Search

Hiroki Osumi, Daisuke Takahari, Keisho Chin, Mariko Ogura, Takashi Ichimura, Takeru Wakatsuki, Takeshi Suzuki, Yumiko Ota, Izuma Nakayama, Akira Ooki, Mitsukuni Suenaga, Eiji Shinozaki, Kensei Yamaguchi Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: Oral fluoropyrimidine plus platinum is a standard first-line treatment for advanced gastric cancer (AGC). However, this treatment is problematic for AGC patients with massive ascites or inadequate oral intake. This study aimed at evaluating the efficacy and safety of modified oxaliplatin (L-OHP) with l-leucovorin (l-LV) and bolus/continuous infusion of 5-fluorouracil (5-FU) (mFOLFOX6) regimen for patients with massive ascites or inadequate oral intake.Methods: This retrospective study was conducted at a single Japanese institute from November 2015 to May 2018. The mFOLFOX6 regimen consisted of 85mg/m2 L-OHP, 400mg/m2 bolus of 5-FU, and 400mg/m2 1-LV on the first day, followed by 2,400mg/m2 of 5-FU as a continuous infusion in 46 hours for first-line treatment. The definition of inadequate oral intake was the need for total parenteral nutrition (TPN). Massive ascites was defined as continuous ascites from the pelvic cavity to the upper abdomen. Improvement in oral intake was defined as no TPN for more than 7 days, and improvement in ascites was defined as a decrease in ascites of more than one grade defined by the Japan Clinical Oncology Study Group trial (JCOG0106).Results: Among the 364 patients with AGC who received first-line chemotherapy, 17 patients (13 [76.5%] had inadequate oral intake, and four [23.5%] had massive ascites) were enrolled in this study. Median time to treatment failure and overall survival were 4.8 (95% CI=1.5–7.5) and 8.8 months (95% CI=2.3–not available), respectively. Objective improvements in oral intake and ascites were seen in 11 of 13 patients (84.6%) and 6 of 12 patients (50%), respectively. The major grade 3 or 4 adverse events were neutropenia (35.3%), febrile neutropenia (5.9%), fatigue (5.9%), anorexia (5.9%), and infection (5.9%). No treatment-related deaths occurred.Conclusion: We found that mFOLFOX6 can be a novel treatment option as the first-line treatment for AGC patients with massive ascites or inadequate oral intake. Keywords: advanced gastric cancer, FOLFOX, massive ascites, inadequate oral intake&nbsp

Yasuyoshi Sato, Satoshi Matsusaka, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan Background: Cetuximab and bevacizumab reportedly improve the survival of patients with metastatic colorectal cancer (mCRC), but their most effective sequence of administration is unknown. The aim of this study was to compare the survival of patients with mCRC treated with cetuximab after bevacizumab failure with that of patients with mCRC without previous bevacizumab therapy. Patients and methods: In total, 190 of 323 patients with mCRC treated with cetuximab from March 2006 to July 2013 were enrolled in our hospital for this retrospective study. Forty-seven patients were treated with cetuximab-based second-line therapy, 21 of whom had received prior bevacizumab; 143 patients were treated with cetuximab-based third-line therapy, 109 of whom had received prior bevacizumab. The Kaplan–Meier method with a log-rank test and Cox regression analysis were performed to evaluate the overall survival and progression-free survival (PFS) of each group of patients. Results: The median follow-up time was 11.8months in patients who received second-line cetuximab-based chemotherapy and 13.7months in those who received third-line cetuximab-based chemotherapy. Univariate analysis revealed that the median PFS was significantly longer in patients without prior bevacizumab therapy than in patients with prior bevacizumab therapy (second line, P=0.048; third line, P=0.0022). Multivariate analysis adjusted for baseline characteristics showed that third-line cetuximab-based chemotherapy with or without prior bevacizumab was significantly associated with PFS (P=0.014). Neither the presence nor the absence of prior bevacizumab administration was associated with overall survival. Conclusion: Cetuximab could be more effective without prior bevacizumab. Prior bevacizumab use may decrease the efficacy of cetuximab. Keywords: cetuximab, bevacizumab, EGFR, VEGF, metastatic colorectal cancer&nbsp

Mitsukuni Suenaga,1 Yoshiya Fujimoto,2 Satoshi Matsusaka,1 Eiji Shinozaki,1 Takashi Akiyoshi,2 Satoshi Nagayama,2 Yosuke Fukunaga,2 Masatoshi Oya,2 Masashi Ueno,2 Nobuyuki Mizunuma,1 Toshiharu Yamaguchi21Department of Gastroenterology, 2Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JapanBackground: Perioperative chemotherapy combined with surgery for liver metastases is considered an active strategy in metastatic colorectal cancer (CRC). However, its impact on initially unresectable, previously untreated advanced CRC, regardless of concurrent metastases, remains to be clarified.Methods: A Phase II study was conducted to evaluate the safety and efficacy of perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced CRC. Patients with previously untreated advanced colon or rectal cancer initially diagnosed as unresectable advanced CRC (TNM stage IIIb, IIIc, or IV) but potentially resectable after neoadjuvant chemotherapy (NAC) were studied. Preoperatively, patients received six cycles of NAC (five cycles of neoadjuvant FOLFOX4 plus bevacizumab followed by one cycle of FOLFOX4 alone). The interval between the last dose of bevacizumab and surgery was at least 5 weeks. Six cycles of adjuvant FOLFOX4 plus bevacizumab were given after surgery. The completion rate of NAC and feasibility of curative surgery were the primary endpoints.Results: An interim analysis was performed at the end of NAC in the 12th patient to assess the completion rate of NAC. The median follow-up time was 56 months. The characteristics of the patients were as follows: sex, eight males and four females; tumor location, sigmoid colon in three, ascending colon in one, and rectum (above the peritoneal reflection) in eight; stage, III in eight and IV in four (liver or lymph nodes). All patients completed six cycles of NAC. There were no treatment-related severe adverse events or deaths. An objective response to NAC was achieved in nine patients (75%), and no disease progression was observed. Eleven patients underwent curative tumor resection, including metastatic lesions. In December 2012, this Phase II study was terminated because of slow registration.Conclusion: Perioperative FOLFOX4 plus bevacizumab is well tolerated and has a promising response rate leading to curative surgery, which offers a survival benefit in initially unresectable advanced CRC with concurrent metastatic lesions.Keywords: bevacizumab, metastatic colorectal cancer, FOLFOX4, perioperative treatment

Yoshihito Ohhara,1,2 Mitsukuni Suenaga,1 Satoshi Matsusaka,1 Eiji Shinozaki,1 Nobuyuki Mizunuma,1 Toshiharu Yamaguchi3 1Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan; 2Department of Medical Oncology, Hokkaido University Graduate School ofMedicine, Sapporo, Hokkaido, Japan; 3Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan Background: A previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients.Methods: Patients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate.Results: A total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%–71.8%, 58.0%–87.0%, and 63.7%–86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004).Conclusion: This study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC. Keywords: bevacizumab, early tumor objective response, oxaliplatin, colorectal cancer

Mitsukuni Suenaga, Nobuyuki Mizunuma, Eiji Shinozaki, Satoshi Matsusaka, Masato Ozaka, Mariko Ogura, Keisho Chin, Toshiharu Yamaguchi Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Background: Doppler ultrasound imaging is useful for management of venous thromboembolism associated with a subclavicular implantable central venous access system in patients receiving bevacizumab (Bev). We investigated the efficacy and safety of our anticoagulant regimen based on Doppler findings.Methods: Patients aged ≤75 years with metastatic colorectal cancer, no history of thromboembolism, and no prior use of Bev received chemotherapy plus Bev. Doppler ultrasound imaging of the deep venous system to detect thrombosis was performed after the first course of Bev and repeated after the third course in patients with asymptomatic thrombosis. Indications for anticoagulant therapy in patients with asymptomatic thrombosis were as follows: enlarging thrombus (E), thrombus >40 mm in diameter (S), thrombus involving the superior vena cava (C), and decreased blood flow (V).Results: Among 79 patients enrolled in this study, asymptomatic thrombosis was detected in 56 patients (70.9%) by Doppler ultrasound imaging after the first course of Bev and there was no thrombus in 23 patients (29.1%). Of these 56 patients, 11 (19.6%) received anticoagulant therapy with warfarin, including eight after the first course and three after follow-up imaging. S + V was observed in four of 11 patients (36.4%), as well as V in two (18.2%), S + V + C in one (9.1%), E + S + V in one (9.1%), E + C in one (9.1%), E in one (9.1%), and C in one (9.1%). All patients resumed chemotherapy, including seven who resumed Bev. Improvement or stabilization of thrombi was achieved in ten patients (90.9%). Only one patient had symptomatic thromboembolism. Mild bleeding due to anticoagulant therapy occurred in six patients (54.5%), but there were no treatment-related severe adverse events or deaths. Severe thromboembolism was not observed in the other 68 patients.Conclusion: Our anticoagulant protocol for asymptomatic thrombosis detected by Doppler ultrasound imaging was effective at preventing severe thromboembolism during continued treatment with Bev. Keywords: venous thromboembolism, Bev, anticoagulant therapy, colorectal cancer