Comprehensive genomic evaluation of advanced and recurrent breast cancer patients for tailored precision treatments.

AIM: The aim of this study was to investigate genetic alterations within breast cancer in the setting of recurrent or de novo stage IV disease. PATIENTS AND METHODS: This study included 22 patients with recurrent breast cancer (n = 19) and inoperable de novo stage IV breast cancer (n = 3). For next generation sequencing, FoundationOneCDx (F1CDx) (Foundation Medicine Inc., Cambridge, MA, USA) was performed in 21 patients and FoundationOneLiquid CDx was performed in 1 patient. RESULTS: Median age was 62.9 years (range, 33.4-82.1). Pathological diagnoses of specimens included invasive ductal carcinoma (n = 19), invasive lobular carcinoma (n = 2), and invasive micropapillary carcinoma (n = 1). F1CDx detected a median of 4.5 variants (range, 1-11). The most commonly altered gene were PIK3CA (n = 9), followed by TP53 (n = 7), MYC (n = 4), PTEN (n = 3), and CDH1 (n = 3). For hormone receptor-positive patients with PIK3CA mutations, hormonal treatment plus a phosphoinositide 3-kinase inhibitor was recommended as the treatment of choice. Patients in the hormone receptor-negative and no human epidermal growth factor receptor 2 expression group had significantly higher tumor mutational burden than patients in the hormone receptor-positive group. A BRCA2 reversion mutation was revealed by F1CDx in a patient with a deleterious germline BRCA2 mutation during poly ADP ribose polymerase inhibitor treatment. CONCLUSION: Guidance on tailored precision therapy with consideration of genomic mutations was possible for some patients with information provided by F1CDx. Clinicians should consider using F1CDx at turning points in the course of the disease.

Multicenter, single-arm, phase II study of the continuous use of panitumumab in combination with FOLFIRI after FOLFOX for RAS wild-type metastatic colorectal cancer: Exploratory sequential examination of acquired mutations in circulating cell-free DNA.

This multicenter single-arm, phase II study evaluated the efficacy and safety of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable/metastatic colorectal cancer (mCRC). Additionally, clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment. Eligible patients with RAS wild-type mCRC who had received the first-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI. Progression-free survival (PFS) at 6 months was the primary endpoint, with threshold and expected values of 35% and 50%, respectively. In total, 54 patients were enrolled between October 2017 and October 2019. The crude 6-month PFS rate was 37.0%, with a 4.8-month median PFS. The response rate and disease control rate were 16.7% and 50.0%, respectively. Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline. The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with wild-type tumors. In conclusion, our study failed to show the expected efficacy of the continuous panitumumab use in the second-line treatment. Liquid biopsy discriminated the duration of PFS according to the mutation status. The effectiveness of continuous treatment with panitumumab should be evaluated in patients with RAS/BRAF wild-type mCRC determined by liquid biopsy at the start of the second-line treatment.

Efficacy of celecoxib as preemptive analgesia for patients undergoing laparoscopic inguinal hernia repair: a randomized trial.

PURPOSE: To investigate the efficacy and safety of preemptive analgesia with a transversus abdominis plane (TAP) block versus celecoxib for patients undergoing laparoscopic transabdominal preperitoneal inguinal hernia repair (LTAPP). METHODS: Sixty patients scheduled for LTAPP were randomized into three groups: a celecoxib group, given 200 mg celecoxib 2 h before surgery; a celecoxib/diclofenac group, given 200 mg celecoxib 2 h before surgery and 50 mg rectal diclofenac sodium on recovery from general anesthesia; and a block group, given a TAP block with 60 mL 0.25% levobupivacaine after general anesthesia. We assessed the numerical rating scale (NRS) scores for pain at rest and with movement 24 h after surgery. Postoperative analgesia use and adverse events were also evaluated. RESULTS: The NRS scores for pain at rest and with movement were lower in the celecoxib group than in the block group, 24 h postoperatively. The time to first request for analgesia tended to be longer in the block group than in the celecoxib group. No significant between-group differences were noted in analgesic use or adverse events. CONCLUSIONS: Celecoxib was not inferior to the TAP block as preemptive analgesia. Thus, celecoxib could be given as simple preemptive analgesia for LTAPP by considering a multimodal analgesic strategy in the early postoperative period.

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study).

LESSONS LEARNED: A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. BACKGROUND: TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2 /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. METHODS: Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). RESULTS: From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2 /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). CONCLUSION: Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

Phase II study of 5-fluorouracil-leucovorin plus bevacizumab for chemotherapy-naïve older or frail patients with metastatic colorectal cancer (OGSG 0802).

BACKGROUND: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients. METHODS: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m2) and l-leucovorin (200 mg/m2) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths. CONCLUSION: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

[A Study on the Status of End-of-Life Chemotherapy for Solid Cancer after the Introduction of New Anti-Cancer Drugs].

BACKGROUND: In recent years, the decision to discontinue chemotherapy has become more difficult, and there is a tendency for chemotherapy to continue until just before death. We investigated the current state of end-of-life(EOL)chemotherapy for solid cancer patients. METHODS: Patients who died of cancer during hospitalization between January and November 2018 were included. Patients were divided into 2 groups, those who received EOL chemotherapy within 30 days of death(Near group: NG)and those who did not receive it(Far group: FG). The contents of each treatment were compared retrospectively. RESULTS: The number of patients were 46(32%)in the NG and 96(68%)in the FG. As EOL chemotherapy, the number of patients received cytotoxic drugs were 27(59%)and 68(71%), molecular targeted drugs were 6(13%)and 16(16%), immune-checkpoint inhibitors were 8(18%)and 12(12%), and hormone drugs were 0(0%)and 5(5%)in patients with NG and FG respectively(p<0.05). DISCUSSION: Minimally invasive drugs were often selected for EOL chemotherapy. It was suggested that the advent of new drugs has expanded the options for EOL chemotherapy.

Phase III randomised trial comparing 6 vs. 12-month of capecitabine as adjuvant chemotherapy for patients with stage III colon cancer: final results of the JFMC37-0801 study.

BACKGROUND: Up to 6-months oxaliplatin-containing regimen is now widely accepted as a standard adjuvant chemotherapy for stage III colorectal cancer (CRC). However, oral fluoropyrimidine monotherapy is used for some part of patients, especially in Asian countries including Japan, and its optimal duration is yet to be fully investigated. METHODS: A total of 1306 patients with curatively-resected stage III CRC were randomly assigned to receive capecitabine (2500 mg/m2/day) for 14 out of 21 days for 6 (n = 654) or 12 (n = 650) months. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were relapse-free survival (RFS), overall survival (OS), and adverse events. RESULTS: The 3- and 5-year DFS were 70.0% and 65.3% in the 6M group and 75.3% and 68.7% in the 12M group, respectively (p = 0.0549, HR = 0.858, 90% CI: 0.732-1.004). The 5-year RFS was 69.3% and 74.1% in the 6M and 12M groups, respectively (p = 0.0143, HR = 0.796, 90% CI: 0.670-0.945). The 5-year OS was 83.2% and 87.6%, respectively (p = 0.0124, HR = 0.727, 90% CI: 0.575-0.919). The incidence of overall grade 3-4 adverse events was almost comparable in both groups. CONCLUSIONS: Although 12-month adjuvant capecitabine did not demonstrate superior DFS to that of 6-month, the observed better RFS and OS in the 12-month treatment period could be of value in selected cases.

Biweekly S-1 plus oxaliplatin (SOX) reintroduction in previously treated metastatic colorectal cancer patients (ORION 2 study): a phase II study to evaluate the efficacy and safety.

BACKGROUND: The reintroduction of oxaliplatin as a third-or-later-line regimen has been a promising option for patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy including oxaliplatin. In this single-arm phase II study, we evaluated the efficacy of biweekly SOX, which is the combination of oxaliplatin reintroduction and S-1, as a third-or-later-line treatment. METHODS: Patients with mCRC who had previously received prior chemotherapy including oxaliplatin and irinotecan and were planned to receive the reintroduction of oxaliplatin were enrolled. Oxaliplatin (85 mg/m2) with/without bevacizumab (5 mg/kg) was given intravenously on day 1. Oral S-1 was administered on day 2-8 at a dose of 40-60 mg (calculated according to the body surface area) twice a day. Cycles were repeated every 2 weeks. The primary endpoint was the progression-free survival (PFS); our hypothesis was that the median PFS would be 3.5 months with a minimum threshold above 2.0 months. The secondary endpoints included the adverse events (AEs), response rate and overall survival (OS). RESULTS: A total of 41 patients from 12 institutes were enrolled. The median PFS and OS survival were 3.3 months (95% confidence interval [CI] 2.7-4.2) and 10.1 months (8.3-14.6), and response rate and disease control rate were 10.0% and 65.0%, respectively. Grade 3 AEs included thrombocytopenia (5.0%), anorexia (5.0%), pneumonia (5.0%) and fatigue (5.0%). There were no cases of grade 4 AEs or treatment-related death. CONCLUSION: Biweekly SOX regimen with reintroduction of oxaliplatin could be exploitable as the third- and/or later-line treatments for patients with mCRC.

[A Case of an Elderly Patient with Multiple Lung Metastases of Postoperative Pancreatic Cancer in Whom Lung Metastases Were Controlled by Biweekly Dose-Down Administration of Gemcitabine].

An 80-year-old woman was diagnosed with pancreatic head cancer, and pancreaticoduodenectomy was performed. Twelve months after the operation, chest CT scans showed the presence ofmultiple nodules in both the lungs. Because ofthe potential negative side effects of anti-cancer drugs, the patient underwent chemotherapy with dose-down biweekly adminis- tration ofgemcitabine (1,000mg/day/body≒750mg/m2. Chest CT examination every 2-3 months revealed no rapid increase in multiple tumors. Nineteen months after starting gemcitabine therapy, there was an elevation in tumor marker and a gradual increase in lung metastases. We performed combination chemotherapy with nab-paclitaxel. However, owing to side effects, only 2 courses of nab-paclitaxel were administered, and the therapy was switched to only gemcitabine administration. Later, respiratory distress accompanied by pleural effusion developed, and the patient died of the original disease 27 months after recurrence. Here, we report a case ofan elderly patient with multiple lung metastases ofpancreatic cancer in whom lung metastases were controlled by biweekly dose-down administration of gemcitabine.

Surgical outcome of laparoscopic hepatic resection for hepatocellular carcinoma: A matched case-control study with propensity score matching.

BACKGROUND: Although the number of reports on laparoscopic hepatic resection (LHR) has increased, studies of long-term outcomes regarding tumor recurrence and patient survival compared to the conventional open approach are limited. We evaluated the long-term survival and feasibility of LHR in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A retrospective analysis was performed on the clinical data of patients who underwent hepatic resection for primary HCC between August 2000 and December 2013. The patients were divided into the LHR or open hepatic resection (OHR) groups. To control for selection bias in the two groups, propensity score matching was used at a 1:1 ratio based on the following covariates: Child-Pugh grade, tumour size, tumour number and tumour location. Following propensity score matching, thirty patients were included in the LHR group and thirty were included in the OHR group. RESULTS: The respective disease-free survival rates at 1 year, 3 years and 5 years were 78.4%, 61.1% and 38.9%, respectively, for the LHR group, and 89.3%, 57.5% and 47.9%, respectively, for the OHR group (P = 0.89). Also, the overall survival rates at 1 year, 3 years and 5 years were 96.4%, 68.2% and 62.5%, respectively, for the LHR group and 100.0%, 95.8% and 72.3%, respectively, for the OHR group (P = 0.44). CONCLUSIONS: According to our study, using propensity score matching, LHR for HCC is safe, feasible and comparative, with good oncologic results.

Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer: Regimen of 1 week on, 1 week off.

A phase II study of S-1 plus leucovorin (LV) given in a 4-week schedule (2 weeks' administration followed by 2 weeks' rest) for patients with untreated metastatic colorectal cancer (mCRC) showed that the combination was effective, but grade 3 toxicities (diarrhea, stomatitis and anorexia) occurred at a relatively high rate. In this phase II study, we evaluated the efficacy and safety of a 2-week schedule of S-1 plus LV. Patients with mCRC received oral S-1 (40-60 mg) and LV (25 mg) twice daily for 1 week, followed by 1 week's rest. Treatment was repeated until disease progression or unacceptable toxicity. The primary endpoint was response rate. The pharmacokinetics of S-1 and LV in Chinese patients were evaluated on day 1 of the first cycle. Seventy-three patients were enrolled in Japan and China. Of 71 eligible patients, the response rate was 53.5%, and the disease control rate was 83.1%. Median progression-free survival and median overall survival were 6.5 and 24.3 months, respectively. The incidences of grade 3 toxicities were diarrhea 8.3%, stomatitis 8.3%, anorexia 2.8% and neutropenia 9.7%. There were no treatment-related deaths. The pharmacokinetics profiles of S-1 plus LV in Chinese patients were similar to those in Japanese patients. This 2-week schedule of S-1 plus LV showed good efficacy and better tolerability than the 4-week schedule. This therapy will be the base regimen for mCRC to be added by other cytotoxic or molecular-targeted drugs. The optimized treatment schedule for S-1 plus LV was 1 week on and 1 week off.

Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.

Multicenter randomized phase II clinical trial of oxaliplatin reintroduction as a third- or later-line therapy for metastatic colorectal cancer-biweekly versus standard triweekly XELOX (The ORION Study).

BACKGROUND: The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen. METHODS: The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m(2)) twice daily on days 1-14 and oxaliplatin (130 mg/m(2)) on day 1 every 21 days (Q3W group) or capecitabine (2,000 mg/m(2)) twice daily on days 1-7 and oxaliplatin (85 mg/m(2)) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs). RESULTS: A total of 46 patients were enrolled in the trial-22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3-4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively. CONCLUSION: There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative.

Level of arterial ligation in sigmoid colon and rectal cancer surgery.

BACKGROUND: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate, and it is unclear whether this confers a survival advantage. Accordingly, the IMA may be ligated at a point just below the origin of the left colic artery (LCA) "low tie" combined with lymph node dissection (LND) around the origin of the IMA (low tie with LND). However, no study has investigated the detailed prognostic results between "high tie" and "low tie with LND." The aim of this study was to assess the utility of "low tie with LND" on survival in patients with sigmoid colon or rectal cancer. METHODS: A total of 189 sigmoid colon or rectal cancer patients who underwent curative operation from 1997 to 2007 were enrolled in this study. The patient's medical records were reviewed to obtain clinicopathological information. Overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method, with differences assessed using log-rank test. RESULTS: Forty-two and 147 patients were ligated at the origin of the IMA (high tie) and just below the origin of the LCA combined with LND around the origin of the IMA (low tie with LND), respectively. No significant differences were observed in the complication rate and OS and RFS rates in the two groups. Further, no significant difference was observed in the OS and RFS rates in the lymph node-positive cases in the two groups. CONCLUSIONS: "Low tie with LND" is anatomically less invasive and is not inferior to "high tie" with prognostic point of view.

The rare BRAF VK600-601E mutation as a possible indicator of poor prognosis in rectal carcinoma ­ a report of a case.

BACKGROUND: The BRAF V600E mutation is reportedly associated with inferior survival among colon cancer patients. Here we report a patient with rectal cancer who carried the novel BRAF mutation VK600-601E, which has analogous molecular functions to those of the conventional BRAF mutation V600E, and may have potential as a prognostic marker for colorectal cancer (CRC). CASE PRESENTATION: The present 65-year-old male patient was diagnosed with recurrent rectal adenocarcinoma (stage II by AJCC TNM staging 7th edition) 14 months after surgery and was treated with modified FOLFOX6 (fluorouracil, leucovorin, and oxaliplatin), radiation, and FOLFIRI (fluorouracil, leucovorin, and irinotecan). The tumor progressed before further treatment could be initiated, resulting in death after 15 months. This survival period was similar to the median overall survival among patients with metastatic CRC and BRAF mutations who were treated with the FOLFIRI regimen with or without cetuximab. CONCLUSIONS: Thus, the BRAF VK600-601E mutation may lead to an aggressive clinical course in CRC patients suffering from rapid progression and potential resistance to multiple therapeutic modalities.

Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study.

BACKGROUND: The clinical benefit of cetuximab combined with oxaliplatin-based chemotherapy remains under debate. The aim of the present multicenter open-label Phase II study was to explore the efficacy and safety of biweekly administration of cetuximab and mFOLFOX-6 or XELOX as first-line chemotherapy in patients with metastatic colorectal cancer. METHODS: Sixty-two patients with previously untreated KRAS/BRAF wild-type metastatic colorectal cancer were recruited to the study between April 2010 and May 2011. Patients received one of two treatment regimens, either cetuximab plus mFOLFOX-6 (FOLFOX + Cmab) or cetuximab plus biweekly XELOX (XELOX + Cmab), according to their own preference. Treatment was continued until disease progression or the appearance of intolerable toxicities. The primary endpoint was response rate; secondary endpoints were progression-free survival, overall survival, disease control rate, dose intensity, conversion rate to surgical resection, and safety. RESULTS: The response rates in the FOLFOX + Cmab (n = 37) and XELOX + Cmab (n = 25) groups were 64.9 % (24/37) and 72.0 % (18/25), respectively. The median PFS in the FOLFOX + Cmab and XELOX + Cmab groups was 13.1 months (95 % confidence interval [CI] 12.1-17.5) and 13.4 months (95 % CI 10.1-17.9), respectively. Neutropenia was the most frequent grade 3/4 adverse event in both groups (33.9 %), followed by anorexia, acneiform eruption, skin fissure and paronychia. A waterfall plot of tumor diameter showed prominent shrinkage of the tumors in 88.7 % of patients. CONCLUSIONS: The results of the present study indicate that biweekly cetuximab plus mFOLFOX-6/XELOX is an effective and tolerable treatment regimen. Biweekly administration of cetuximab requires only one hospital visit every 2 weeks, and may become a convenient treatment option for patients with KRAS/BRAF wild-type metastatic colorectal cancer. TRIAL REGISTRATION: This study is registered with University Hospital Medical Information Network (UMIN 000003253 ). Registration date is 02/24/2010.

Capecitabine and oxaliplatin combined with bevacizumab are feasible for treating selected Japanese patients at least 75 years of age with metastatic colorectal cancer.

BACKGROUND: Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥ 75 years with mCRC. METHODS: This prospective, open-label phase II trial recruited patients aged ≥ 75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m(2) of oxaliplatin on day 1 of each cycle combined with 2000 mg/m(2) of oral capecitabine per day on days 1-14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival. RESULTS: Thirty-six patients (male 58%; median age 78 years; colon cancer 67%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3%) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2%) and neuropathy (13.9%). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1%). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7%, respectively. Median progression-free and overall survival times were 11.7 months (95% confidence interval, 8.0-13.4 months) and 22.9 months, respectively. CONCLUSION: XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥ 75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit.

The SOFT trial: a Phase III study of the dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine S-1 and oxaliplatin (SOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer.

A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.

[Relationship between Polymorphisms and the Efficacy of Cetuximab].

BACKGROUND AND OBJECTIVES: Cetuximab has shown efficacy in patients with metastatic colorectal cancer (mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC), mediated via the fragment c gamma receptors(FcgR)in mCRC. Since the establishment of KRAS mutations as a major negative predictor of efficacy, additional biomarkers have been found to be useful for the improvement of selection of patients likely to be responsive to cetuximab. We investigated the relationship between polymorphisms and the outcome of mCRC patients treated with cetuximab. METHODS: In this study, 57 patients were evaluated. The relationships of FcgR polymorphisms with response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: The FcgR polymorphisms were not significantly related to RR, PFS, and OS. Compared with the other haplotypes, the haplotype containing the 131H and 158V alleles was related to a lower RR (p=0.018). The diplotypes containing 131H and 158V alleles had significantly lower RR than the other diplotypes (p=0.038). CONCLUSION: Our data suggest that FcgR polymorphisms may be associated with the outcome of mCRC patients treated with cetuximab and FOLFIRI. However, these results are currently controversial, and detailed investigations are needed to confirm the relationship between FcgRs polymorphisms and cetuximab efficacy.

[A Case of Gastric Cancer Associated with Sjögren's Syndrome and Interstitial Pneumonia].

A 77-year-old man presented with poor appetite and dyspnea. A gastroendoscopy showed an advanced gastric cancer and a CT scan demonstrated diffuse interstitial infiltrative shadows in both lungs. Laboratory data showed high level of anti-SSA and anti-SSB antibodies, suggestive of interstitial pneumonia associated with Sjögren's syndrome. Although the levels of KL-6 and SP-D, markers of interstitial pneumonia, decreased after steroid and immunosuppressive therapy, the CT findings of interstitial pneumonia showed no remarkable change. Surgery was performed 2 months after the administration of prednisolone since the respiratory function had improved, allowing the administration of general anesthesia. A CT scan revealed remarkable improvement of the lung lesions after the surgery. Therefore, it is likely that Sjögren's syndrome and interstitial pneumonia manifested as paraneoplastic syndromes in the presented case.