The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Oxaliplatin-induced increase in splenic volume: experiences from multicenter study in Japan.

BACKGROUND: Chemotherapy with oxaliplatin is known to induce sinusoidal obstruction syndrome (SOS). In a previous single-center study, we reported that oxaliplatin-induced increase in splenic volume (SV) is strongly indicative of SOS, and that this increase in SV persisted for > 1 year after completing chemotherapy. The aim of this study was to confirm the oxaliplatin-induced SV change in a multicenter study in patients with stage III colon cancer in Japan. METHODS: We enrolled 59 patients who underwent curative resection for stage III colon cancer in the FACOS study in a phase II multi-center clinical study. Participants received mFOLFOX6 or CAPOX as adjuvant chemotherapy. SV change was assessed three times by computed tomographic volumetry: before surgery, on completion of adjuvant chemotherapy, and 1 year after completing adjuvant chemotherapy. RESULTS: SV on completing and 1 year after chemotherapy was significantly higher than that before surgery (P < 0.001). Oxaliplatin-induced SOS persisted for > 1 year after the completion of adjuvant chemotherapy in half of the patients. There was no difference in 3-year disease-free survival with respect to the presence or absence of increased SV. An increase in SV was observed in 72% of patients treated with mFOLFOX6 and 94% of patients treated with CAPOX (P = 0.13). CONCLUSION: This study can be verified the findings observed in our previous single-center study, oxaliplatin-based adjuvant chemotherapy was associated with an increase in SV. Furthermore, this increase can persist for > 1 year. The continuous presence of SOS may have a negative impact on prognosis in patients that develop recurrent disease.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

Safety of mFOLFOX6/XELOX as adjuvant chemotherapy after curative resection of stage III colon cancer: phase II clinical study (The FACOS study).

PURPOSE: Adjuvant chemotherapy with oxaliplatin combined with a fluoropyrimidine derivative is widely accepted as standard therapy for patients with stage III colon cancer, since few clinical data are available for Japanese patients. The FACOS trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) and XELOX regimens in Japanese colon cancer patients. METHODS: Twelve cycles of mFOLFOX6 or 8 cycles of XELOX were given to patients with eligibility: stage III curatively resected colon cancer, performance status of 0-1, age from 20 to 75 years, and adequate organ function. The primary endpoint was 3-year disease-free survival. Secondary endpoints were the incidence of adverse events (AEs) and the completion rate of study therapy. RESULTS: From April 2010 to April 2014, a total of 132 patients were enrolled. Safety was analyzed in 130 patients, with finalized data from 73 patients receiving mFOLFOX6 and 57 patients receiving XELOX. A total of 130 patients (100%) experienced AEs (any grade), and 52 patients (40.0%) experienced AEs of grade ≥ 3. No significant difference in the frequency of grade ≥ 3 AEs was observed between mFOLFOX6 and XELOX groups. Continuation of the planned cycle rate of protocol treatment was 69.9% in the mFOLFOX6 group and 68.4% in the XELOX group. Treatment was discontinued because of AEs in 14 patients (19.2%) in the mFOLFOX6 group and 8 (14.0%) in the XELOX group. Mean relative dose intensity for oxaliplatin was 78.0% in the mFOLFOX6 group and 82.8% in the XELOX group. CONCLUSION: As adjuvant chemotherapy for stage III colon cancer, mFOLFOX6/XELOX regimens are acceptable.

Efficacy and safety of neoadjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and levofolinate for T3 or T4 stage II/III rectal cancer: the FACT trial.

PURPOSE: A multicenter phase II clinical study was performed in patients with T3 or T4 stage II/III rectal cancer to evaluate the efficacy and safety of neoadjuvant chemotherapy with 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6). METHODS: Patients received four 2-week cycles of mFOLFOX6 therapy (oxaliplatin at 85 mg/m2 + leucovorin at 200 mg/m2 + fluorouracil as a 400 mg/m2 bolus followed by infusion of 2400 mg/m2 over 46 h, all on Day 1). They were evaluated by computed tomography after completion of the fourth cycle. If there was no disease progression, two additional cycles were administered and then surgery was performed. Adjuvant chemotherapy was generally administered for 6 months using appropriate regimens at the discretion of the physician. RESULTS: mFOLFOX6 therapy was given to 52 patients with locally advanced rectal cancer. The preoperative response rate was 48.8% and the operation rate was 80.8%. Serious adverse events of Grade 3-4 were neutropenia (n = 5), leukopenia (n = 1), thrombocytopenia (n = 1), febrile neutropenia (n = 1), nausea (n = 1), vomiting (n = 1), and peripheral neuropathy (n = 2). The R0 resection rate, pathologic complete response rate, and sphincter preservation rate were 91.0, 11.9, and 73.8%, respectively. Postoperative complications were tolerable. CONCLUSIONS: The present results suggested that neoadjuvant therapy with mFOLFOX6 is safe and effective, representing a reasonable treatment option for locally advanced rectal cancer.

Comparison of the risk of surgical site infection and feasibility of surgery between sennoside versus polyethylene glycol as a mechanical bowel preparation of elective colon cancer surgery: a randomized controlled trial.

PURPOSE: To validate the usefulness of sennoside as a substitute for polyethylene glycol (PEG) as a mechanical bowel preparation (MBP) for elective colon cancer surgery. METHODS: We performed a prospective randomized non-inferiority trial comparing the use of sennoside and PEG in MBP for elective colon cancer surgery, in terms of the risk of surgical site infection (SSI) and the feasibility of surgery. RESULTS: The overall incidence of SSIs was 2.9 % in the sennoside group (n = 68) and 6.3 % in the PEG group (n = 63) with a difference of 3.4 % (95 % confidence interval 6.9-10.6 %). The intraoperative spillage of the stool materials in the sennoside and PEG groups was 4.4 and 3.1 %, respectively, and was not significantly different (p = 0.71), even the upstream stool consistency, was more frequently observed to be non-stool in the PEG group (65.1 vs. 30.9 %, p < 0.01). CONCLUSION: MBP with sennoside could be a substitution for PEG in elective colon cancer surgery.

[Adjuvant chemotherapy comprising modified FOLFOX6 after curative resection of synchronous or metachronous metastasis from colorectal cancer].

PURPOSE: This retrospective study evaluated the outcome of adjuvant chemotherapy comprising modified FOLFOX6 (mFOLFOX6) after potentially curative metastasectomy from colorectal cancer. PATIENTS AND METHODS: The subjects were 40 patients with colorectal cancer who underwent potentially curative metastatectomy without any prior chemotherapy between December 2003 and November 2011. Patient background, type of adjuvant chemotherapy, and prognosis were examined. RESULTS: Adjuvant chemotherapy was given in 30 patients (mFOLFOX6, n=26; oral fluoropyrimidines, n=4). The median relapse-free survival tended to be longer in patients treated with mFOLFOX6 compared to those treated with fluoropyrimidines (28.5 months vs 14.8 months; p=0.11). The median overall survival did not differ significantly between the 2 groups (37.9 months vs 31.3 months, p=0.56). When the analysis was restricted to patients treated with mFOLFOX6, no significant differences were found in relapse-free survival (p=0.46), overall survival (p=0.29), and frequency of adverse events during chemotherapy(Grade 3, p=0.32) between patients with synchronous metastasis(n=11) and those with metachronous metastasis (n=15). CONCLUSION: These results suggest that mFOLFOX6 might contribute to prolonging the time to relapse and that the timing of developing metastasis(synchronously or metachronously) may not have any effect on the outcome of adjuvant mFOLFOX6.

Usefulness of sennoside as an agent for mechanical bowel preparation prior to elective colon cancer surgery.

OBJECTIVE: We retrospectively evaluated the usefulness of sennoside as an agent for mechanical bowel preparation prior to elective colon cancer surgery. METHODS: A total of 86 patients were given 12 mg of sennoside on the evening prior to resective surgery for colon cancer, followed by intravenous antimicrobial prophylaxis used on the day of surgery or until postoperative day 2. RESULTS: The incidence of surgical site infection in the study group was 4.7%, which was comparable to that in the historical control patients (3.5%, p>0.99), who had received polyethylene glycol for mechanical bowel preparation prior to colon surgery. On multivariate logistic regression analysis, only body mass index (p=0.04) was an independent significant factor affecting the surgical site infection. The intraoperative spillage was not influenced by the presence of stenosis, although the amount of fecal matter was higher in the upstream colon segment (p<0.01) and downstream segment (p=0.07) in patients with a stenotic lesion occupying more than two-thirds of the lumen (n=29) than in those without such severe stenosis (n=57). CONCLUSION: Sennoside seems to be an acceptable agent for mechanical bowel preparation even in patients with stenosis.

[The clinical outcome of mFOLFOX6 treatment for colorectal cancer patients who underwent resection of liver metastasis -comparison between synchronous and metachronous liver metastasis].

Only a few reports have suggested the efficacy of adjuvant chemotherapy including oxaliplatin based regimens following surgical resection of liver metastases from colorectal cancer. Since an administration of mFOLFOX6 was approved to medical insurance for advanced colorectal cancer as adjuvant chemotherapy, we applied mFOLFOX6 treatment (6 to 12 courses) to the patients who underwent curative resection of colorectal liver metastasis. The subjects were 14 patients who underwent curative resection for synchronous or metachronous colorectal liver metastasis and received mFOLFOX6 treatment postoperatively from January 2006 to January 2011. We retrospectively analyzed the patient's characteristics, relapse free survival, overall survival, and adverse events in these patients. Synchronous liver metastasis was found in 5 patients, while metachronous liver metastasis was observed in 9 patients. There were no significant differences between these patients in terms of clinical characteristics, the relapse free survival and overall survival. All patients had some adverse events including bone-marrow suppression and diarrhea. Especially, grade 3 or higher bone-marrow suppression were recognized in 6 patients (42.8%). Neurologic toxicity (≤ grade 2) was observed in 10 patients (71.4%). Adjuvant chemotherapy with mFOLFOX6 treatment following surgical resection of synchronous or metachronous liver metastasis was safely administered. We will further examine the benefit of mFOLFOX6 treatment for the patients who undergo a surgical resection of liver metastasis in the future.

[Administration of polysaccharide K (PSK) for stage III colorectal cancer in clinical practice].

PURPOSE: This retrospective study was performed to evaluate the administration and effect of PSK in patients with stage III colorectal cancer in clinical practice. PATIENTS AND METHODS: The subjects were 55 patients with stage III colorectal cancer who received adjuvant chemotherapy, comprising UFT in 44, UFT/calcium folinate (Leucovorin) in 4 and 5-FU/levofolinate calcium (l-LV) in 7, between April 2000 and December 2006. The rate of administering PSK, disease-free survival time, and overall survival time were evaluated. RESULTS: The rate of administering PSK was 82%. There was no significant difference in disease-free survival and overall survival between patients who received PSK and those without. Among the patients in stage IIIa, the patients who received PSK tended to show a longer overall survival time than those without PSK (p =0.15). CONCLUSIONS: The rate of administering PSK is high in patients with stage III colorectal cancer. But further cases would be needed to evaluate the effect of PSK with 5-FU-based adjuvant chemotherapy.

[Effect of cimetidine with chemotherapy on stage IV colorectal cancer].

We herein report the result of a prospective study to investigate the efficacy of cimetidine administration in conjunction with chemotherapy for stage IV colorectal cancer. Sixty-two patients treated with Leucovorin/5-fluorouracil therapy were enrolled from 1996 to 2000. Both groups were well matched for pre-treatment characteristics. There was no difference in survival in cur B patients. However, the cimetidine group had significantly prolonged survival in the patients with cur C or non-resectable carcinoma. This study suggests that cimetidine treatment may improve the survival of patients with non-curative surgery for stage IV colorectal cancer.