bluuebunny/crossref_metadata_2025 huggingface dataset:
TAS-102 versus placebo plus best supportive care in patients with metastatic colorectal cancer refractory to standard therapies: Final survival results of the phase III RECOURSE trial.
Authors: Mayer Robert J. , Ohtsu Atsushi , Yoshino Takayuki , Falcone Alfredo , Garcia-Carbonero Rocio , Tabernero Josep , Sobrero Alberto F. , Peeters Marc , Benedetti Fabio , Makris Lukas , Ambe Hiroshi , Zaniboni Alberto , Shimada Yasuhiro , Yamazaki Kentaro , Komatsu Yoshito , Hochster Howard S. , Lenz Heinz-Josef , Tran Ben , Van Cutsem Eric ,   on behalf of the RECOURSE Study Group
Published: February 2017

634

Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial. Original results of RECOURSE based on the cut-off date of January 24, 2014, in which 72% of mortality events had occurred, demonstrated a significant improvement in overall survival (OS) with TAS-102 vs placebo. Here we report results of an updated survival analysis from RECOURSE and a retrospective analysis of OS outcomes based on a clinical prognostic risk index. Methods: Patients were randomized 2:1 to receive TAS-102 or placebo. Study treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was OS; final survival data were collected on October 8, 2014. A clinical OS prognostic risk score was assessed to evaluate OS effect in patients from low to high prognostic score. Prognostic factors contributing to the risk index were from those prespecified in the multivariate modeling assessment of OS outcome. Results: At data cut-off for the final survival analysis, 89% of the 800 patients randomly assigned to TAS-102 or placebo had died, accounting for 138 events in addition to 574 (72%) events included in the original analysis. The updated results for OS are shown in the Table. Conclusions: An updated survival analysis confirmed that OS benefit with TAS-102 was maintained and increased to a full 2 months; improvement in 1-year survival surpassed 10% in these heavily pretreated patients. OS benefit appears to be maintained for all patients in the trial regardless of prognostic status at trial entry. Clinical trial information: NCT01607957. [Table: see text]
Efficacy and safety of first-line cetuximab + FOLFIRI in older and younger patients (pts) with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the CRYSTAL study.
Authors: Van Cutsem Eric , Köhne Claus-Henning , Folprecht Gunnar , Guenther Silke , Beier Frank , Papamichael Demetris
Published: February 2017

647

Background: Pts with mCRC are often older, thus prompting interest in subgroup analyses based on age. Adding cetuximab to FOLFIRI in the first-line CRYSTAL trial improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in pts with RAS wt mCRC. This subgroup analysis evaluated the efficacy and safety of FOLFIRI ± cetuximab within age-defined subgroups from the RASwt population of CRYSTAL. Methods: PFS, OS, ORR, and safety were evaluated in RAS wt pt subgroups in CRYSTAL, defined by age and treatment arm. Older pts were categorized as aged ≥65 y; younger pts were aged <65 y. Among pts ≥65 y, only 26 and 10 pts in the cetuximab + FOLFIRI arm and only 10 and 10 pts in the FOLFIRI arm were aged 70-75 y and ≥75 y, respectively; therefore, an analysis of an older-age cutoff was not performed. Results: Among 367 pts with RASwt tumors, 115 were older and 252 were younger. Baseline characteristics were similar between treatment arms in the younger subgroup; however, in the older subgroup, baseline ECOG status (ECOG=0; 45.9% vs 61.1%) and quality of life (>median; 36.1% vs 51.9%) favored the FOLFIRI arm. This study was not designed to assess differences within and between age subgroups; therefore, interpretation is limited by baseline imbalances and the small number of older pts. Efficacy and safety data are summarized below. Conclusions: In RAS wt CRYSTAL pts, adding cetuximab to FOLFIRI improved ORR, PFS and, to a lesser extent, OS in both older and younger pts. Clinical trial information: NCT00154102. [Table: see text]
Outcome of patients with KRAS exon 2 wildtype (KRAS-wt) metastatic colorectal carcinoma (mCRC) with cetuximab-based first-line treatment in the noninterventional study ERBITAG and impact of comorbidity and age.
Authors: Sahm Stephan , Goehler Thomas , Hering-Schubert Christiane , Janssen Jan , Neumann Ulf Peter , Schwittay Michael , Zahn Mark-Oliver , Stenzel Karsten Guenter , Steinbach-Buechert Alma Katharina , Overkamp Friedrich
Published: February 2017

651

Background: Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase ORR, PFS, OS of KRAS-wt mCRC patients (pts). ERBITAG aimed to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in pts with unresectable KRAS-wt mCRC. Methods: KRAS-wt pts on a cetuximab-based first-line treatment with written informed consent could be enrolled in this prospective, non-interventional study. Primary endpoint was ORR, secondary endpoints were amongst others PFS, OS, TTF, and resection rate of liver metastasis. Comorbidities were documented and evaluated by the Charlson Comorbidity Index (CCI). Results: 817 eligible KRAS-wt mCRC pts were enrolled at 144 sites across Germany, documentations for 456 pts were finalised and evaluated. The median age was 65 [27-87] yrs, with 51.5% ≤65 yrs, 34.0% >65-75 yrs, and 14.5% >75 yrs. ECOG performance status was 0, 1, 2, or missing in 34.4%, 49.6%, 8.8%, and 7.2% of pts, respectively. CCI was 0 in 54.4%, and ≥1 in 45.6%. Resection of liver and/or lung metastases was done in 17.3% of pts, 13.4% were R0 resected. For pts with liver limited disease resection rate and R0-rate were 29.3% and 23.8%, respectively. Pts with CCI 0 had no different outcome regardless of age (table). Pts with CCI ≥1 and >75 yrs had a lower ORR and decreased TTF, pts >65-75 yrs had only a decreased TTF as compared to the ≤ 65 yrs age group (table). Conclusions: In this large observational trial outcomes (ORR and PFS) of KRAS-wt mCRC pts on a cetuximab-based first-line treatment were comparable to those reported in pivotal trials. Pts older than 75 yrs without comorbidities (CCI =0) showed no difference to younger pts in ORR, PFS, and TTF. Pts >75 yrs with CCI ≥ 1 had a significant lower ORR and decreased TTF. Clinical trial information: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_455. [Table: see text]
X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).
Authors: Strickler John H. , Rangwala Fatima A. , Rushing Christel , Niedzwiecki Donna , Altomare Ivy , Uronis Hope Elizabeth , Hsu Shiaowen David , Zafar Yousuf , Morse Michael , Chang David Z. , Wells James Leroy , Blackwell Kimberly L. , Marcom P. Kelly , Webb Anna Renee , Dropkin Evan , Arrowood Christy , Hurwitz Herbert
Published: February 2017

687

Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.
Longitudinal follow-up of quality of life in gastrointestinal cancer patients after curative surgery in South Korea.
Authors: Zang Dae Young , Jung Hyun Ae , Han Boram , Kim Jung Hoon , Choi Dae Ro , Kim Hyeong Su , Jang Geundoo , Kwon Jung Hye , Kim Ho Young , Kim Jung Han , Jung Joo Young , Kim Hyo Jung , Yoon Hyunsook , Park Young Suk , Lee Hyun Woo , Kang Seok Yun , Cho Ji Woong , Song Hun Ho
Published: February 2017

697

Background: Early detection of cancer and improved treatment have led to higher survival rates and an increasing number of long-term survivors in oncology practice. But there are few longitudinal Quality of Life (QoL) studies in patients who experienced cancer surgery. To investigate the longitudinal change in QoL of elderly gastrointestinal cancer patients, we designed prospective study for QoL in resected gastrointestinal cancer patients. Methods: A prospective longitudinal cohort study was designed. Patients from Hallym, Ajou, and Samsung medical center in South Korea were enrolled consecutively from February to September of 2012. Patients over 55 years old who received curative resection due to gastrointestinal cancer were included. They were given questionnaires every 6 months since then, and we’ve been using EORTC QLQ C-30 as quality of life scale. We selected patients using propensity score matching(PSM). The mean scores of the patients completing the interview at the 3 time points were compared using mixed model. Results: A total of 353 patients with gastrointestinal cancer were interviewed at baseline. We dichotomized patients into 2 groups ( < 70 years old vs. > = 70 years old). There were significant difference in ECOG performance status between 2 groups. After balancing with PSM, we selected 272 patients. Overall QoL did not show significant difference between 2 groups at baseline interview. After repeated interview, the score of global health status, physical functioning, and pain showed significantly higher in younger group ( < 70 years old). But other items didn't show significant difference.Especially patients in both group felt financial difficulty increased. Conclusions: Although the elderly gastrointestinal cancer patients showed lower score in global health status, physical function, they preserved relatively well in other functional status after curative surgery. Most patients felt increased financial burden.
A multicenter phase II trial of mFOLFOX6 plus bevacizumab as treatment for liver-only metastases from colorectal cancer unsuitable for upfront resection (TRICC0808): Final analysis for survival.
Authors: Tamagawa Hiroshi , Uetake Hiroyuki , Ishiguro Megumi , Mizunuma Nobuyuki , Kinugasa Yusuke , Mochizuki Izumi , Hamaguchi Tetsuya , Hasegawa Junichi , Katsumata Kenji , Ishibashi Keiichiro , Ogata Yutaka , Takii Yasumasa , Ooshiro Mitsuru , Kagimura Tatsuo , Sugihara Kenichi ,   TRICC0808 Study Group
Published: February 2017

704

Background: TRICC0808 trial is a phase II trial to evaluate the liver resection rate and safety after mFOLFOX6 + bevacizumab therapy for liver-only metastasis that is unsuitable for upfront resection (H2 and H3) from colorectal cancer. Primary endpoint was the R0 resection rate, which was reported to be 44.4% (Ann Surg Oncol 22: 908-915, 2015). Final analysis of TRICC0808 was performed (February 16, 2015 data fixation). Methods: Forty six patients were registered and OS was analyzed for 45 patients (FAS). In 24 cases with liver resection after protocol chemotherapy, RFS, recurrence rate and recurrence patterns were analyzed. Results: The1, 2 and 3 year OS rate in FAS from the starting date of the chemotherapy was 91.1%, 68.9%, 44.0%, respectively, with 2.80 years of MST. The 3 year OS rate in 31 patients with liver resection including resection after additional chemotherapy was 61.3% with 3.59 years of MST, which was better than 0% of the 3 year OS rate with 1.75 years of MST in patients without liver resection. In 24 who underwent liver resection after 6 cycles of protocol chemotherapy, the 1, 2 and 3 year RFS rate was 29.2%, 12.5%, 8.3%, respectively, with 3.07 years of MST. The recurrence rate for 20 patients with R0 liver resection was 80%, and 100% in those with R1 and R2 liver resection. In the 20 patients with R0 liver resection, the 3 year OS rate of 16 patients with technically resectable liver metastasis at registration and 4 with technically unresectable tumors was 53.6% and 50.0%, respectively. Conclusions: The present final analysis of TRICC0808 trial disclosed good OS in the patients with liver resection, though the large population of the patients recurred afterward. The results were concordant with those of other reported trials for liver metastasis which is unsuitable for upfront resection. Liver resection was thought to be effective for liver metastasis which converted from unresectable to resectable after chemotherapy. Clinical trial information: UMIN000010209.
Systemic therapy in anorectal melanomas: Does choice of systemic therapy matter?
Authors: Singhal Nitin Kumar , Ostwal Vikas S. , Shrikhande Shailesh V. , Saklani Avanish , Arya Supreeta , Ramadvar Mukta
Published: February 2017

731

Background: Anorectal melanomas are relatively uncommon and there is no consensus on the optimal systemic therapy regime with survival advantage. Methods: Retrospective analysis of prospectively maintained database of patients treated at our institute between January 2102 and July 2015. SPSS 20 used for statistical analysis. The survival benefit was assessed in the form of progression free survival (PFS) and overall survival (OS) with the systemic therapy. Results: Out of 74 anorectal melanoma patients seen during this period 50 patients had metastatic disease and were evaluated for outcome analysis. Median follow up of patients was 8 months. Of these 50 patients, 36 received chemotherapeutic regimes (taxanes with platinums with or without oral metronomic therapy (OMT), dacarbazine/temozolamide or OMT alone) as per the description of treating physician, while 11 patients did not receive any systemic therapy due to poor general condition at presentation, or refused therapy. 3 patients defaulted during the initial work up. Median age at presentation was 54 years and common sites of metastasis were Liver, lung and lymph nodes. Median OS for patients who underwent excision was 22 months. In patients who received systemic therapy median OS was 13 months versus 8 months for those who did not receive it (p = 0.253). The Median PFS after 1st line systemic therapy was 3 months. 5 patients had grade III toxicities in the form of neutropenia, diarrhea. PFS was 3 months for temozolamide/dacarbazine, OMT along with chemotherapy or OMT alone whereas it was 5 months for taxanes with platinum. (p = 0.045). OS was 11 months for OMT with or without chemotherapy and 18 months for taxanes with platinum (p = 0.43). Conclusions: Palliative systemic therapy has some survival advantage in metastatic anorectal Melanomas. Taxanes with platinums appear to be the most efficacious among the presently used regimens even in anorectal melanomas. OMT also has the survival benefit with the advantage of oral therapy in palliative setting
Regorafenib for previously treated metastatic colorectal cancer (mCRC): A subgroup analysis of 364 patients in the USA treated in the international, open-label phase IIIb CONSIGN study.
Authors: Verma Udit , Arriaga Yull Edwin , Lenz Heinz-Josef , Henderson Charles A. , Fuloria Jyotsna , Cartwright Thomas H. , Khojasteh Ali , Stella Philip J. , Saltzman Marc , Cohn Allen Lee , Philip Philip Agop , Kappeler Christian , Kalmus Joachim , Grothey Axel , Van Cutsem Eric , Hochster Howard S. , Arena Francis P.
Published: February 2017

735

Background: In the phase III CORRECT study, regorafenib significantly improved overall survival and progression-free survival (PFS) vs placebo in patients with treatment-refractory mCRC. CONSIGN (NCT01538680) was a large phase IIIb study that included 2872 patients from 25 countries; it was designed to provide continued access to regorafenib for patients with mCRC who failed standard therapy and to further characterize the safety of regorafenib. In CONSIGN, adverse events (AEs) and PFS were consistent with those reported in phase III studies. We present a retrospective subgroup analysis of patients enrolled in CONSIGN in the USA. Methods: Patients with mCRC who progressed on standard therapies and had an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety. PFS (per investigator) was the only efficacy variable assessed. Results: A total of 364 patients in the USA were assigned to treatment (all evaluable for safety). The median age was 60 years; 38% and 62% had ECOG PS 0 and 1, respectively. KRAS mutation was present in 59%, KRAS wt in 38%; 74% had ≥ 3 prior regimens for metastatic disease. Median duration of treatment was 2.3 months (range: 0–30). Median PFS (95% CI) was 2.3 (2.0–2.6) months (2.1 months KRAS wt; 2.3 months KRAS mutant). NCI-CTCAE v4.0 grade ≥ 3 AEs occurred in 81% of patients and were considered drug-related in 53% (Table). Grade ≥ 3 hepatobiliary disorders occurred in 2%. Grade ≥ 3 treatment-emergent laboratory toxicities included bilirubin (9%), AST (6%), and ALT (3%). Conclusions: In patients from the USA enrolled in CONSIGN, the safety profile of regorafenib was consistent with that of the overall population and the known safety profile of regorafenib in mCRC. Median PFS was in the range of that reported in phase III trials. Clinical trial information: NCT01538680. [Table: see text]
Phase II study of irinotecan and bevacizumab plus alternate day S-1 as second-line treatment in patients with metastatic colorectal cancer.
Authors: Tanaka Chihiro , Matsuda Chu , Kondo Ken , Tokunaga Yukihiko , Takahashi Takao , Kosugi Chihiro , Takemoto Hiroyoshi , Iwamoto Shigeyoshi , Oba Koji , Sakamoto Junichi , Mishima Hideyuki
Published: February 2017

749

Background: The recommended dose of combination chemotherapy of irinotecan, bevacizumab and oral S-1 is 100mg/m2, 5mg/kg and 80-120mg/body respectively. To evaluate whether the dose of irinotecan could be raised to 150mg/m2 with modified administration of S-1, we have conducted a phase II study of irinotecan and bevacizumab plus alternate day S-1 in patients with metastatic colorectal cancer (UMIN000008947). Methods: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatine and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1was administered on alternate days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. Results: A total of 51 patients were evaluated in the first fouur cycles. Grade 3 and 4 neutropenia were 10% (10/51) and 13.7%(7/10), grade 3 and 4 thrombocytopenia were 0%(0/51) and 2.0% (1/51). Grade 2 and 3 mucositis were 13.7% (7/51) and 3.9% (2/51). Grade 2 and 3 nausea were 11.8% (6/51) and 2.0% (1/51). Grade 2 and 3 diarrhea were 17.6% (9/51) and 15.7% (8/51). The relative dose intensities were 84.8% for irinotecan, 87.5% for bevacizumab, and 84.8% for S-1 respectively in the first four cycles. Conclusions: Our data suggest that irinotecan (150 mg/m2) and bevacizumab was administered safely with alternate day S-1 as second-line tratment in patients with metastatic colorectal cancer. Clinical trial information: 000008947.
Outcomes after resection of pulmonary metastases in patients with colorectal cancer.
Authors: Mi Kaihong , McNamara Michael J. , Jia Xuefei , Sawalha Yazeed , Glass Katherine , Khorana Alok A.
Published: February 2017

757

Background: Surgical resection of liver metastases provides a significant survival benefit, and potential for cure, in selected patients with metastatic colorectal cancer. There are very limited data on resection of lung metastases in patients with colorectal lung metastases. We evaluated outcomes after resection of lung metastases in patients with colorectal cancer. Methods: We conducted a retrospective cohort study in patients who underwent resection of pulmonary metastases between 2/2006 and 6/2013 at Cleveland Clinic. Clinical, pathologic, and outcome data were collected by electronic medical records review. Overall survival (OS) as the primary endpoint was summarized by Kaplan-Meier method and analyzed by log-rank tests. Results: The study population comprised 32 patients. Overall, 20 patients were male and median age at diagnosis of lung metastasis was 60.0 years (range 30.4-81.9). All patients had resection of primary tumor. Eleven patients had preoperative chemotherapy and 12 had adjuvant chemotherapy. Patients with unilateral metastases comprised the majority of patients (N = 22, 68.8%); 59% (N = 19) had a solitary metastasis. The median diameter of lung metastases was 20.5 mm (range 7.0 -50.0). Ten patients had concurrent liver metastases, eight of whom had liver resection as well. Overall, 31% (10/32) of patients recurred, with 50% (16/32) of recurrences in the lung, and 28% died. Estimated median OS was 55.0 months. Estimated 5-year OS was 32% ± 17%. Higher CEA level ( ≥ 4.5 ng/mL) at the time of diagnosis of lung metastasis was associated with worsened OS (p = 0.026). Other potential prognostic factors, such as laterality, number of lung metastases, and extrapulmonary lesions, were not associated with overall survival in this study population. Conclusions: Our study showed resection of lung metastases in select patients with colorectal cancer can be associated with prolonged survival in the range seen with resection of liver metastases. Higher CEA level at time of diagnosis of lung metastasis is associated with poorer prognosis. More data are necessary to identify approaches to patient selection in the metastatic colorectal setting.
The cancer vaccine therapy using DCs derived from iPS cells (iPSDCs) expressing TAA gene.
Authors: Iwamoto Hiromitsu , Ojima Toshiyasu , Kitadani Junya , Tabata Hiroaki , Hayata Keiji , Katsuda Masahiro , Miyazawa Motoki , Nakamura Masaki , Nakamori Mikihito , Yamaue Hiroki
Published: February 2017

768

Background: Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that play a critical role in the initiation of anti-tumor immune responses. Many cancer patients have previously been treated by the cancer vaccine therapy using DCs worldwide. We have employed a study of a cancer vaccine therapy using genetically modified DCs expressing tumor-associated antigen (TAA) gene. Clinically DCs are generated from the peripheral blood monocytes of patients. Thus the number of monocytes and potential of them are limited, so they are serious obstacle. Recent studies have revealed that induced pluripotent stem (iPS) cells can be generated from murine fibroblasts. Furthermore, it has been reported that DCs can be successfully derived from murine iPS cells (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of naive DCs, then the above-mentioned problems may be solved. Methods: We have induced iPSDCs from murine iPS cells by 4 steps and examined the efficacy as APCs of iPSDCs compared with naive DCs. We also examined whether a vaccine therapy using genetically modified iPSDCs can induce strong therapeutic antitumor immunity compared with naive DCs. Next, we examined the therapeutic antitumor immunity of iPSDCs expressing CEA gene compared with that of naive DCs in pre-clinical study with CEA transgenic mice. Results: We have clarified that genetically modified iPSDCs have an equal efficacy as APCs and TAA-specific therapeutic antitumor immunity, equivalent to naive DCs. And we also have clarified that genetically modified iPSDCs expressing CEA gene have a TAA-specific therapeutic antitumor immunity. Conclusions: This vaccine strategy using genetically modified iPSDCs has an equal capacity with naive DCs in terms of a therapeutic efficacy. Now, we are engaging another pre-clinical study with human, in an effort to apply in a clinical setting.
Adjuvant chemotherapy with or without concurrent radiotherapy in stage IB patients with gastric cancer: Subgroup analysis of the adjuvant chemoradiotherapy in stomach tumors (ARTIST) phase III trial.
Authors: Song Haa-na , Cho Jinhyun , Jung Ki Sun , Lee Su Jin , Kim Seung Tae , Lee Jeeyun , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: February 2017

95

Background: To evaluate the risk of recurrence in patients with pathologically staged Ib, according to the American Joint Committee on Cancer (AJCC) 2002 staging system, gastric cancer (GC) in the phase III adjuvant chemoradiotherapy in stomach tumors (ARTIST) trial. Methods: Among 458 GC patients enrolled in ARTIST, 99 had stage Ib (T2N0 or T1N1) disease. Patients were randomly assigned to receive adjuvant chemoradiotherapy with capecitabine plus cisplatin (XP, n = 50)) or chemoradiotherapy (XPRT, n = 49). Kaplan-Meier method was used to calculate disease-free survival (DFS). Cox proportional hazard models were employed to determine associations between the addition of radiotherapy to XP and DFS after adjustment for patient and disease characteristics. Additionally, analyses were performed according to the AJCC 2010 staging system. Results: With 7 years of follow-up, there were 18 recurrences. The 5-year DFS rates were 88% and 84% in XP and XPRT patients, respectively (P = 0.537). When we reviewed the pathologic stages of the patients according to the AJCC 2010 system, stage migration from Ib to II occurred in 71% of the patients: 98% of the T2N0 patients were reclassified as T3N0, and 42% of the T1N1 patients were reclassified as T1N2. The patients classified as stage Ib according to the AJCC 2002 system and reclassified as stage II exhibited worse, although statistically insignificant, prognosis than the patients who remained in stage Ib (5-year DFS 83% vs. 93%, P = 0.183, HR 1.178, 95% CI 0.420-3.311, P = 0.158). When we compared 5-year DFS in 70 stage II (AJCC 2010 system) patients, the addition of radiotherapy to XP chemotherapy resulted, although again statistically insignificant (P = 0.234), in worse outcome in XPRT arm (77%) than in XPRT arm (88%). Conclusions: This subgroup analysis confirms the clinical relevance of the AJCC 2010 staging system in GC. The role of adjuvant chemotherapy in stage II GC warrants further investigation.
A phase II trial to assess the activity and safety of the hypoxia-activated prodrug evofosfamide (TH-302) in combination with sunitinib in patients with disseminated grade 1 and 2 pancreatic neuroendocrine tumors (pNET) as a first-line approach: The GETNE-1408 trial.
Authors: Grande Enrique , Castellano Daniel E. , Custodio Ana B. , Garcia-Carbonero Rocio , González Encarnación , López-López Carlos , Munarriz Javier , Sevilla Isabel , Teule Alexandre , Benavent Viñuales Marta , Alonso Teresa , Gajate Borau Pablo , Palacios José , Capdevila Jaume
Published: February 2017

TPS479

Background: Pancreatic-NETs are highly vascular tumors. The anti-angiogenetic sunitinib was approved in advanced pNETs based on prolongation of progression-free survival. Upregulation of several proangiogenic factors that reflects intratumor hypoxia conditions might drive resistance to sunitinib in pNETs. Evofosfamide is a prodrug that under hypoxic conditions preferentially releases a brominated version of isophosphoramide mustard and has shown activity in cell lines from neural crest derived tumors such as melanoma and glioblastoma/astrocytoma. We hypothesize that evofosfamide may have activity in the pathologic hypoxic conditions present in the tumor environment of neuroendocrine tumors inducing responses that may be consolidated and prolonged with sunitinib in patients with advanced pNETs that are naïve for systemic treatment. Methods: This is a prospective, non randomized, open-label, phase II study that is being conducted in 10 university sites belonging to the Spanish Task Force Group for NETs (GETNE) in Spain. Patients with histologically proven diagnosis of progressive unresectable or metastatic pNET with Ki67 < 20% and grade 1 or 2 will receive sunitinib orally at 37.5 mg PO daily on days 1 to 28 of a 28-day cycle (4 weeks) plus evofosfamide administered at 340 mg/m2 by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a 28-day cycle (4 weeks). Hypoxia-related tumor markers, single nucleotide polymorphisms related to activity and metabolism of antiangiogenic agents (VEGFR2, VEGFR3, PDGFR-α, VEGF-A, IL8, CYP3A4, CYP3A5, ABCB1-2) will be correlated with clinical outcome. In this study it is planned to include 43 patientsbased on a two-stage Simon’s phase II design (α = 0.05, β = 80%). If the trial shows 8 responses or more among 43 patients, the treatment will be considered for further investigation. EudraCT number: 2014-004072-30 Clinical trial information: NCT02402062.
PARADIGM study: A multicenter, randomized, phase III study of 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.
Authors: Yoshino Takayuki , Uetake Hiroyuki , Tsuchihara Katsuya , Shitara Kohei , Yamazaki Kentaro , Oki Eiji , Sato Takeo , Naitoh Takeshi , Komatsu Yoshito , Kato Takeshi , Iwasaki Kouji , Soeda Junpei , Hihara Masamitsu , Yamanaka Takeharu , Ochiai Atsushi , Muro Kei
Published: February 2017

TPS776

Background: Optimal combination of monoclonal antibody (anti-VEGF vs. anti-EGFR antibody) with standard chemotherapy as first-line treatment in patients (pts) with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. FIRE-3 study demonstrated a significant improvement in overall survival (OS) with anti-EGFR over bevacizumab in pts with KRAS exon 2 wild type mCRC, while CALGB 80405 study did not. PARADIGM study is designed to compare panitumumab vs. bevacizumab combined with mFOLFOX6 in pts with RAS wild-type chemotherapy-naive mCRC. Methods: Eligible pts are aged 20-79 years with ECOG performance status (PS) 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. 800 pts will be randomly assigned in a 1:1 ratio to mFOLFOX6 plus panitumumab or bevacizumab, and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil (5-FU) iv 400 mg/m2 at day 1, 5-FU civ 2400 mg/m2 at day 1-3, and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg at day 1 every two weeks. The primary endpoint is the OS; the study was designed to detect the OS hazard ratio of 0.76, with a one-sided type I error of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. One interim analysis is planned for the OS when approximately 70% of the targeted 570 events has been observed. Exploratory endpoint is to investigate possible biomarkers including oncogenic mutations using tumor tissue and circulating tumor DNA (Study ID: NCT02394834). As of August 2015, 21 pts have been randomized and recruitment is ongoing. Clinical trial information: NCT02394795.
RX-5902: A phosphorylated p68 targeting agent to treat subjects with advanced solid tumors.
Authors: Gutierrez Martin , Eckhardt S. Gail , Gluck W Larry , Benaim Ely
Published: February 2017

TPS778

Background: Phosphorylated p68 may play a vital role in cell proliferation and tumor/cancer progression. RX-5902 is a novel compound that targets phosphorylated p68 RNA helicase (also known as DDX5), a member of the DEAD box family of RNA helicases. As a single agent, RX-5902 inhibits tumor growth and enhances survival in a variety of xenograft tumor models (e.g., pancreatic, renal, ovarian, melanoma). Methods: This Phase 1, open-label, multicenter study evaluates the efficacy and safety of RX-5902 in subjects with solid tumors. RX-5902 is administered orally 1, 3 or 5 times per week for 3 weeks with 1 week of rest in each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single Grade 2 or greater adverse event that is considered at related to RX-5902. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms as well as the description of any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to discontinuation of study treatment. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [Tmax], maximum observed plasma concentration [Cmax], trough concentration [Ctrough], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate, time to response, duration of response, and progression-free survival during treatment. Exploratory endpoints are biochemical levels of drug targets in blood and tumor samples. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. There is no limit on the number of prior treatment regimens. Clinical trial information: NCT02003092.
Neo-adjuvant chemotherapy followed by surgery versus surgery alone in high-risk patients with resectable colorectal liver metastases: The CHARISMA randomized multicenter clinical trial.
Authors: van der Stok Eric P , Verhoef Cornelis , Grunhagen Dirk J. ,   CHARISMA Study Group
Published: February 2017

TPS790

Background: Colorectal carcinoma is a leading cause of cancer death worldwide, mostly as a consequence of metastatic disease. If metastases are confined to the liver, surgical resection is the only therapy providing potential for cure. Efforts to improve the outcome of hepatectomy for colorectal liver metastases (CRLM) by combining surgery with chemotherapy have failed to demonstrate overall survival (OS) benefit. This may partly be explained by the fact that previous trials on this subject involved strict inclusion criteria. Consequently, patients with a high oncological risk profile - who might benefit the most from chemotherapy – might have been underrepresented in previous trials. Several Clinical Risk Scores (CRS) have been developed predicting patients’ prognosis after resection of CRLM. The most widely used and validated CRS was described by Fong et al., which characterizes 2 risk groups (high versus low) based on 5 independent clinicopathologic prognostic variables. Each variable is assigned 1 point. Multiple retrospective observations showed that neo-/adjuvant chemotherapy induced significant OS benefit in patients with a high-risk profile (CRS of 3 to 5 points). The CHARISMA trial evaluates the impact of neo-adjuvant chemotherapy in patients with high-risk, primarily resectable liver-only colorectal metastases. We hypothesize that adding neo-adjuvant chemotherapy to surgery improves OS in this high-risk patient group. Methods: The CHARISMA trial is a randomized (1:1) phase III trial. Patients receive either surgery only for CRLM (arm A) or 6 cycles of neo-adjuvant Oxaliplatin + Capecitabine, followed by surgery (arm B). The primary endpoint is OS. On basis of retrospective data, the expected hazard ratio for arm B is 0.60. With an expected 5-year OS of 25% in arm A, a two-sided significance level α = 0.05 and power 1 - β = 0.8, 224 patients have to be recruited. Major eligibility criteria are: liver-only metastases, primarily resectable CRLM, high-risk patients (CRS 3-5). The trial is currently accruing in 10 Dutch liver centers and is registered in the “Dutch Trial Register”: NTR4893 ( www.trialregister.nl ). Clinical trial information: NTR4893.
Effect on clinical trial participation by integration of a clinical pathway program into an electronic health record (EHR).
Authors: Shamah Corey J. , Saphner Thomas James
Published: February 2017

167

Background: Patient enrollment to clinical trials is lower than desired. Even large organizations with extensive research support services have many barriers to recruitment and poor rates of enrollment. Barriers to clinical trial participation can be physician related, system related, or patient related. Physician related issues are the largest barrier to patient accrual. Physicians are often not aware that a trial may be available for a patient. While all initial patients are manually screened in our system, screening for subsequent lines of therapy are not. Provider awareness and appropriate patient identification are areas of potential improvement in a large, multisite, hospital affiliated, community oncology setting. Methods: Our oncology group recently implemented Via Oncology (Via), an EHR-integrated clinical pathway decision support tool. Information about the patient, their disease, and goals of care generate a recommended treatment algorithm. The pathways are expected to speed the integration of new treatments into practice and improve accrual to clinical trials. Use of Via is required for all new therapy changes. Within the decision algorithm, an appropriate available clinical trial is suggested as the first option when available. Clinical trial enrollment statistics are being tracked to determine if this method of potential patient identification results in increased enrollments. Results: After 11 months of Via implementation and 103,515 visits, the visit capture rate was 82.7% suggesting that providers adapted to the pathways quickly. With 3,844 decisions made, 83.9% of all treatment decisions were on pathway. Clinical trial enrollment was 122 patients in the 459 days prior to Via implementation, and 102 patients in the 271 days afterwards. This increase in accrual rate was significant (p = 0.00174.) Conclusions: Early results suggest that Via implementation has resulted in a significant increase in clinical trial accrual. The system will eventually be able to track how often a trial is offered and how often it is accepted. We are hopeful that with complete visit capture of all patients, there will be continued improvement in our rate of clinical trial enrollment.
Breast cancer specific mortality in patients with early-stage hormone receptor–positive invasive breast cancer and oncotype DX recurrence score results in the SEER database.
Authors: Shak Steven , Petkov Valentina , Miller Dave P , Howlader Nadia , Gliner Nathan , Howe Will , Schussler Nicola C. , Cronin Kathleen , Baehner Frederick L. , Penberthy Lynne
Published: February 2017

176

Background: NCI’s SEER Program provides cancer incidence and survival statistics for ~28% of the US. New research models are needed to characterize the use and impact of genomic tests on patient outcomes. Genomic Health and SEER collaborated to electronically supplement SEER registries with Recurrence Score (RS) results, and have evaluated breast cancer specific mortality (BCSM) in early stage hormone receptor (HR)+ HER2- invasive breast cancer. Methods: Pts were eligible for pre-specified node negative (N-) disease analysis if HR+, HER2- (by RT-PCR), no prior malignancy, 40-85 years of age, and diagnosed between Jan 2004 (Oncotype DX available Jan 2004) and Dec 2011 (SEER survival analysis complete through 2012). BCSM was defined as previously described (Howlader et al, JNCI 2010). Additional analyses of BCSM were performed for pts with N+ disease. Results: Of 169,158 eligible N- pts, 38,568 (23%) had a RS, increasing from 2% in 2004 to 35% in 2011. Pts with RS had median age of 57yr, were 99.4% female, 84% white, 29% grade 1 & 54% grade 2, 25% < 1cm & 53% 1-2cm. Median FU was 39mo. 8,239 pts had > 5yrs follow-up. Among RS < 18 (N = 21,023), RS 18-30 (N = 14,494) and RS ≥ 31 (N = 3,051) pts, chemotherapy use was reported in 7%, 34%, & 69%, respectively, and 5yr N- BCSM was 0.4% (95% CI, 0.3-0.6), 1.4% (95% CI, 1.1-1.7) and 4.4% (95% CI,3.4-5.6), respectively. Multivariate showed that RS was significantly associated with BCSM after adjusting for age, grade, and tumor size (p < 0.001), and when stratified by treatment (p < 0.001). BCSM results in additional N- subgroups (e.g., socioeconomic), and in > 60,000 N+ pts will be presented. Conclusions: 5yr survival outcomes are excellent in the over 21,000 N- pts with RS < 18 disease. RS ≥ 31 disease is associated with greater 5yr mortality despite addition of chemotherapy. The large sample size of this population-based observational study provides important information on prospective outcomes in subsets of pts that are often underrepresented in randomized clinical trials.
Cost-effectiveness of brentuximab vedotin in relapsed or refractory systemic anaplastic large cell lymphoma.
Authors: Hux Margaret , Zou Denise , Ma Esprit , Sajosi Peter , Engstrom Andreas , Selby Ross , Benson Eugene , Teasell Jeremy , Richhariya Akshara , Briggs Andrew , Bonthapally Vijayveer
Published: February 2017

18

Background: Systemic anaplastic large cell lymphoma (sALCL) is a rare T-cell lymphoma. For patients who fail front-line therapy, outcomes are poor and there is no current defined standard of care. Brentuximab vedotin has demonstrated high objective response rates and is approved for patients with relapsed or refractory (R/R) sALCL. However, the cost-effectiveness of brentuximab vedotin compared with conventional chemotherapy has not been explored. Methods: A lifetime Excel-based partitioned survival model was used to compare survival outcomes from the pivotal phase-2 single-arm brentuximab vedotin trial of 58 R/R sALCL patients with good Eastern Corporative Oncology Group (ECOG) performance status after one or more prior therapies (SG035-0004); with 40 sALCL patients from a Canadian cancer registry receiving first-line conventional salvage chemotherapy (65% with ECOG 0 or 1) between 1980 and 2012 and followed for up to 20 years. Extrapolation of brentuximab vedotin survival after the trial period assumed the same rate of change as for conventional chemotherapy. A United Kingdom National Health Service perspective was adopted. Costs included drug acquisition and administration, and medical care for adverse events and pre- and post-progression. Utility values elicited by response and by progression, and disutilities associated with adverse events were applied to estimate quality-adjusted life years (QALYs). Results: The incremental cost-effectiveness ratio (ICER) for brentuximab vedotin was £35,390 per QALY gained versus conventional chemotherapy. ICERs were between £28,112 and £61,921 across a range of alternative model assumptions. Comparing only first-line salvage patients in both groups reduced the ICER to £26,766. Conversely, considering only patients with good ECOG performance status increased the ICER to £38,186. Using probabilistic sensitivity analysis, at willingness-to-pay of £38,000, the probability that brentuximab vedotin is cost-effective was > 50%. Conclusions: Brentuximab vedotin may represent a cost-effective intervention compared to conventional chemotherapy for this patient population with limited therapeutic options.
Improving anti-emetics in chemotherapy induced nausea and vomiting.
Authors: Toutounji Sandra , Fung Ron , Enright Katherine
Published: February 2017

220

Background: Chemotherapy induced nausea and vomiting (CINV) remains one of the most feared treatment-related toxicities in cancer patients. CINV has been shown to decrease quality of life and to increase dose modifications and unplanned hospital visits. Cancer Care Ontario (CCO) and the American Society of Clinical Oncology (ASCO) updated their CINV guidelines in 2013. These changes included a reclassification of many regimens from moderate (MEC) to highly emetogenic (HEC) and a decrease in the duration of serotonin inhibitors (5HT3i). Uptake of the new guidelines at Trillium Health Partners has been slow. We aimed to improve CINV by increasing the percentage of patients who received guideline concordant anti-emetics with their first cycle of HEC/MEC chemotherapy. Methods: The first 25 patients started on MEC/HEC chemotherapy during 3 time periods (pre-guidelines, 6 months post guidelines, 1.5 years post guidelines) were identified. The primary measure of interest was the percentage of patients receiving MEC/HEC who were treated in concordance with the updated CINV guidelines. Secondary measures included the percentage of MEC/HEC patients who experienced grade 2+ CINV. The collected data was used with quality improvement techniques to guide the development of interventions to improve guideline concordance. Results: The concordance of anti-emetics on the day of chemotherapy improved over time, but post-chemotherapy concordance remained at 0% (table). The primary driver for concordance was the use of NK1inhibitors on chemotherapy day, and the duration of 5HT3i post-chemotherapy. Using quality improvement methodology, the highest impact intervention was identified as changing the default settings in the computerized order entry system (CPOE) to reflect the updated guidelines. These changes are currently in progress and a test of this change will be presented. Conclusions: Concordance with CINV guidelines improved over time resulting in lower CINV and less need for reactive CINV interventions. Further work to target duration of 5HT3i is ongoing. [Table: see text]