Pathological Findings of the Host Immune Reaction in the Tumor Microenvironment of Gastroenteropancreatic Neuroendocrine Neoplasms.

Objective Neuroendocrine neoplasms (NENs) are rare and indolent diseases, but the efficacy of treatment without surgical resection is temporary and limited. Targeted immunotherapy is an important treatment strategy in several cancers. However, the tumor and host immune reactions in the NEN microenvironment are poorly understood. Therefore, we investigated the immune checkpoint system and host immune response in pathological NEN specimens. Methods The expression of the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1 was immunohistochemically detected in archival tissue samples obtained from 20 patients with gastroenteropancreatic NENs. We additionally assessed the expression of programmed death (PD)-1, PD-L1, and the tumor-infiltrating lymphocyte (TIL) markers CD8 and family of transcription factor P3 (FOXP3). Results All 20 NENs expressed the mismatch repair proteins MSH2, MSH6, PMS2, and MLH1. The PD-L1 and/or PD-1 expression in the tumor cells and/or TILs was confirmed in 75% of the cases. PD-1-, CD8-, and FOXP3-positive TILs were more frequently associated with PD-L1-positive tumors than with PD-L1 negative tumors (PD-1: 19.5 vs. 7.3, CD8: 18.1 vs. 7.1, FOXP3: 13.2 vs. 3.2, p=0.438, p=0.419, P=0.603, respectively). The number of cells positive for PD-1 tended to gradually increase in increasing grade of NENs but did not reach significance (Grade 1: 5.8, Grade 2: 10.2, NEC: 18.1, p=0.903). Conclusion NENs consistently express mismatch repair proteins but have a high expression of PD-L1 and/or PD-1 in the tumor microenvironment. NEC and PD-L1-positive NENs may be immunologically "hot" tumors, so an immunological approach may be an appropriate treatment strategy for these tumors.

[Differences in Concepts between Hospital Oncologists and Home Physicians].

Although many patients with terminal cancers desire to be cared for at home, frequently, such patients cannot be shifted to home care due to their unstable symptoms. In severe cases, emergency hospitalizations may be frequently required after introducinghome medical care. We report a case of makinghome medical care difficult due to repeated emergency hospitalizations despite of the patient's deep desire. Interviews were conducted with both the oncologist in charge of the case and a home physician, and their viewpoints were compared. For patients and their families to achieve desired livingconditions, it was considered necessary to give supportive medical care that meet their desires until the end of their lives as mutual viewpoints are taken in a good balance.

Sarcopenia is a reliable prognostic factor in patients with advanced pancreatic cancer receiving FOLFIRINOX chemotherapy.

BACKGROUND/OBJECTIVES: FOLFIRINOX is the reliable treatments for pancreatic cancer, but it has a relatively high toxicity and the selection of suitable patients for this regimen remains challenge. On the other hand, sarcopenia is one of the important prognostic factors of pancreatic cancer. The aim of this study was to investigate the effect of sarcopenia on overall survival (OS) and time to treatment failure (TTF) in patients with pancreatic cancer who received FOLFIRINOX. METHODS: Clinical data of consecutive patients treated with FOLFIRINOX at our institution from 2011 to 2017 was retrospectively reviewed. Skeletal muscle index (SMI) and adipose tissue index (ATI) at the third lumbar spine level was calculated from computed tomography (CT) images. The association between clinical factors (SMI and ATI), and OS and TTF were determined using univariate and multivariate analyses. RESULTS: We assessed 82 patients. The median OS of sarcopenia and the non-sarcopenia patients were 11.3 and 17.0 months, respectively (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.43-4.32; p = 0.001). Median TTF was 3.0 and 6.1 months in the sarcopenia and the non-sarcopenia patients, respectively (HR, 1.67; 95% CI, 1.03-2.71; p = 0.032). Multivariate analyses revealed that sarcopenia (HR, 1.37; 95% CI, 1.01-1.87; p = 0.045) was an independent prognostic factor of OS. High ATI (p = 0.022) and sarcopenic obesity (p = 0.008) were significantly associated with hematologic toxicity. CONCLUSIONS: Sarcopenia is an independent indicator of poor prognosis in patients with pancreatic cancer who received FOLFIRINOX, while ATI and sarcopenic obesity predicted severe hematologic toxicity.

[Combination Therapy of Oxycodone and Tapentadol Was Effective for Intractable Pain Caused by Breast Cancer Bone Metastasis - A Case Report].

A 52-year-old woman had been prescribed oral medication of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and oxycodone for intractable pain associated with thoracic metastasis of breast cancer. However, the pain control was poor. Although pregabalin and gabapentin were used as supplementary analgesics, they could not be continued because of their side effects. Based on the noradrenalin reincorporation-inhibiting action of tapentadol, a combination therapy of tapentadol and oxycodone was introduced and satisfactory pain control was achieved. No side effects from the combined opioids were observed. This finding indicates the potential of administrating a combination therapy of m-opioid receptor agonists(such as morphine, oxycodone, and fentanyl)with tapentadol, which has a noradrenaline reincorporation-inhibiting action, as an effective remedy for alleviating intractable pain complicated with neuropathic pain.

[Fentanyl Citrate Sublingual Tablets Were Effective in Relieving Symptoms of Akathisia - A Case Report].

Akathisia is a condition wherein sitting calmly and quietly is impossible, with a representative complaint of restless legs. It is generally assumed to be caused by anti-dopamine activity. In severe cases, it has been known to result in suicide attempt. We reported a case of drug-induced akathisia with difficulty in oral intake, in which fentanyl citrate sublingual tablets were found to be effective in relieving symptoms. The patient was a female aged 50's who had a gastric cancer with peritoneal dissemination causing pain and vomiting. Palliative care was requested for management of symptoms. Metoclopramide and haloperidol were administered for vomiting. However, because of the complaints of restless legs, the case was diagnosed as drug-induced akathisia. Fentanyl citrate sublingual tablets were then administered for pain management, resulting in temporary improvement of akathisia symptoms.

[Usefulness of Suvorexant for Complicated Delirium in Cancer Patients Who Experience Sleep Disturbance during Hospitalization].

We investigated the usefulness of suvorexant for complicated delirium in patients with cancer who experience sleep disturbance during hospitalization. Nine patients with malignant tumors complicated with symptoms of delirium and insomnia were included in this study; their palliative care was managed by the palliative care team of our hospital for a period of one year from April 2016 to March 2017. A retrospective follow-up study was then conducted. The Japanese version of DRS-R98 was used to evaluate the severity of the patient's delirium. The total severity score of DRS-R98 significantly decreased after the administration of suvorexant when compared to the score before its administration(6.66±1.73 vs 10±3.20, p=0.0031). In addition, suvorexant did not exhibit any harmful effects. Our results indicate that suvorexant was useful in alleviating delirium symptoms in cancer patients who experience sleep disturbance.

[Assessing Patient Factors Influencing the Discontinuation of Opioids after Intra-Arterial Chemotherapy for Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for oral cancer induces the complication of mucositis. Although the associated pain is controlled using opioids, major questions from patients in clinical practice are as follows:(1)the mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration, and(2)patient factors enabling the discontinuation of opioids. The purpose of this study was to clarify these points. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who discontinued opioids, and the other who did not. Clinical backgrounds and data were compared between the 2 groups. The mean number of days from the completion of superselective intra-arterial chemoradiation therapy to the discontinuation of opioid administration was 51±34.4 days. The absence of diabetes and deliria during treatment were determined as factors contributing to the discontinuation of opioids.

[Patient Factors Enabling the Decannulation of the Gastrostomy Tube after Superselective Intra-Arterial Chemoradiation Therapy for Locally Advanced Oral Cancer - A Retrospective Study].

Superselective intra-arterial chemoradiation therapy for locally advanced oral cancer induces complications such as mucositis, which impedes oral intake. Thus, at our hospital, a gastrostomy is performed in almost all patients during the treatment period to ensure the presence of an alternative administration route for nutrition and drugs. The purpose of this study was to calculate the mean number of days from completion of superselective intra-arterial chemoradiation therapy to the decannulation of gastrostomy, and extract patient factors for the decannulation. A retrospective follow-up study was conducted from April 2016 to March 2017 on patients who underwent superselective intra-arterial chemoradiation therapy at our department of oral surgery. The patients were divided into 2 groups:one who was decannulated and the other who did not. Clinical backgrounds and data were compared between the 2 groups. In the group with the decannulation, the mean period from treatment completion to the decannulation was 132±51.6 days. Heavy alcohol consumption, absence of haphalgesia before treatment, and possible securement of the opening with the breadth of 3 fingers, were determined as factors contributing to the decannulation of gastrostomy tube.

Clinical Usefulness of Somatostatin Receptor Scintigraphy in Japanese Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND/AIMS: Somatostatin receptor (SSTR) scintigraphy (SRS) is the standard imaging modality for evaluation of gastroenteropancreatic neuroendocrine tumor (GEP-NET) in Western countries. However, this modality was not approved in Japan until recently. The purpose of this study was to evaluate the clinical efficacy of SRS for detecting GEP-NET in Japanese patients. METHODS: Japanese patients with advanced GEP-NET were enrolled and evaluated by the SRS and CT. We also compared SRS and immunohistochemical expression of SSTR type 2a (SSTR2a). RESULTS: We enrolled 16 patients and the primary sites were the pancreas in 9, the stomach in 1, the small intestine in 2, the colon in 3, and unknown in 1. SRS showed positive findings in 3 (100%) of grade 1 (G1) and in 12 (92.3%) of grade 2 (G2) lesions. In the liver, SRS and CT detected lesions in 13 and 14 cases, respectively. The concordance rate of SSTR2a expression with SRS findings was 93.8% in the whole body and 92.9% in the liver. CONCLUSIONS: SRS could detect almost all of G1 and G2. SRS could be useful to detect lesions, with a high concordance rate with CT and pathological findings. We confirmed that SRS is a useful and reliable modality for Japanese patients.

Effect of FOLFIRINOX as second-line chemotherapy for metastatic pancreatic cancer after gemcitabine-based chemotherapy failure.

BACKGROUND: This study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity, and efficacy of second-line chemotherapy with FOLFIRINOX after gemcitabine (GEM)-based chemotherapy failure in metastatic pancreatic cancer (MPC). METHODS: We studied 18 histopathologically proven MPC patients. The schedule was 85 mg/m oxaliplatin, irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-fluorouracil (5-FU) as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion biweekly. The dose of irinotecan was defined as follows: level 0: 100 mg/m, level 1: 125 mg/m, level 2: 150 mg/m, and level 3: 180 mg/m. The doses of other drugs were fixed. The primary endpoint of phase II study was the response rate (RR). RESULTS: We initially evaluated 6 patients in a phase I study. One patient developed neutropenia and 1 patient developed hyperglycemia and severe infection. Accordingly, level 1 was chosen as the MTD. According to a phase II study, the RR was 22.2% and the disease control rate was 61.1%. The progression-free survival and overall survival were 2.8 (range, 0.7-19.1) and 9.8 (2.4-19.8) months, respectively. The most common severe adverse event was neutropenia (66.7%). Febrile neutropenia occurred in 1 (5.6%) case. CONCLUSION: The recommended dose was 85 mg/m oxaliplatin, 100 mg/m irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-FU as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion. These results indicate that second-line FOLFIRINOX is a marginally effective treatment for GEM-based chemotherapy failure cases.

Sorafenib Monotherapy in a Patient with Unresectable Hepatic Epithelioid Hemangioendothelioma.

A 49-year-old Japanese man had multiple huge masses (max. size 60 mm diameter) in his liver. These tumors were pathologically diagnosed by tumor biopsy as epithelioid hemangioendotheliomas of the liver. In this case, multiple liver tumors existed in both lobes. Also this patient did not agree to receive surgical resection including liver transplantation. Chemotherapy with sorafenib at a dose of 400 mg/body twice a day was started. About 6 months later, CT findings revealed that these tumors were shrinking slightly; 33 months later, the tumors obviously showed a partial response in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). Also 60 months later, the partial response continued with sorafenib monotherapy.

S-1 and irinotecan with or without bevacizumab versus 5-fluorouracil and leucovorin plus oxaliplatin with or without bevacizumab in metastatic colorectal cancer: a pooled analysis of four phase II studies.

PURPOSE: S-1, a novel oral prodrug of 5-fluorouracil (5-FU), and irinotecan with or without bevacizumab is known to be effective in metastatic colorectal cancer (mCRC). However, it is not clear whether S-1 and irinotecan confers benefits compared to 5-FU and leucovorin plus oxaliplatin (FOLFOX) in patients with mCRC. Our aim was to compare the efficacy and safety of these regimens. METHODS: We analyzed 187 patients with previously untreated mCRC who were enrolled in four phase II studies: SIR (S-1 and irinotecan, n = 40), SIRB (S-1 and irinotecan with bevacizumab, n = 51), FOLFOX (5-FU and leucovorin plus oxaliplatin, n = 46), and STOX (stop-and-go strategy of modified FOLFOX-6 with bevacizumab, n = 50). We evaluated efficacy and safety between SIR/SIRB and FOLFOX/STOX. RESULTS: Baseline characteristics were similar in the two groups composed of SIR/SIRB (n = 91) and FOLFOX/STOX (n = 96). The overall response rates were not significantly different between the two groups (65% in SIR/SIRB vs. 52% in FOLFOX/STOX, p = 0.125). The median progression-free survival was 10.9 months in SIR/SIRB versus 12.1 months in FOLFOX/STOX (p = 0.59). The median overall survival was 27.3 months in SIR/SIRB versus 26.8 months in FOLFOX/STOX (p = 0.97). Gastrointestinal adverse events were the most common toxicities in SIR/SIRB, while neutropenia and sensory neuropathy were the most common toxicities in FOLFOX/STOX. CONCLUSIONS: S-1 and irinotecan with or without bevacizumab was well tolerated and showed similar response rates and survival compared to the FOLFOX regimen. This combination should be considered as an experimental first-line treatment for mCRC.

Early effects of oral administration of esomeprazole and omeprazole on the intragastric pH.

BACKGROUND/AIMS: The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral dose of a proton pump inhibitor, esomeprazole 20 mg and omeprazole 20 mg. METHODOLOGY: A total of 14 Helicobacter pylori-negative male subjects participated in this study. Intragastric pH was monitored continuously for 6 hours after a single oral dose of omeprazole 20 mg and a single oral dose of esomeprazole 20 mg. Each administration was separated by a 7-day washout period. RESULTS: During the 6-hour study period, the average pH after administration of esomeprazole was higher than that after the administration of omeprazole. Also during the 6-hour study period, each of pH > 2, 3, 3.5, 4, and 5 was maintained for a longer duration after administration of esomeprazole 20 mg than after administration of omeprazole 20 mg (median: 75.4% vs. 53.8%, p = 0.0138; 52.1% vs. 33.4%, p = 0.0188; 45.8% vs. 28.2%, p = 0.0262; 42.5% vs. 20.7%, p = 0.0414; 35.8% vs. 11.6%, p = 0.0262; respectively). CONCLUSIONS: In Helicobacter pylori-negative healthy male subjects, single oral administration of esomeprazole 20 mg increased the intragastric pH more rapidly than single oral administration of omeprazole 20 mg.

Endoscopic inside stent placement is suitable as a bridging treatment for preoperative biliary tract cancer.

BACKGROUND: Endoscopic biliary stenting (EBS) is one of the most important palliative treatments for biliary tract cancer. However, reflux cholangitis arising from bacterial adherence to the inner wall of the stent must be avoided. We evaluated the use of EBS above the sphincter of Oddi to determine whether reflux cholangitis could be prevented in preoperative cases. METHODS: Fifty-seven patients with primary biliary tract cancer were retrospectively recruited for the evaluation of stent placement either above (n = 25; inside stent group) or across (n = 32; conventional stent group) the sphincter of Oddi. We compared the stent patency periods prior to the time of surgical resection. RESULTS: The preoperative periods were 96.3 days in the conventional stent group and 96.8 days in the inside stent group (P = 0.979). Obstructive jaundice and/or acute cholangitis occurred in 7 patients (28.0%) in the inside stent group and in 15 patients (46.9%) in the conventional stent group during the preoperative period (P = 0.150). The average patency periods of the stents were 85.2 days (range, 13-387 days) for the inside stent group and 49.1 days (range, 9-136 days) for the conventional stent group (log-rank test: P = 0.009). The mean numbers of re-interventions because of stent occlusion were 0.32 for the inside stent group and 1.03 for the conventional stent group (P = 0.026). Post-endoscopic retrograde cholangiopancreatography complications occurred in 2 patients in the inside stent group and 4 patients in the conventional stent group (P = 0.516). Postoperative liver abscess occurred in 1 patient in the inside stent group and 5 patients in the conventional stent group (P = 0.968). Inside stent placement was the only significant preventative factor associated with stent obstruction based on univariate (hazard ratio [HR], 0.286; 95% confidence interval [CI], 0.114-0.719; P = 0.008) and multivariate (HR, 0.292; 95% CI, 0.114-0.750; P = 0.011) analyses. CONCLUSION: Temporary plastic stent placement above the sphincter of Oddi is a better bridging treatment than conventional stent placement in preoperative primary biliary tract cancer.

Effects of ramosetron oral disintegrating tablets on gastric emptying: crossover study using the 13C-acetic acid breath test.

BACKGROUND/AIMS: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13C-acetic acid breath test. METHODOLOGY: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13C acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in the calculated parameters, including T 1/2, T lag, GEC or ß and κ, were observed between the two test conditions. CONCLUSIONS: The present study revealed that 0.1 mg ramosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

A phase I/II study of XELIRI plus bevacizumab as second-line chemotherapy for Japanese patients with metastatic colorectal cancer (BIX study).

BACKGROUND: Capecitabine is used mainly with oxaliplatin to treat metastatic colorectal cancer (mCRC). Results from capecitabine plus irinotecan (XELIRI) with or without bevacizumab (BV) have been reported in Europe but not in Japan. Consequently, the safety and efficacy of XELIRI plus BV in Japanese patients with mCRC were assessed in a single-arm phase II study. METHODS: Eligible patients had had prior chemotherapy containing BV for mCRC and wild-type or heterozygous UGT1A1. Therapy in each 21-day treatment cycle consisted of capecitabine (800 mg/m(2) twice daily on days 1-15), irinotecan (200 mg/m(2) on day 1), and BV (7.5 mg/kg on day 1). The primary endpoint was dose-limiting toxicity in phase I and progression-free survival (PFS) in phase II. RESULTS: A total of 34 patients (6 in phase I, 28 in phase II) were enrolled from May 2010 to June 2011. Baseline characteristics included a median age of 60 years (range: 22-74 years) for 24 men and 10 women. No dose-limiting toxicities appeared in phase I. Median PFS was 240 days (95% confidence interval: 179-311 days). Overall response rate was 18.1%, and the disease-control rate was 90.9%. The incidence of adverse events frequently associated with irinotecan and capecitabine were neutropenia (any grade, 55.9%; grade 3 or 4, 11.8%), diarrhea (any grade, 50%; grade 3 or 4, 5.9%), and hand-foot syndrome (any grade, 61.8%; grade 3 or 4, 5.9%). CONCLUSION: Our results suggest that XELIRI plus BV is well tolerated and effective as a second-line treatment for mCRC in Japanese patients. This regimen could be especially appropriate for patients resistant to oxaliplatin-based regimens.

Colorectal laterally spreading tumors show characteristic expression of cell polarity factors, including atypical protein kinase C λ/ι, E-cadherin, ß-catenin and basement membrane component.

Colorectal flat-type tumors include laterally spreading tumors (LSTs) and flat depressed-type tumors. The former of which shows a predominant lateral spreading growth rather than an invasive growth. The present study examined the morphological characteristics of LSTs, in comparison with polypoid- or flat depressed-type tumors, along with the expression of atypical protein kinase C (aPKC) λ/ι, a pivotal cell polarity regulator, and the hallmarks of cell polarity, as well as with type IV collagen, ß-catenin and E-cadherin. In total, 37 flat-type (24 LSTs and 13 flat depressed-type tumors) and 20 polypoid-type colorectal tumors were examined. The LSTs were classified as 15 LST adenoma (LST-A) and nine LST cancer in adenoma (LST-CA). An immunohistochemical examination was performed on aPKC λ/ι, type IV collagen, ß-catenin and E-cadherin. The LST-A and -CA showed a superficial replacing growth pattern, with expression of ß-catenin and E-cadherin in the basolateral membrane and type IV collagen along the basement membrane. In addition, 86.6% of LST-A and 55.6% of LST-CA showed aPKC λ/ι expression of 1+ (weak to normal intensity staining in the cytoplasm compared with the normal epithelium). Furthermore, ~45% of the polypoid-type adenomas showed 2+ (moderate intensity staining in the cytoplasm and/or nucleus) and 66.7% of the polypoid-type cancer in adenoma were 3+ (strong intensity staining in the cytoplasm and nucleus). A statistically significant positive correlation was observed between the expression of aPKC λ/ι and ß-catenin (r=0.842; P<0.001), or type IV collagen (r=0.823; P<0.001). The LSTs showed a unique growth pattern, different from the expanding growth pattern presented by a polypoid tumor and invasive cancer. The growth characteristics of LST appear to be caused by adequate coexpression of ß-catenin, type IV collagen and aPKC λ/ι.

[A case of post-operative recurrence of pancreatic cancer in the residual pancreas treated by resection of the residual pancreas following radiological complete response achieved with second-line FOLFIRINOX].

A 65-year-old woman with carcinoma of the pancreatic body underwent Whipple's operation. After surgery, adjuvant chemotherapy with gemcitabine alone, and S-1 combined with gemcitabine was conducted. But one year later, a recurrent tumor was detected in the pancreatic tail. We administered FOLFIRINOX treatment for the recurrent tumor. After 6 courses, FOLFIRINOX treatment resulted in a partial response, and after 9 courses, a radiological complete response was achieved. We could then perform total pancreatotectomy and resection of the metastatic liver tumor. FOLFIRINOX as a second-line treat- ment was effective and safe in this case. In cases of gemcitabine and/or S-1 failure, FOLFIRINOX treatment should be considered.

Phase I study of combination therapy with irinotecan, leucovorin, and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for advanced colorectal cancer in Japanese patients.

BACKGROUND: Irinotecan, leucovorin, and bolus and continuous-infusion 5-fluorouracil administered every two weeks (FOLFIRI regimen) is active in patients with metastatic colorectal cancer. However, the efficacy and toxicity of this regimen in Japanese patients with metastatic colorectal cancer remain unknown. PATIENTS AND METHODS: We investigated the maximum tolerated dose, dose-limiting toxicity, and recommended dose at Step 1. Twenty-one patients with metastatic colorectal cancer were enrolled in Step 1. At the five dose levels, fixed doses of bolus 5-fluorouracil (400 mg/m(2)) and leucovorin (200 mg/m(2)) were administered in combination with escalating doses of irinotecan from 120-180 mg/m(2) with 46-h continuous infusion of 5-fluorouracil 2000-3000 mg/m(2) every two weeks. In Step 2, an additional 24 patients received the recommended doses determined in Step 1, and safety and antitumor efficacy were evaluated in terms of tumor response. RESULTS: No dose-limiting toxicities were observed at dose levels 1-4. Four out of eight patients experienced a dose-limiting toxicity at level 5; therefore, this level was considered the maximum tolerated dose. Consequently, the recommended doses were determined to be 180 mg/m(2) of irinotecan and 2,400 mg/m(2) of 5-fluorouracil in continuous i.v. infusion. At this level (FOLFIRI-180), National Cancer Institute common terminology criteria grade 3-4 neutropenia, leukopenia, and vomiting were common but manageable. Other hematological and non-hematological toxicities were mild. Seven out of 23 response-assessable patients achieved an objective response (response rate=30%). CONCLUSION: This FOLFIRI-180 regimen is manageable and effective in Japanese patients with metastatic colorectal cancer.