Real-world treatment costs of first-line treatment for metastatic colorectal cancer: a survey of the JCOG colorectal cancer study group.

BACKGROUND: Although treatment outcomes for metastatic colorectal cancer (mCRC) have dramatically improved over the past few decades, drug costs have also significantly increased. This study aimed to investigate which first-line treatment regimens for mCRC are actually used (frequency) in Japanese practice and at what cost. METHODS: We collected data on patients with mCRC who received first-line treatment at 37 institutions of the Japan Clinical Oncology Group Colorectal Cancer Study Group from July 2021 to June 2022, and calculated the cost of regimens. The cost per month of each regimen was estimated based on standard usage, assuming a patient with a weight of 70 kg and a body surface area of 1.8 m2. We categorized the regimens into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month), and others (<500 000 JPY/month). RESULTS: The study included 1880 participants, 24% of whom were ≥ 75 years. Molecular targeted containing regimens were received by 78% of the patients. The most frequently used regimen was the doublet regimen (fluoropyrimidine with either oxaliplatin or irinotecan) plus bevacizumab (43%), followed by doublet plus cetuximab or panitumumab (21%). The cost of molecular targeted drugs-containing regimens (ranging from 85 406 to 843 602 JPY/month) is much higher than that of only cytotoxic drug regimens (ranging from 17 672 to 51 004 JPY/month). About 16% received high-cost treatments that included panitumumab-containing regimens and pembrolizumab (17% of patients aged ≤74 years and 11% of patients aged ≥75 years). CONCLUSION: About 16% of mCRC patients received first-line treatment with regimens costing >500 000JPY/month, and molecular targeted drugs being the main drivers of cost.

Oxaliplatin Added to Fluoropyrimidine/Bevacizumab as Initial Therapy for Unresectable Metastatic Colorectal Cancer in Older Patients: A Multicenter, Randomized, Open-Label Phase III Trial (JCOG1018).

PURPOSE: Doublet chemotherapy with fluoropyrimidine (FP) and oxaliplatin (OX) plus bevacizumab (BEV) is a standard regimen for unresectable metastatic colorectal cancer (MCRC). However, the efficacy of adding OX to FP plus BEV (FP + BEV) remains unclear for older patients, a population for whom FP + BEV is standard. We aimed to confirm the superiority of adding OX to FP + BEV for this population. METHODS: This open-label, randomized, phase III trial was conducted at 42 institutions in Japan. Patients with unresectable MCRC age 70-74 years with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 and those 75 years and older with ECOG-PS 0-2 were randomly assigned (1:1) to an FP + BEV arm or an OX addition (FP + BEV + OX) arm. Fluorouracil plus levofolinate calcium or capecitabine was declared before enrollment. The primary end point was progression-free survival (PFS). The study was registered in the Japan Registry of Clinical Trials (identifier: jRCTs031180145). RESULTS: Between September 2012 and March 2019, 251 patients were randomly assigned to the FP + BEV arm (n = 125) and the FP + BEV + OX arm (n = 126). The median age was 80 and 79 years in the respective arm. The median PFS was 9.4 months (95% CI, 8.3 to 10.3) in the FP + BEV arm and 10.0 months (9.0 to 11.2) in the FP + BEV + OX arm (hazard ratio [HR], 0.84 [90.5% CI, 0.67 to 1.04]; one-sided P = .086). The median overall survival was 21.3 months (18.7 to 24.3) in the FP + BEV arm and 19.7 months (15.5 to 25.5) in the FP + BEV + OX arm (HR, 1.05 [0.81 to 1.37]). The proportion of any grade ≥3 adverse events was higher in the FP + BEV + OX arm (52% v 69%). There was one treatment-related death in the FP + BEV arm and three in the FP + BEV + OX arm. CONCLUSION: No benefit of adding OX to FP + BEV as first-line treatment was demonstrated in older patients with MCRC. FP + BEV is recommended for this population.

Updated Efficacy Outcomes of Anti-PD-1 Antibodies plus Multikinase Inhibitors for Patients with Advanced Gastric Cancer with or without Liver Metastases in Clinical Trials.

PURPOSE: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. PATIENTS AND METHODS: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. RESULTS: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors. CONCLUSIONS: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.

Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603).

PURPOSE: This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS: Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS: Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability-high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair-proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION: The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

Chemoradiotherapy with FOLFOX for esophageal squamous cell cancer with synchronous rectal cancer: Four case reports and a literature review.

Chemoradiotherapy (CRT) is a valuable treatment option for localized esophageal cancer. Conventional baseline chemotherapy for this type of cancer includes cisplatin and fluorouracil. Recently, CRT with leucovorin-fluorouracil-oxaliplatin (FOLFOX) has become popular due to its convenience and lower toxicity. In Japan, the use of oxaliplatin for esophageal cancer is not yet approved, so experience with this treatment is limited to cases with colorectal cancer. As such patients are not usually included in clinical trials, little is known on the efficacy and safety of this treatment for this patient subpopulation, and treatment generalization in Japan is not allowed. We herein share our experience with CRT and FOLFOX for cases with esophageal cancer and synchronous rectal cancer at our institution. The clinical data of 4 patients who were treated for esophageal cancer with CRT/FOLFOX at our hospital between 2007 and 2016, who also had synchronous rectal cancer, were retrieved and analyzed. All the patients were male and had esophageal squamous cell cancer and synchronous rectal cancer. The median patient age was 68 years (range, 65-77 years). One patient received neoadjuvant CRT followed by surgery, and the other 3 patients received definitive CRT for esophageal cancer. FOLFOX was administered biweekly during radiotherapy (41.4-60 Gy). All 4 patients completed the treatment schedule and responded to CRT. No patients experienced progression of rectal cancer during treatment. Notably, 1 patient also achieved a complete response (CR) of rectal cancer after CRT for esophageal cancer. Moreover, 2 patients without dysphagia were treated as outpatients and achieved a CR. Encephalopathy was the only reported grade 3 adverse event. Although the present study included a limited number of cases, the findings suggest that CRT with FOLFOX may be a valuable option for the treatment of patients with esophageal squamous cell cancer and synchronous rectal cancer.

Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise: A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402).

BACKGROUND: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib-related fatigue and/or malaise. PATIENTS AND METHODS: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1-28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute's CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in-cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). RESULTS: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade ≥2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). CONCLUSION: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise.

First-line bolus 5-fluorouracil plus leucovorin for peritoneally disseminated gastric cancer with massive ascites or inadequate oral intake.

BACKGROUND: There are few chemotherapeutic options for advanced gastric cancer with severe disseminated peritoneal metastases, which are usually accompanied by ascites. Bolus 5-fluorouracil (5-FU) plus leucovorin therapy has been widely used against gastrointestinal malignancies, with resulting mild toxicities. METHODS: We retrospectively analyzed the efficacy and safety of first-line chemotherapy with bolus 5-FU plus l-leucovorin in 30 advanced gastric cancer patients who had massive ascites and/or inadequate oral intake. This therapy consisted of 5-FU (600 mg/m2 IV bolus) plus l-leucovorin (250 mg/m2 2-h IV infusion) administered on a 6 weeks on/2 weeks off schedule. RESULTS: Among all the patients, 26 (87%) were unable to eat and 12 (40%) had massive ascites. Major grade 3 or 4 adverse events were neutropenia (17%), nausea (7%), fatigue (7%), and diarrhea (3%); no treatment-related deaths were observed. The median progression-free survival and overall survival (OS) were 2.4 months [95% confidence interval (CI), 0.6-4.1] and 6.0 months (95% CI, 2.1-9.9), respectively. Objective improvement in oral intake was seen in 7 patients (27%). Improvement in ascites occurred in 9 (39%) of 23 patients. In multivariate analyses, the presence of both massive ascites and inadequate oral intake was significantly associated with worse OS (hazard ratio, 5.25; 95% CI, 1.61-17.1). The median OS for patients (n = 22) without this factor was 7.2 months (95% CI, 4.2-10.3). CONCLUSION: Our study suggests that bolus 5-FU plus l-leucovorin therapy is feasible and has clinical activity as palliative therapy in patients with severe peritoneal metastases from gastric cancer.

Correlation between human epidermal growth factor receptor 2 expression level and efficacy of trastuzumab beyond progression in metastatic gastric cancer.

There is currently no clinical data regarding the efficacy of trastuzumab treatment for the progression of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) occurring during trastuzumab-based chemotherapy. The aim of this study was to retrospectively examine the clinical benefits of trastuzumab for HER2-positive AGC patients who progressed during first-line trastuzumab-based chemotherapy. Among the 108 patients treated with trastuzumab combined with fluoropyrimidine and cisplatin as first-line therapy, 46 HER2-positive AGC patients who received cytotoxic agents with or without trastuzumab subsequent to disease progression were included. Of these, the efficacy and safety outcomes of 26 patients who continued trastuzumab were compared with those of the 20 patients who discontinued trastuzumab. No difference in response rate (18.2 vs. 15.8%, P=1.00) was observed between the two groups. Progression-free survival (PFS) time was numerically longer in the chemotherapy combination with trastuzumab group than in the chemotherapy combination without trastuzumab group (median, 4.0 vs. 2.3 months), with no significance [hazard ratio (HR), 0.63; P=0.14]. In the subset analysis, continuation of trastuzumab significantly improved PFS time in selected subgroups of patients with tumors exhibiting HER2 expression scores of 3+ (HR, 0.41; P=0.04), intestinal-type histology (HR, 0.32; P<0.01), and a first PFS time of >6 months (HR, 0.44; P=0.04). The survival times for the trastuzumab beyond progression (TBP) and non-TBP groups were similar (HR, 1.06; P=0.88), with equivalent overall survival times in the subgroups with immunohistochemistry scores of 3+ (HR, 0.97; P=0.94), intestinal-type histology (HR, 0.53; P=0.19), and a first PFS time of >6 months (HR, 0.62; P=0.31). There were no differences in the incidence rates of toxicity, including cardiac dysfunction, between the two groups. The study results suggest that selected HER2-positive AGC patients may benefit from trastuzumab continuation during first progression, and further prospective studies are warranted.

A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma.

BACKGROUND: Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. PATIENTS AND METHODS: This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20-80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. RESULTS: Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31-79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7-40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0-10.2) and 17.3 months (95% CI 11.7-19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. CONCLUSIONS: Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

Lymph Node Ratio as a Risk Factor for Recurrence After Adjuvant Chemotherapy in Stage III Colorectal Cancer.

BACKGROUND: Although several markers, including the lymph node ratio (LNR), have been proposed as a clinically prognostic tool for colorectal cancer (CRC), it remains unclear which markers have the most relevance in determining recurrence following adjuvant chemotherapy for stage III CRC. METHODS: Independent risk factors for recurrence-free survival (RFS) were retrospectively determined using the Cox proportional hazard model in 360 stage III CRC patients and validated using an independent cohort comprising 172 stage III CRC patients. RESULTS: The LNR was independently associated with RFS (HR, 1.96; 95% CI, 1.11 to 3.28; P = 0.020). A higher LNR value was significantly associated with recurrence, microsatellite stable, and shorter time to recurrence. A combination of the LNR with pre-chemotherapy CEA and CA19-9, other independent risk factors, provided accurate risk stratification of RFS and conferred additional information on recurrence within each stage III CRC subgroup, which was then validated in an independent cohort. A beneficial effect in patients at risk of recurrence, and a reduced effect in patients at low risk, was exhibited by the addition of oxaliplatin to 5-fluorouracil-based adjuvant chemotherapy. CONCLUSION: A higher LNR is one of the most aggressive phenotypes with recurrence risk following adjuvant chemotherapy for stage III CRC.

[Five-Year Recurrence-Free Survival after mFOLFOX6 Administration, Right Hemicolectomy, and Lymphadenectomy for Portal Venous Tumor Thromboembolism].

A 71-year-old woman was admitted for fever and appetite loss. She was diagnosed with ascending colon cancer, with portal vein tumor thromboembolism extending to the portosplenic junction. This was deemed unresectable despite the absence of distant metastasis. She underwent 16 courses of mFOLFOX6 therapy, and because the effect of chemotherapy was PR, right hemicolectomy with high ligation of the ileocolic vessels and the right branch of the middle colic vessels was performed. The tumor stage was yp-T3N1bM0, StageⅢB with a few remaining cancer cells in the portal venous system. Staging after chemotherapy effect was Grade 1a. Postoperatively, 13 courses of mFOLFOX6 were administered. A repeat CT scan showed lymph node recurrence along the SMV, which was subsequently resected again. After the second operation, 9 courses of the DeGramont regimen was administered and discontinued. Five years after the last operation, the patient remains well and without any recurrences. Colonic carcinoma with portal venous tumor thromboembolism has been reported in 9 cases, including ours. Among these, 8 cases involved the ascending colon. Seven of the affected patients were female while 3 were poorly differentiated adenocarcinoma. None of the other patients, except for our case, reported a 5 year patient survival rate without recurrence.

[Recurrence of Rectal Cancer with Submucosal Invasion in the Bone and Lymph Nodes 89 Months after Surgery--A Case Report].

A woman in her 60s showed positive results on a fecal occult blood test and consulted her doctor. Early-stage cancer of the lower rectum was diagnosed, and a transanal local excision was performed. Histopathological examination revealed that the depth of submucosal invasion was ≧1,000 mm, and the submucosal invasive part of the tumor was a poorly differentiated adenocarcinoma. Therefore, she was referred to our hospital for additional resection. Intersphincteric resection was performed 11 months after the initial operation. The cancer stage was T1N0M0, Stage Ⅰ(UICC 7th edition), and the cancer did not recur. The patient visited our hospital again, 78 months after the additional resection, because of left hip-joint pain. Positron-emission tomography revealed fluorodeoxyglucose uptake in the left acetabulum, para-aortic lymph nodes, and left external iliac lymph nodes; these findings indicated recurrence of the rectal cancer. The patient received radiation therapy (57 Gy) and FOLFIRI; bevacizumab was added from the third course onward. The therapy reduced the size of the tumor recurrence in the bone. This was a rare case of rectal cancer with submucosal invasion that showed recurrence in the bone and lymph nodes 78 months after the additional resection.

Combined microsatellite instability and BRAF gene status as biomarkers for adjuvant chemotherapy in stage III colorectal cancer.

BACKGROUND: The clinical relevance of combined microsatellite instability (MSI) and BRAF status for adjuvant treatment in stage III colorectal cancer (CRC) remains elusive. METHODS: In 405 patients with curatively resected stage III CRC, the prognostic value of combined MSI and BRAF status was assessed in four groups, as follows: high-levels of microsatellite instability (MSI-H) and BRAF-wild type, MSI-H and BRAF-mutation, microsatellite stable (MSS) and BRAF-wild type, and MSS and BRAF-mutation. RESULTS: Combined MSI and BRAF status provided significant prognostic stratification of disease-free survival (DFS), and was independently associated with worse DFS. The MSI-H and BRAF-wild type group had similar outcomes to stage II CRC patients, despite no benefit from 5-FU monotherapy. Further, patients in the MSS and BRAF-wild type group with stage IIIA CRC had favorable outcomes to 5-FU monotherapy, similar to those with stage II CRC. In contrast, 5-FU monotherapy was insufficient among patients in the MSS and BRAF-wild type group with stage IIIB or IIIC CRC or patients in the MSS and BRAF-mutation group with stage III CRC. CONCLUSIONS: The combination of MSI and BRAF status serves as both a prognostic and predictive marker and may provide much-needed guidance during the planning of therapeutic strategies.

Inverse effect of mucinous component on survival in stage III colorectal cancer.

BACKGROUND: Although mucinous adenocarcinoma (MAC) is has been recognized as a separate entity in colorectal cancer (CRC), adenocarcinoma with a mucinous component (ACM) remains poorly understood. METHODS: The association of MAC and ACM with disease-free survival (DFS) and overall survival (OS) was examined using the Cox proportional hazard model in 425 consecutive stage III CRCs. RESULTS: Compared with conventional adenocarcinoma (CAC), patients with MAC exhibited independently worse DFS (hazard ratio [HR], 2.64; 95% CI, 1.21-5.80; P = 0.014) and OS (HR, 3.56; 95% CI, 1.53-8.30; P = 0.003). Unexpectedly, ACM was significantly associated with worse OS than CAC (P = 0.002), despite having a similar DFS to CAC. Further, ACM patients after recurrence exhibited significantly worse OS than CAC patients (P < 0.001), similar to MAC. CONCLUSIONS: Although ACM is similar to CAC with regard to estimated risk of recurrence, the outcome is extremely poor once recurrence occurs and is identical to MAC; one of the most aggressive phenotypes of stage III CRC. Thus, both MAC and ACM are adverse prognostic factors for OS.

Everolimus dramatically improves glycemic control in unresectable metastatic insulinoma: a case report.

Hypoglycemia poses a significant management challenge in patients with unresectable metastatic insulinoma. A 57-year-old woman with pancreatic neuroendocrine tumor with multiple liver metastases was referred to our institution. During the clinical course of pancreatic neuroendocrine tumor, she had experienced palpitations, cold sweats and faintness between meals that indicated her tumors had attained the characteristics of an insulinoma, and her quality of life was impacted by frequent hypoglycemic episodes which could not be prevented by conventional therapies. Shortly after the approval of everolimus for pancreatic neuroendocrine tumor in Japan, we began oral administration at 10 mg per day, which produced a rapid and substantial improvement in glycemic control. The serum insulin level decreased dramatically despite the tumor size remaining stable on computed tomography evaluation. Despite a dose reduction of everolimus to 5 mg per day in response to the adverse reaction of interstitial pneumonitis and a subsequent moderate increase in the serum insulin level, the patient has maintained normoglycemia for a year. Everolimus might represent the treatment of choice for unresectable insulinoma in terms of not only tumor stabilization but also glycemic control.

[Therapeutic strategy for recurrent gastric cancer and efforts aimed at finding a cure].

Recurrent gastric cancer, in general, is an incurable systemic disease for which the standard of care is systemic chemotherapy. Combination treatment with fluoropyrimidine plus platinum and the addition of trastuzumab for patients with human epidermal growth factor receptor 2(HER2)-positive tumors are widely accepted standard regimens. Fluoropyrimidines include 5-fluorouracil(5-FU), S-1, and capecitabine. There has been an accumulation of data showing the non-inferiority of oxaliplatin to cisplatin. Moreover, the importance of salvage chemotherapy has also been proven in prospective studies. However, retrospective analyses still indicate that the 5-year survival rates associated with metastatic gastric cancer are only a few percent with chemotherapy. To improve survival, newer triplet regimens, such as a combination of docetaxel, cisplatin, and S-1(DCS)and modified folinic acid, 5-FU, oxaliplatin, and irinotecan(modified FOLFOXIRI), are now under clinical investigation. Despite the limitations of retrospective data, surgical resection for gastric cancer liver metastases appears to be beneficial in carefully selected patients. Currently, the implication of surgical resection for metastatic gastric cancer is being evaluated in clinical trials. These efforts will result in further clinical advances with tailored treatment strategies.

A phase I study of intravenous aflibercept with FOLFIRI in Japanese patients with previously treated metastatic colorectal cancer.

Aflibercept, a recombinant fusion protein, is a potent inhibitor of vascular endothelial growth factor (VEGF)-A, VEGF-B, and the placental growth factor (PlGF). The present study was an open-label, sequential-cohort, dose-escalation trial of intravenous aflibercept administered every 2 weeks in combination with 5-fluorouracil, levofolinate, and irinotecan (FOLFIRI) in patients with previously treated metastatic colorectal cancer (mCRC). We aimed to assess the safety, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary efficacy of the combination therapy to determine the recommended phase II dose (RPTD) for Japanese patients. Two doses of aflibercept (2.0 and 4.0 mg/kg) were set, and DLTs were evaluated in the first 2 cycles. The subjects comprised 16 patients (n = 3 and 13 for 2.0 and 4.0 mg/kg aflibercept, respectively) who received a total of 149 cycles of aflibercept with FOLFIRI. No DLTs were observed at both doses. The frequent adverse events encountered were leukopenia, neutropenia, anemia, diarrhea, fatigue, decreased appetite, stomatitis, dysphonia, nausea, and epistaxis. The most common grade 3/4 adverse events were neutropenia for both doses and hypertension for the 4.0 mg/kg dose. Free aflibercept exposure increased with the dose, whereas exposure to VEGF-bound aflibercept remained similar at both doses. The response rate and progression-free survival at 4.0 mg/kg was 8.3 % and 7.59 months, respectively. In conclusion, the combination of aflibercept and FOLFIRI was well tolerated at both doses. The RPTD of aflibercept in combination with FOLFIRI for Japanese patients with mCRC was determined to be 4.0 mg/kg every 2 weeks. ClinicalTrials.gov identifier: NCT00921661.

Amrubicin for the treatment of neuroendocrine carcinoma of the gastrointestinal tract: a retrospective analysis of five cases.

PURPOSE: A standard chemotherapy regimen for neuroendocrine carcinoma of the gastrointestinal tract (GI-NEC) has not been established. Treatment usually consists of platinum doublets, consistent with the standard treatment for small-cell lung cancer (SCLC), with which it shares clinicopathological similarities. Here, we retrospectively examined responses of five GI-NEC patients treated with amrubicin chloride (AMR) which has shown activity against SCLC as salvage therapy. METHODS: Five patients with histologically proven unresectable GI-NEC in whom previous chemotherapy regimens had failed were treated with AMR, a synthetic anthracycline with potent topoisomerase II inhibition. RESULTS: Primary tumors were located in the esophagus in three patients, anus in one, and colon in one. AMR was administered intravenously at 35-40 mg/m(2) on days 1-3 every 3 weeks for a median of six treatment cycles (range, 2-8). Although all patients had received one to four previous chemotherapy regimens, including cisplatin doublets, three of five achieved objective responses to AMR. All three had esophageal NEC in relapse following combination treatment with irinotecan plus cisplatin. The most common adverse events of ≥ grade 3 were neutropenia (75%), anemia (60%), thrombocytopenia (20%), and febrile neutropenia (20%). CONCLUSIONS: Single-agent AMR achieved objective responses in three of five patients with GI-NEC. This compound may be a candidate for prospective evaluation in a larger series.

A prospective randomized trial of lafutidine vs rabeprazole on post-ESD gastric ulcers.

AIM: To compare the effects of rabeprazole and lafutidine on post-endoscopic submucosal dissection (ESD) gastric ulcers. METHODS: Patients with gastric tumors indicated for ESD were prospectively studied. After ESD, all patients were treated with intravenous omeprazole for the first 3 d. Patients were then randomly assigned to oral lafutidine or rabeprazole. Ulcer size, ulcer size reduction rate, and ulcer stage were evaluated 4 wk later. Occurrence of complication was monitored throughout the 4-wk period. RESULTS: Sixty five patients were enrolled in the study, and 60 patients were subjected to the final analysis. In the lafutidine group (30 lesions in 29 patients), initial and 4-wk post-ESD ulcer sizes were 33.3 ± 9.2 and 10.5 ± 4.8 mm, respectively. In the rabeprazole group (34 lesions in 31 patients), the values were 34.7 ± 11.3 and 11.8 ± 6.7 mm, respectively. Ulcer size reduction rates in lafutidine and rabeprazole groups were 32.3% and 33.5%, respectively (P = 0.974). Ulcer stage 4 wk post-ESD did not differ significantly between the two groups (P = 0.868). Two cases in the rabeprazole group and no cases in the lafutidine group developed ulcer bleeding during the oral dose period, although the difference of bleeding rate between the two groups was not statistically significant (P = 0.157). CONCLUSION: Lafutidine and rabeprazole have equivalent therapeutic effects on post-ESD gastric ulcers.