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Purpose: The incidence and time of onset of acute chemotherapy-induced peripheral neuropathy (ACIPN) caused by oxaliplatin remain unclarified. Hence, we investigated the prevalence, onset time, and location of ACIPN symptoms in patients with colorectal cancer (CRC) receiving oxaliplatin without cold stimulation., Methods: The study cohort comprised patients receiving oxaliplatin for CRC at our hospital between April 2017 and August 2018. Patients were instructed not to touch and/or drink cold things and were monitored for ACIPN symptoms in the hospital for 24 h after chemotherapy. ACIPN symptoms that appeared > 24 h after chemotherapy were recorded at the next visit. Symptom appearance time was defined as the duration from the administration of chemotherapy until the appearance of paresthesia classified as grade 1 using the Common Terminology Criteria for Adverse Events., Results: Forty-five patients received chemotherapy, comprising 23 men and 22 women, aged 67 years (29-88 years). The location of ACIPN was the fingers in 55.6% of cases, pharynx in 26.7%, perioral region in 24.4%, and feet in 6.7%. The average duration from oxaliplatin administration to symptom development was 182 min (range 62-443 min) for the fingers, 291 min (176-432 min) for the pharynx, 311 min (127-494 min) for the perioral region, and 297 min (234-355 min) for the feet. Pharyngeal symptoms were more common in patients older than 65 years than in those younger than 65 years., Conclusions: The incidence and time of the onset of ACIPN caused by oxaliplatin varies between the body and regions.

Numbness and pain are currently evaluated using subjective methods such as the visual analogue scale (VAS). PainVision (PV) is an analytical instrument that was designed to quantitatively assess sense perception and nociception in patients. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most important adverse events that renders prolonged chemotherapy difficult. To assess the features of CIPN, we aimed to compare PV methods with existing methods. A total of 73 patients received oxaliplatin for metastatic colorectal cancer. Registered patients included 37 men and 36 women in the range of 37 to 89 years (median 70). CIPN was evaluated a total of 483 times (median per patient six times). Our study examined the correlation between evaluation methods of CIPN using VAS and PV, respectively. The average VAS (hand), VAS (foot) and PV scores of CIPN were 18.4 (range: 0-100), 23.8 (range: 0-100), and 24.7 (range: 0-496), respectively. VAS (hand), VAS (foot), and FACT/GOG-NTX (NTX2, NTX4 and NTX8) were significantly correlated with PV. PV showed no correlation with a Disk-Criminator or the monofilament test used as a quantitative evaluation. The evaluation of CIPN is complex, and further improvement is required for evaluation with PV.

This phase II clinical trial compared the efficacy and safety of second-line irinotecan and panitumumab treatment (IRI + Pmab) with that of irinotecan, fluoropyrimidines and panitumumab treatment (control) in patients with KRAS wild-type mCRC. The primary endpoint was progression-free survival. In addition, early predictive markers of treatment efficacy were explored. Eighty patients were planned to be recruited. Due to a slow accrual rate, only 48 patients were recruited from 2012 to 2016, of which 23 were allocated to the control group and 25 were allocated to the IRI + Pmab group. The median progression-free survival was 254 days (95% confidence interval, 159-306) for control, and 190 days (95% confidence interval, 159-213) for IRI + Pmab (log-rank test, P = 0.26). The response rate without confirmation was 21.7% (5/23) for control and 40.0% (10/25) for IRI + Pmab. Neutropenia, leukopenia, and anorexia were the most common Grade 3/4 adverse events, and several early drop-outs from the treatment protocol were observed in the control group. As for the biomarkers, carcinoembryonic antigen and lactate dehydrogenase (LDH) smoothly declined immediately after the initial dosing in patients with a partial response or stable disease. After starting treatment, LDH-1 and - 2 increased, while LDH-4 and - 5 decreased, irrespective of tumor response. However, exceptions were frequent. In conclusion, this study failed to prove the safety and efficacy of irinotecan and panitumumab treatment due to insufficient patient accrual. Although LDH and its isozymes changed after initiation of treatment, their ability to predict the tumor response may not surpass that of carcinoembryonic antigen levels.The University Hospital Medical Information Network Clinical Trial Registry: UMIN000007658.

Background: Adoptive immunotherapy for cancer has evolved through development of novel technologies for generating a large number of activated killer cells, such as αβ T-cells, γδ T-cells, and natural killer cells. There has been no prospective trial of combination therapy involving adoptive immunotherapy and first-line chemotherapy for stage IV colorectal cancer. The present pilot study aimed to evaluate the safety and feasibility of combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer (COMVI study)., Patients and Methods: The COMVI study was a prospective, single-arm pilot trial. Therapy in each 21-day treatment cycle involved XELOX (130 mg/m 2 of oxaliplatin on day 1 plus 1,000 mg/m 2 of capecitabine twice daily on days 1-14), bevacizumab (7.5 mg/kg on day 1), and αβ T-lymphocytes (over 5×10 9 on day 18) cultured ex vivo with an immobilized antibody to CD3 and interleukin-2., Results: The study included six patients (two men and four women) between June 2013 and September 2014. The median patient age was 68 years (range=55-75 years). The overall response rate was 83.3% [complete response in two (33.3%); partial response in three (50.0%); stable disease in one (16.7%); no cases of progressive disease]. The tumor volume reduction rate was 53% (range=38.0-100%). The median progression-free and overall survival durations were 567 and 966 days, respectively. Most adverse events were mild-to-moderate in intensity, and no grade 4 adverse events occurred in the six patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study., Conclusion: Combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are needed to confirm the safety and efficacy of such chemoimmunotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Various types of chemoimmunotherapies for malignant tumors have been reported. However, there are few reports on hepatectomy after chemoimmunotherapy. We evaluated the safety and efficacy of hepatectomy for patients with stage IV colorectal liver metastases (CLM) after chemoimmunotherapy using activated αβ T-cells., Patients and Methods: From June 2012 to December 2016, five patients who underwent hepatectomy after receiving capecitabine and oxaliplatin (XELOX) plus bevacizumab and ex vivo-expanded αβ T-lymphocytes as first-line chemoimmunotherapy were included., Results: The median age of the five patients (two men, three women) was 61.4 (range=56-75) years. The surgical procedure was partial hepatectomy in two, laparoscopic partial hepatectomy in two, and one case of partial hepatectomy with subsegmentectomy. There was no postoperative complication of Clavien-Dindo grade 3A or higher. One patient had multiple lung metastases., Conclusion: Hepatectomy after chemoimmunotherapy using activated αβ T-cells for CLM can be performed safely., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large numbers of αβ and γδ T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for stage IV colorectal cancer (CRC)., Patients and Methods: Fifteen patients with advanced or recurrent CRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy., Results: Median age of the 15 patients (4 men, 11 women) was 65 years (range=49-80). Median progression-free survival was 21.3 months. Response rate was 80% (complete response (CR)=26.7%, partial response (PR)=53.3%, stable disease (SD)=20% and progressive disease (PD)=0%). Most adverse events were mild to moderate regarding their intensity and immunotherapy-associated toxicity was minimal., Conclusion: Combination of adoptive αβ T cell immunotherapy with chemotherapy for stage IV CRC is feasible and safe., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Neutropenia is a major factor affecting continuation of chemotherapy for colorectal cancer. In many clinical trials, a neutrophil count of >1500 is targeted for continuation; for a count of <1500, medication is commonly discontinued. However, there is no definitive evidence supporting the need for a neutrophil count of 1500 for continuation of chemotherapy. In the clinical trials that we conducted, we discontinued chemotherapy when the neutrophil count was <1000 (grade 3); for a count of 1000-1500 (grade 2), chemotherapy was continued. Therefore, even practical treatment uses the same setting. Our aim was to examine neutrophil counts during continuation of chemotherapy in colorectal cancer patients with counts of 1000-1500 and to assess the need for discontinuation of medication for neutrophil counts in this range. Moreover, we examined neutrophil counts during the previous course of chemotherapy when they fell below 1000., Methods: The study included 144 patients who received XELOX + bevacizumab therapy and XELOX therapy for advanced or recurrent colorectal cancer., Results: Thirty (20.8 %) patients had neutrophil counts of 1000-1500. One (3.3 %) of 30 patients had a neutrophil count of <1000 during the following course of chemotherapy. Moreover, among the patients with neutrophil counts of <1000, 27.3 % had counts of 1000-1500 during the previous course of chemotherapy and 72.7 % had counts of >1500., Conclusions: Based on these results, grade 2 neutropenia cannot predict the risk of grade 3 neutropenia. Continuation of chemotherapy in patients with neutrophil counts of 1000-1500 may be appropriate, and discontinuation of therapy is not always required.

Background: Repeated venous punctures are usually required during chemotherapy administration for cancer patients. Central venous catheters and implantable port systems have substantially facilitated vascular access, and safe, easy-to-handle port systems have become an integral part of daily clinical routines in oncology. However, several serious complications are associated with central venous ports (CV-ports), and recent developments of combined oral capecitabine and oxaliplatin (XELOX) therapies allow CV-port-free administration. In this study, the safety and efficacy of CV-port-free chemotherapy administration via the median cubital vein was assessed in metastatic colorectal cancer patients., Methods: This study included 144 patients who received XELOX + bevacizumab (BV) or XELOX therapy for metastatic colorectal cancer without CV-port implantation., Results: Eighty-five patients experienced transient vascular pain. The drip infusion route was switched to the opposite side following vascular pain in only 1 patient. No patients required CV-port implantation or delayed treatment due to adverse events associated with drug administration via the peripheral vein. Grade 3 or higher hemotoxicity and grade 3 or higher non-hematological toxicity was noted in 12.5 and 17.4 % of patients, respectively., Conclusions: Port-free-chemotherapy administration via the median cubital vein is appropriate for patients with colorectal cancer, thereby avoiding complications associated with CV-ports.

Here we report a case of unresected gastric cancer that maintained long tumor dormancy by use of paclitaxel+S-1 combination therapy. A 58-year-old woman was admitted to the hospital for peritoneal dissemination of unresectable gastric cancer. The patient further showed ileus with peritoneal dissemination in computed tomography(CT), and we performed resection of the intestine to release the stenosis. In addition, combination chemotherapy using paclitaxel(60mg/m2, weekly) and S-1(80mg/m2, every 2 weeks)was started after the operation. The patient was discharged from the hospital 7 3 days after the operation, and we continued combination chemotherapy as an outpatient over the following 3 years without serious side effects. Furthermore, tumor makers for gastric cancer were stable, although we could not examine tumor size since the patient rejected examinations such as CT. After 3 years, the patient was admitted to the hospital with cholecystitis, and we were able to evaluate the benefit of the chemotherapy against gastric cancer. The tumor size clearly remained unchanged compared to previous measurements, suggesting that the tumor maintained dormancy in this case.

Background: The start of chemotherapy usually requires a delay of about 4 weeks after surgical resection of colorectal cancer. However, there is no evidence for the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. We therefore conducted a pilot study to determine the safety and feasibility of an early start of chemotherapy after the resection of colorectal cancer with distant metastases., Methods: Five patients were enrolled. They received XELOX therapy (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1 to 14) on the 7th postoperative day and XELOX + bevacizumab (7.5 mg/kg of bevacizumab on day 1) after the 2nd cycle of chemotherapy., Results: Five patients underwent open surgery. The procedures included right hemicolectomy in 1 patient, sigmoidectomy in 2 patients, high anterior resection in 1 patient, and Hartmann procedure in 1 patient. All patients started chemotherapy on postoperative day 7. The median number of cycles of chemotherapy was 11 (8 to 22). No postoperative complications were observed. The tumor reduction rate was 44.3% (32.0 to 66.6%). Progression-free survival was 10.3 months., Conclusions: An early start of chemotherapy after surgery is feasible and safe. These findings suggest possible changes in the start time of chemotherapy after surgery in the future. We have already started a new phase II trial to confirm the effects of the early start of chemotherapy after surgery., Trial Registration: UMIN000004361.

Purpose: For recurrent or metastatic colorectal cancer, a combination of leucovorin and fluorouracil with oxaliplatin (FOLFOX)is a standard first-line regimen. Although various FOLFOX regimens are widely used, the neutropenia caused by FOLFOX is often problematic. The purpose of this study was to evaluate the clinical significance of bolus 5-fluorouracil for recurrent or metastatic colorectal cancer treated with FOLFOX+bevacizumab therapy., Methods: Thirty-nine patients who had metastatic lesions from colorectal cancer treated with FOLFOX+Bevacizumab at the Osaka Rosai Hospitalfrom January 2008 to December 2009 were included. This study compared mFOLFOX6+Bevacizumab(mF6+BV)with mFOLFOX7+Bevacizumab( mF7+BV)to assess the clinical significance of bolus 5-fluorouracil., Results: Grade 3/4 neutropenia was significantly less in mF7+BV(58. 8%: median 12 courses)than in mF6+BV(22. 7%: median 11 courses)(P=0. 02). Response rates were 52. 9%in mF6+BV and 54. 5%in mF7+BV(P=N. S.). Relative dose intensities(RDI)during the first four courses of oxaliplatin were 89% in mF6+BV and 94. 6% in mF7+BV, respectively(P=N. S.). Completion rates were 52. 9% in mF6 +BV and 68. 2% in mF7+BV, respectively(P=N. S.). The main factors in RDI and completion rate decrease were hematologic toxicity. The median PFS was 12. 5 months in mF6+BV compared with 14. 8 months in mF7+BV(P=0. 91)., Conclusions: The mFOLFOX7+BV regimen seems beneficialas first-line therapy in recurrent or metastatic colorectal cancer, demonstrating a decreased toxicity with an acceptable response rate and PFS. Bolus 5-fluorouracil may be unnecessary in a FOLFOX regimen. Further study is needed to fully evaluate bolus 5-fluorouracil.

We previously reported that mitochondrial transcription factor A (mtTFA) preferentially recognizes cisplatin-damaged DNA via physical interaction with p53 and is upregulated by treatment with cisplatin and fluorouracil (5-FU). The aim of the present study was to evaluate whether expression of mtTFA predicts the clinical outcome in patients with metastatic colorectal cancer treated with modified 5-fluorouracil, leucovorin and oxaliplatin 6 (mFOLFOX6). Fifty-nine patients with metastatic lesions from colorectal cancer treated with mFOLFOX6 were included in this study. The subjects consisted of 25 women and 34 men with a median age of 62 years. The patients were treated with oxaliplatin (85 mg/m(2) ) plus leucovorin (200 mg/m(2) ) as a 2-h infusion on day 1, followed by 5-FU (400 mg/m(2) ) bolus and 46-h continuous infusion of 2400 mg/m(2) . The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemical analysis. Of the 59 patients, 33 (complete response 1, partial response 32) achieved a confirmed response to therapy. The positive cytoplasmic staining rate for mtTFA was 44.1% and that for p53 was 59.3%, respectively. Strong expression of mtTFA was detected in eight of 33 complete response/partial response (24.2%) and in 18 of 26 SD/PD (69.2%), indicating that mtTFA expression was significantly correlated with response to chemotherapy (P<0.01). Median overall survival was significantly longer in patients without mtTFA expression (P=0.0493). Multivariate analysis revealed that mtTFA expression significantly affected overall survival (hazard ratio 2.10, P=0.036). Immunohistochemical study of mtTFA may be useful for predicting the clinical outcome of metastatic colorectal cancer patients treated with FOLFOX., (© 2011 Japanese Cancer Association.)