 101 (63.5%) − 28.5 (24.5–32.3) 159 109 (68.6%) − 13.3 (11.1–14.8)
16.4 (10.3–31.2) 29 19 (65.5%) 7.5 (3.6–16.6)
Conclusions: ETS at 8 weeks appears to be associated with longer PFS and OS in RAS-WT patients receiving FOLFOX or FOLFIRI + cetuximab once every 2 weeks in the phase 2 APEC study. These findings are comparable to earlier subgroup analyses of analogous pivotal studies involving weekly cetuximab. Conflict of interest: Advisory Board: Eisai, Exelixis Inc., Daiichi Sankyo.
2113 POSTER Initial safety survey report from early post-marketing phase vigilance (EPPV) on TAS-102 for metastatic colorectal cancer (mCRC) K. Muro1 , H. Uetake2 , N. Fujita3 , T. Furuta4 , N. Hara5 , J. Katori5 , T. Yoshino6 . 1 Aichi Cancer Center Hospital, Department of Clinical Oncology and Outpatient Treatment Center, Aichi, Japan; 2 Graduate School, Tokyo Medical and Dental University, Department of Surgical Specialties, Tokyo, Japan; 3 Taiho Pharmaceutical CO., LTD., Medical Affairs Department, Tokyo, Japan; 4 Taiho Pharmaceutical CO., LTD., Medical Affairs Project Management Office, Tokyo, Japan; 5 Taiho Pharmaceutical CO., LTD., Pharmacovigilance Department, Tokyo, Japan; 6 National Cancer Center Hospital East, Department of Gastroenterology and Gastrointestinal Oncology, Chiba, Japan Background: Pharmaceuticals and Medical Devices Agency in Japan requires Marketing Authorization Holder (MAH) to survey EPPV for new drugs approved in Japan. MAH takes safety assurance activities within a period of 6 months after a product launch in order to promote proper use of new drug in clinical practice, and to ensure early detection of serious Adverse Drug Reactions (SADRs). TAS-102 is comprised of an active component, trifluridine (FTD) and tipiracil hydrochloride, a thymidine phosphorylase inhibitor that prevents degradation of FTD. Based on the results of a phase 2 trial, TAS-102 was approved first in Japan in March, 2014. The global phase 3 RECOURSE trial demonstrated a significant improvement in overall survival and progression-free survival with TAS102 over placebo with hazard ratio of 0.68 and 0.48, respectively (both P < 0.0001). Material and Methods: All mCRC patients (pts) who would intend to receive TAS-102 were pre-registered via FAX from the institutes to Taiho Pharmaceutical Patient Registration Center, on which survey was conducted to capture occurrence of any ADR from May 26th to November 25th 2014. Definition of “serious” and “ADR” are based on ICH-E2D and ICH-E2A guidelines, respectively. Results: During the 6-month period of EPPV, a total of 370 ADRs were reported in 219 pts that included 89 SADRs in 51 pts and 281 non-SADRs in 183 pts (a patient was counted twice if one experienced both SADR and non-SADR), out of 3373 pts from 1209 institutes. Out of 370 ADRs, a total of 185 ADRs of myelosuppression and related infection were reported in 125 pts, of which 58 ADRs in 31 pts were SADRs and 127 ADRs in 98 pts were non-SADRs. The most common ADRs were myelosuppression, consisting of neutropenia in 77 pts, leukopenia in 28 pts, thrombocytopenia in 23 pts, anemia in 20 pts, and febrile neutropenia (FN) was observed in 19 pts. A total of 162 ADRs of the 167 ADRs (97%) were confirmed to have resolved or been resolving. Half of non-serious neutropenia tends to occur from day 19 to day 25 in the first cycle, while most of serious neutropenia and FN tend to occur around day 15 in the first cycle. Treatment-related death due to infection induced by neutropenia was reported in 2 pts, of whom the patient experienced FN on day 15, and the other patient had neutropenia and thrombocytopenia on day 14 and FN on day 18. Interstitial pneumonia was noted in 7 pts, diarrhea in 25 pts, nausea/vomiting in 38 pts, anorexia in 31 pts, fatigue in 17 pts and cardiac events in 2 pts. There were no unexpected safety signals. Conclusions: This is the first to show mild safety profile of TAS-102 in clinical practice which is consistent with those from TAS-102 clinical trials. Careful monitoring of myelosuppression should be taken, especially for pts showing serious neutropenia around on day 15 in the first cycle, to prevent from FN. No conflict of interest.
2114 POSTER Chemotherapy tolerance and oncologic outcomes in patients with inflammatory bowel disease and gastrointestinal malignancy: The Mount Sinai Hospital experience J. Axelrad1 , S. Itzkowitz1 , J.F. Colombel1 , N. Harpaz1 , R. Holcombe1 , U. Ozbek1 , C. Ang1 . 1 Icahn School of Medicine at Mount Sinai, Medicine, New York City, USA Background: Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is an established risk factor for the development of gastrointestinal (GI) malignancies. Chemotherapy (CTX) toxicities may compound existing chronic GI tract inflammation and vice versa, raising concerns about the ability of patients with IBD and cancer to tolerate CTX. We sought to review CTX tolerance and oncologic outcomes in patients with IBD who developed GI malignancies. Material and Methods: We reviewed the medical records of patients with IBD who were treated for a GI malignancy between 2008–2013 at The
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Abstracts
Mount Sinai Hospital, NY. We examined IBD and cancer demographics, CTX treatments and tolerance, cancer recurrence, and survival. Results: We identified 109 patients with IBD [n = 46 (42%) CD; n = 63 (58%) UC] who developed a GI malignancy: 69 (63%) colon adenocarcinoma (adenoCa); 18 (17%) rectal adenoCa, 10 (9%) small bowel adenoCa; 9 (8%) anal squamous cell carcinoma (SCC); 2 (2%) appendiceal carcinoid; and 1 (1%) rectal SCC. At cancer diagnosis, median age was 57 years (range 24−92) and median duration of IBD was 25 years (range 1−59). Of patients with known pathology, cancer stage at diagnosis was 1, 2, 3, 4 in 31 (32%), 26 (27%) 26 (27%), 14(14%). Sixty-nine patients (73%) had active IBD on pathology at the time of cancer diagnosis, 52 (75%) of whom had colorectal cancer. Of patients with known cancer treatment plans, 87 (90%) underwent surgery, 62 (71%) received CTX [Table 1], and 24 (38%) received radiotherapy. Among patients who received CTX, 7 (11%) required dose modifications, 8 (12%) experienced treatment delays; 9 (15%) required treatment discontinuation for an overall treatment modification rate of 13%. Eight (13%) were hospitalized for treatmentrelated toxicities. Of patients with treatment modification or hospitalization for treatment-related toxicities, 67% had active IBD. Median follow up after cancer diagnosis was 21 months (range 1–121 months) and 21 (27%) developed cancer recurrence. There was no difference in overall survival between patients with stage 1 (88%) versus stage 2/3 (78%) cancers (p > 0.05). The difference in 5-year recurrence-free survival in patients with stage 1 (89%) compared to stage 2/3 (54%) cancers was borderline significant (p = 0.05). Conclusions: In this series, most IBD patients with GI malignancies received and completed CTX uneventfully. The incidence of cancer treatment discontinuations and complications resulting in hospitalization is comparable to that reported in the literature. Prospective studies are needed to further assess the relationship between IBD, CTX tolerance, and overall survival. Table 1 Chemotherapy
Number exposed
FOLFOX/CAPOX FOLFIRI 5FU/LV Bevacizumab 5FU/MMC Cetuximab Docetaxel/cisplatin/5FU/LV Regorafenib Panitumumab Carboplatin/paclitaxel >1 line of CTX
36 8 7 6 5 3 1 1 1 1 7
No conflict of interest. 2115 POSTER The role of adjuvant chemotherapy in patients with stage II/III upper-rectal cancer P. Barata1 , D.A. Costa2 , F. Filipe1 , J. Barreira1 , S. Oliveira1 , J. Penedo1 , L. Batarda1 , C. Almeida1 . 1 Centro Hospitalar Lisboa Central, Medical ˆ de Oncologia de Lisboa, Oncology, Lisbon, Portugal; 2 Instituto Portugues Medical Oncology, Lisbon, Portugal Background: Despite the advances in the treatment of rectal cancer, about one third of all patients treated with curative intent will recur. No clear benefit was found with the addition of adjuvant chemotherapy (AC) after preoperative chemo-radiation (CR) and surgery. However, in subgroup analysis, AC might benefit patients with a tumor 10−15 cm from anal verge, according to recent prospective studies and meta-analysis. In this study, we explore the effect of adjuvant fluoropyrimidine-based chemotherapy in patients with stage II/III upper-rectal cancer treated with preoperative CR followed by surgery. Material and Methods: We retrospectively analyzed data of 200 consecutive patients admitted at Central Lisbon Hospital Center, with clinical stage II/III rectal cancer at diagnosis, between 01/2008 and 06/2014. We analyzed the cohort of patients with histologically confirmed rectal cancer between 10 and 15 cm from anal verge, treated with preoperative concomitant long-course radiotherapy and fluorouracil-based chemotherapy, and submitted to R0 resection. The cohort was organized in two groups: patients who received AC and patients who did not receive any adjuvant treatment and underwent observation (O). Patient characteristics and outcomes were evaluated with univariate analysis. Kaplan–Meier curves were used to study the effect of selected variables on survival free
from invasive disease and overall survival; curves were compared with logrank test. Results: Forty-four patients, 70% men, median age 69 (range, 43−83), were identified. Median time between end of CR and surgery was 8.1 weeks (4.9−44). Pathologic complete responses were observed in 30% of the cases. The majority (95%) was submitted to anterior resection. Twentynine patients (66%) received fluorouracil-based chemotherapy, median length of 4 months (2−6). Twenty-seven patients completed planned AC, with no major toxicities. Fifteen patients (34%) underwent observation (O) (mainly to physician’s choice. No significant difference was found in relative proportion of clinical stage II-III disease in these 2 groups. The variables gender, age, time between AC and surgery, histologic regression and staging were not associated with different outcomes, in univariate analysis. The median follow-up period was 2.0 years. Among the 6 relapses seen, all of them occurred in patients treated with AC, mainly after 1 year of follow-up. The lung was the most common site of relapse, in 67% of the cases. The 2-year mortality of the cohort was 20%; among the 9 deaths observed, only 3 were cancer-related no toxic deaths were reported. Conclusions: Despite the limitations of this retrospective analysis, our data does not suggest a benefit with the addition of AC in patients with stage II-III upper-rectal cancer treated with CR and surgery. Prospective studies for this subgroup of patients are warranted. No conflict of interest. 2116 POSTER A multicenter phase I/II study of TAS-102 with bevacizumab for metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE) K. Yamazaki1 , Y. Kuboki2 , T. Nishina3 , E. Shinozaki4 , K. Shitara2 , W. Okamoto2 , T. Kajiwara3 , T. Matsumoto3 , T. Tsushima1 , N. Mochizuki5 , M. Fukutani6 , M. Nakamoto6 , Y. Hasegawa6 , A. Sugama6 , S. Nomura6 , A. Sato6 , A. Ohtsu7 , T. Yoshino2 . 1 Shizuoka Cancer Center, Division of Gastrointestinal Oncology, Shizuoka-pref., Japan; 2 National Cancer Center Hospital East, Department of GI oncology, Chiba-pref., Japan; 3 Shikoku Cancer Center, Department of Gastrointestinal Medical Oncology, Ehime-pref., Japan; 4 Cancer Institute Hospital of Japanese Foundation for Cancer Research, Department of Gastroenterology, Tokyo, Japan; 5 National Cancer Center Hospital East, Department of pharmacy, Chiba-pref., Japan; 6 National Cancer Center, Center for Research Administration and Support, Chiba-pref., Japan; 7 National Cancer Center, Exploratory Oncology Research & Clinical Trial Center, Chiba-pref., Japan Background: In global phase III RECOURSE trial, TAS-102 significantly improved overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) over placebo for metastatic colorectal cancer (mCRC) patients (pts) refractory to standard therapies. In preclinical models, TAS102 with bevacizumab (BEV) demonstrated enhanced activity against CRC cells compared with either drug alone. This phase I/II study was conducted to determine the recommended phase II dose (RP2D) and evaluate the efficacy, safety and pharmacokinetics of this combination in pts with mCRC refractory to standard therapies. Methods: Eligibility criteria were: mCRC pts who were refractory or intolerant to fluoropyrimidines, irinotecan, oxaliplatin, anti-angiogenesis therapy and anti-EGFR antibody (if KRAS wild-type) and had no prior regorafenib treatment. Phase I was designed to determine RP2D in the dose de-escalation design of TAS-102 (35 mg/m2 BID on days 1−5 and 8−12 q4w for level 1 and 30 mg/m2 BID for level −1) with a fixed BEV dose (5 mg/kg q2w). Primary endpoint was centrally assessed PFS rate at 16 weeks in pts treated with RP2D. Using a single stage binomial design, this study required 21 pts, with a centrally assessed PFS rate at 16 weeks of 50% deemed promising and 25% unacceptable (alpha=0.1; beta=0.2). Results: From February to July 2014, 25 pts were enrolled. In phase I, dose-limiting toxicity was not observed in 6 pts at level 1, which was determined as the RP2D. Centrally assessed PFS rate at 16 weeks (n = 21) was 42.9% (80% confidence interval: 27.8–59.0%). Median PFS and DCR by central assessment were 3.7 months and 64.0%, and by investigator assessment were 5.4 months and 72.0%, respectively (n = 25). Median OS was not reach. The median number of treatment cycles was 4 (range: 2−8). The median relative dose intensity of TAS-102 and BEV were 100% (range: 83.3–100%) and 100% (range: 75.0%-100%), respectively. In patients with KRAS exon 2 wild-type tumors (n = 10), median PFS and DCR by central assessment were 3.7 months and 70.0%, and by investigator assessment were 5.4 months and 80.0%, respectively. In patients with KRAS exon 2 mutant-type tumors (n = 15), median PFS and DCR by central assessment were 3.8 months and 60.0%, and by investigator assessment were 3.9 months and 66.7%, respectively. There was no significant difference in PFS or DCR between the KRAS exon 2 mutation status. The most common grade 3 or worse adverse events were neutropenia (68%), anemia (12%),