Takayuki Kii

Phase I/II trial of 2‐weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807)

We carried out a phase I/II trial of adding 2‐weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2‐weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2‐weekly docetaxel (30 mg/m2 [dose level (DL)1] or 40 mg/m2 [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed‐dose CF (80 mg/m2 cisplatin, day 1; 800 mg/m2 fluorouracil, days 1–5) repeated every 4 weeks. The primary endpoint was dose‐limiting toxicity (DLT) in phase I and central peer review‐based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty‐two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48–75%); median overall survival and progression‐free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment‐related death in one patient. The 2‐weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer

Background:This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC).Methods:Ninety patients were randomised to a standard dose of wPTX (80 mg m−2) or an escalated dose of wPTX (80–120 mg m−2) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8.Results:The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34).Conclusion:Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.

Phase II study of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer

Background:The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus.Methods:Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30–40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS).Results:From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy.Conclusions:Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

A randomized controlled Phase III trial comparing 2-weekly docetaxel combined with cisplatin plus fluorouracil (2-weekly DCF) with cisplatin plus fluorouracil (CF) in patients with metastatic or recurrent esophageal cancer: rationale, design and methods of Japan Clinical Oncology Group study JCOG1314 (MIRACLE study)

Chemotherapy with cisplatin plus fluorouracil is the current standard treatment for metastatic or recurrent esophageal cancer. We have developed a 2-weekly docetaxel combined with CF regimen and conducted a Phase I/II trial for metastatic or recurrent esophageal cancer (JCOG0807). Promising efficacy and safety were shown in JCOG0807, and we have commenced a Phase III trial in September 2014 to confirm the superiority of 2-weekly DCF to CF for patients with metastatic or recurrent esophageal cancer. A total of 240 patients will be accrued from 41 Japanese institutions over a period of 4 years. The primary end point is overall survival. The secondary end points are progression-free survival, response rate and proportion of adverse events. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015107 (http://www.umin.ac.jp/ctr/index.htm).

Retrospective Study as First-Line Chemotherapy Combined Anti-VEGF Antibody with Fluoropyrimidine for Frail Patients with Unresectable or Metastatic Colorectal Cancer

Background/Aim: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. Methods: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. Results: The median age was 72 years (range 66–84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. Conclusion: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

Efficacy of Prophylactic G-CSF in Patients Receiving FOLFIRINOX: A Preliminary Retrospective Study.

OBJECTIVE Recent guidelines have adopted an incidence of febrile neutropenia (FN) threshold of 20% for the use of prophylactic granulocyte colony-stimulating factor (G-CSF). In a Japanese phase II study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) for Japanese patients with advanced pancreatic cancer, the incidence of FN and severe neutropenia were 24.7% and 77.8%, respectively, without G-CSF prophylaxis. The aim of this retrospective study was to investigate the incidence of FN or severe neutropenia induced by full-dose FOLFIRINOX administration with G-CSF prophylaxis during the first cycle of treatment. METHODS Patients with advanced pancreatic cancer who received FOLFIRINOX with G-CSF prophylaxis during the first cycle of treatment from January 2014 to August 2014 were investigated and the frequency of adverse events during the first cycle was measured. RESULTS Among seven patients who received FOLFIRINOX, six patients met the eligibility criteria. The patient characteristics were as follows: median age (range), 57 (50-66); men/women, 3/3; performance status 0/1, 2/4. Grade 3/4 hematological adverse events were as follows: leukopenia in 33% of the patients, neutropenia in 33% of the patients, thrombocytopenia in 33% of the patients and FN in 17% of the patients. One patient was heterozygous for the UGT1A1*6 and UGT1A1*28 polymorphisms and experienced FN. Grade3/4 non-hematological adverse events were as follows: anorexia in 33% of the cases and nausea in 50% of the cases. CONCLUSION Although the present study was retrospective and small, the simultaneous administration of G-CSF might be effective for the prevention of severe neutropenia and FN in patients treated with FOLFIRINOX.

Efficacy and feasibility of neoadjuvant chemotherapy and chemoradiotherapy for elderly patients with stage IB/II/III (excluding T4) esophageal cancer: Retrospective study.

135 Background: Neoadjuvant chemotherapy (NAC) of 5-fluorouracil plus cisplatin infusion (FP) is standard therapy for stage IB/II/III (excluding T4) esophageal cancer from results of JCOG9907 and definitive chemoradiotherapy (dCRT) of FP is one of the curative options for resectable esophageal cancer with organ preservation results of JCOG9906 in Japan. However, the efficacy and feasibility of NAC FP and CRT for elderly patients (pts) are unclear. Methods: We examined stage IB/II/III (excluding T4) esophageal cancer pts aged 70 or over, who received NAC FP or dCRT at our institution between April 2008 and August 2015, retrospectively. Results: 16 pts received NAC FP at least 1 course, while 5 pts received dCRT because of intolerability for surgery, reject of surgery, and patients wish. Median age was 73/75 (NAC FP/dCRT) and pts in NAC FP had more advanced stage cancer compared with pts in dCRT (p = 0.02). With respect to the toxicity, bone marrow depression developed in dCRT with more high frequency comp...

A phase II study of panitumumab plus irinotecan for metastatic colorectal cancer with wild KRAS, resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese (OGSG1001).

607 Background: Anti-epidermal growth factor receptor (EGFR) antibody therapy showed to be effective in treatment for metastatic colorectal cancer (mCRC) with wild KRAS. Especially, combination chemotherapy with anti-EGFR antibody plus irinotecan is expected more effective than anti-EGFR antibody alone, resistant to irinotecan. We conducted a phase II trial of panitumumab plus irinotecan for mCRC with wild KRAS resistant to fluoropyrimidine, oxaliplatin, and irinotecan in Japanese. Methods: Subjects were mCRC patients with wild KRAS, who showed resistance to fluoropyrimidine, oxaliplatin, and irinotecan and had measurable disease, ECOG PS 0-2. Panitumumab (6 mg/kg) plus irinotecan (same dose as prior irinotecan) was administered every two weeks. This treatment was provided until progression. The primary endpoint was response rate (RR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), response duration, and adverse event (AE). Results: A total of ...

1492PTHE IMPACT OF ADDING APREPITANT FOR THE PATIENTS RECEIVING MODERATE RISK OF EMETOGENIC CHEMOTHERAPY, A PROSPECTIVE, RANDOMIZED, CROSS-OVER TRIAL.

ABSTRACT Aim: Aprepitant, a neurokinin 1 antagonist, showed efficacy for chemotherapy-induced nausea and vomit(CINV). Antiemetic guidelines recommend aprepitant for high emetogenic chemotherapy(HEC). This prospective, randomized, cross-over trial aimed to evaluate the efficacy of aprepitant for patients(pts) receiving moderate emetogenic chemotherapy(MEC). Methods: Gastrointestinal cancer pts receiving MEC were randomly assinged to GroupA and B. We administered as follows; in GroupA; on first course, pts received palonosetron (0.75mg iv on day 1) and dexamethasone (9.9mg on day 1, and 8mg p.o. on days 2-3) (control premedication) and on second course, pts received oral aprepitant (125mg on day 1 and 80mg on days 2-3) with control premedication (dexamethasone; 4.95mg iv and 4mg p.o.). In GroupB, pts received aprepitant with control premedication on the first course and they received control premedication on second course. The primary endpoint was rate of CR (complete response; neither emesis nor rescue therapy) and degree of nausea. Results: From January 2011 to March 2013, 100 pts were enrolled, and 83 pts were analyzed(female/male, 35/48; median age, 65 years; colorectal/gastric, 64/19; irinotecan/oxaliplatin 53/30). The CR rates of aprepitant/control were 73.5%/60.2%(p = 0.064). The degree of nausea was(more than intermediate) was 4.9%/19.0%(p = 0.02). Conclusions: Adding aprepitant significantly reduced moderate and severe emesis compared with standard premedication. Although the rate of CR was not statistically significant, aprepitant reduced the degree of nausea. Adding aprepitant is promising for gastrointestinal cancer pts receivig MEC. Disclosure: All authors have declared no conflicts of interest.

NASOGALLBLADDER DRAINAGE FOR MIRIZZI’S SYNDROME

The authors experienced a case of Mirizzi’s syndrome successfully treated with endoscopic nasogallbladder drainage (ENGBD). The patient was a 63‐year‐old man. He was admitted with abdominal pain and jaundice. Laboratory data indicated leukocytosis and elevation of serum bilirubin level. Abdominal ultrasound showed marked swelling of gallbladder and debris in the gallbladder, therefore, the authors strongly suspected Mirizzi’s syndrome. He had past history of acute myocardial infarction and treated with anticoagulation therapy. Then, the authors couldn’t perform surgical removal or percutaneous transhepatic drainage, and tried endoscopic transpapillary drainage. Endoscopic retrograde cholangiopancreatography revealed smooth stricture in the superior portion of common bile duct and occlusion of the cystic duct, and ENGBD was then performed. After ENGBD, his complaints, laboratory data, swelling of gallbladder and stricture of common bile duct were all remarkably improved.