Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

Double-blind, placebo-controlled, randomized phase II study of TJ-14 (Hangeshashinto) for infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy-induced oral mucositis.

PURPOSE: Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a double-blind, placebo-controlled, randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with colorectal cancer. METHODS: Ninety-three patients with colorectal cancer who developed moderate-to-severe COM (WHO grade ≧1) during any cycle of chemotherapy using FOLFOX, FOLFIRI, and/or XELOX treatment were randomly assigned to receive either TJ-14 (n = 46) or placebo (n = 47). Patients received the administration of placebo or TJ-14 for 2 weeks at the start of the next course of chemotherapy. Patients were assessed three times per week for safety and for COM incidence and its severity using the WHO grading. RESULTS: Ninety eligible patients (TJ-14; 43, placebo; 47) per protocol set analysis were included in the analysis after the key-opening. Although the incidence of grade ≧2 oral mucositis was lower for patients treated with TJ-14 compared to those treated with placebo, there was no significant difference (48.8 vs. 57.4 %; p = 0.41). The median duration of grade ≧2 mucositis was 5.5 versus 10.5 days (p = 0.018). No difference in other treatment toxicity was observed between the two groups, and patients exhibited high compliance in dosing administration. CONCLUSION: The present study results did not meet the primary endpoint. However, TJ-14 demonstrated a significant effect in the treatment of grade ≧2 mucositis in patients with colorectal cancer compared to the placebo.

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205.

BACKGROUND: NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection. METHODS: Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193). FINDINGS: Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported. INTERPRETATION: Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Multicenter phase II study of second-line cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type metastatic colorectal cancer: the FLIER study.

BACKGROUND: This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping. PATIENTS AND METHODS: Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%). CONCLUSION: Second-line cetuximab plus FOLFIRI was effective and well-tolerated.

Leucovorin, fluorouracil, and oxaliplatin plus bevacizumab versus S-1 and oxaliplatin plus bevacizumab in patients with metastatic colorectal cancer (SOFT): an open-label, non-inferiority, randomised phase 3 trial.

BACKGROUND: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. METHODS: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. FINDINGS: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). INTERPRETATION: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. FUNDING: Taiho.

Goshajinkigan oxaliplatin neurotoxicity evaluation (GONE): a phase 2, multicenter, randomized, double­blind, placebo­controlled trial of goshajinkigan to prevent oxaliplatin­induced neuropathy.

PURPOSE: Oxaliplatin-induced peripheral neurotoxicity (OPN) is frequent and potentially severe, but successful treatment of this condition is still an unmet clinical need. We aimed to determine whether treatment with goshajinkigan (TJ-107), a traditional Japanese medicine, is better than placebo in preventing OPN in patients with advanced or recurrent colorectal cancer patients treated with standard FOLFOX regimens. METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, patients undergoing oxaliplatin-based chemotherapy were randomized to receive either oral TJ-107 (7.5 g) or matching placebo daily. The severity of OPN was assessed according to the Common Toxicity Criteria for Adverse Events at baseline, every 2 weeks until the 8th cycle, and every 4 weeks thereafter until the 26th week. The primary endpoint was the incidence of grade 2 or greater OPN until the 8th cycle of chemotherapy. RESULTS: Analyses were done by intention to treat. Eighty-nine patients were randomly assigned to receive either TJ-107 (n = 44) or placebo (n = 45) between May 2009 and March 2010. The incidence of grade 2 or greater OPN until the 8th cycle was 39 and 51 % in the TJ-107 and placebo groups, respectively (relative risk (RR), 0.76; 95 % CI, 0.47­1.21). The incidence of grade 3 OPN was 7 % (TJ-107) vs. 13 % (placebo) (0.51, 0.14­1.92). No concerns regarding toxicity emerged with TJ-107 treatment. CONCLUSIONS: TJ-107 appears to have an acceptable safety margin and a promising effect in delaying the onset of grade 2 or greater OPN without impairing FOLFOX efficacy.

Multi-center phase II study of FLOX for advanced colorectal cancer patients in Japan: SWIFT 3 study.

AIM: This is a multicenter phase II study to assess the efficacy and toxicity of the 5-FU, leucovorin, and oxaliplatin (FLOX) (SWIFT 3) regimen in Japanese patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Fifty-two patients were enrolled and evaluated from 12 institutions. The median age was 66 years, with 40.4% of patients with colon cancer and 59.6% with rectal cancer. RESULTS: Forty-one patients underwent chemotherapy for first-line therapy and 11 patients for second-line. The response rate for first-line was 46.3% and that for second-line was 9.1%. The response rates categorized by metastatic sites were 59.4% for liver, 33.3% for lung, and 22.2% for lymph nodes. Grade 3/4 neutropenia occurred in 21.2% and Grade 3/4 non-hematologic toxicity in 46.1%. There were no deaths within 60 days following the administration. CONCLUSION: Standard FLOX regimen can be administered for Japanese patients. It is suggested that FLOX is an appropriate option for adjuvant therapy in CRC.

Does 1 year adjuvant chemotherapy with oral 5-FUs in colon cancer reduce the peak of recurrence in 1 year and provide long-term OS benefit?

The objective of our study was to clarify the characteristics of survival and hazard function in patients who received adjuvant chemotherapy after surgery for colon cancer. The data of 2848 patients with curatively resected colon cancer were analyzed; we used the patient data provided by the Japanese Foundation for Multidisciplinary Treatment for Cancer in three trials, namely, JFMC7-1 (n = 869), JFMC7-2 (n = 978) and JFMC15 (n = 1001). The total number of events were 605 (overall survival) and 724 (disease-free survival). The disease-free survival events consisted of 117 cases of death and 607 cases of disease recurrences. Logrank test showed a borderline significant difference in both overall survival (P = 0.0452) and disease-free survival (P = 0.0462). The 5 year overall survival proportion was 0.769 (control) and 0.802 (treated), and the absolute drug effect was 3.3%. The difference between the 5 year disease-free survival proportion (0.728 [control] and 0.760 [drug]) was 3.2%, which is almost similar to the result of overall survival. The disease-free survival curve of the treated group differed from that of the control group after 1 year, whereas the overall survival curve of the treated group became distinct from that of the control group after 2 years. The hazard rate plots indicated the possibility that 1 year adjuvant chemotherapy with oral 5-fluorouracils may translate the short-term reduction in the risk of recurrence in patients with resected colon cancer into a delayed advantage in overall survival.

Preventive effect of goshajinkigan on peripheral neurotoxicity of FOLFOX therapy: a placebo-controlled double-blind randomized phase II study (the GONE Study).

We conducted a controlled double-blind randomized study in patients with advanced/recurrent colorectal cancer to investigate the efficacy of Goshajinkigan (GJG) for peripheral neurotoxicity induced by FOLFOX therapy. The primary endpoint is the incidence of peripheral neurotoxicity > or = Grade 2 after eight cycles of chemotherapy. The secondary endpoints are the incidence of peripheral neurotoxicity of each grade after each cycle, the psychometric properties of the FACT/GOG-Ntx, time to occurrence of neurotoxicity, time to treatment failure, progression-free survival, response rate and toxicity. Eighty patients are required in the study (40 patients per group).

[Evaluation of prophylactic hepatic arterial infusion chemotherapy after curative hepatectomy for metastatic colorectal cancer].

We evaluated the effect of hepatic arterial infusion (HAI) chemotherapy after curative resection of liver metastases of colorectal cancer. A total of 161 patients underwent curative resection of liver metastases. Among them, 50 patients underwent HAI of 5-FU, and 111 patients had no HAI therapy. The 50% disease-free survival time (50% DFS) was 758 days and 342 days in the HAI group and the non-HAI group (logrank test, p<0.01), and the 50% overall survival time (50% OS) was 978 days versus 730 days (p<0.05), respectively. Among the 71 patients with multiple resectable metastases (H2 or H3), the HAI group had a significantly superior 50% DFS. HAI therapy seems to be an effective form of adjuvant chemotherapy after hepatic resection of metastatic colorectal cancer.

[Effectiveness of chemoradiotherapy for three cases of squamous cell anal carcinoma].

We report three patients with squamous cell anal carcinoma who were treated by chemoradiotherapy. Case 1: A 62-year-old female with squamous cell anal carcinoma invading the vagina underwent a posterior pelvic exenteration. She had paraaortic lymph node metastases. She was treated by chemoradiotherapy with 5-FU/CDDP and external irradiation (50 Gy) as an adjuvant therapy, and survived for 5 years. Case 2: A 74-year-old female with anal squamous cell carcinoma Stage II was treated by chemoradiotherapy with tegafur/uracil, external irradiation (30 Gy) and interstitial irradiation (24 Gy). She is currently living without any signs of recurrence for 3 years and 8 months. Case 3: A 53-year-old female with anal squamous cell carcinoma Stage IIIa was treated by chemoradiotherapy using 5'-DFUR and external irradiation (66 Gy). She is currently living without any signs of recurrence for 1 year and 9 months. The prognosis of anal squamous cell carcinoma that received Cur B or C resection was extremely poor with a median survival time (MST) of 7 or 6 months. Chemoradiotherapy seems to be effective as the first line treatment.