The emerging emetogenicity of trifluridine/tipiracil (TAS­102) from patient self-reporting: a multicenter, prospective, observational study.

BACKGROUND: Trifluridine/tipiracil (TAS-102) is an oral anticancer drug with adequate efficacy in unresectable colorectal cancer, but frequently also induces chemotherapy-induced nausea and vomiting (CINV). To investigate the occurrence of CINV and antiemetic therapy in patients with colorectal cancer treated with TAS-102 (JASCC-CINV 2001). METHODS: We conducted a multicenter, prospective, observational study in patients with colorectal cancer who received TAS-102 without dose reduction for the first time. Primary endpoint was the incidence of vomiting during the overall period. Secondary endpoints were the incidence of nausea, significant nausea, anorexia, other adverse events (constipation, diarrhea, insomnia, fatigue, dysgeusia) and patient satisfaction. Patient diaries were used for primary and secondary endpoints. All adverse events were subjectively assessed using PRO-CTCAE ver 1.0. and CTCAE ver 5.0. RESULTS: Data from 100 of the 119 enrolled patients were analyzed. The incidence of vomiting, nausea, and significant nausea was 13%, 67%, and 36%, respectively. The incidence of vomiting in patients with and without prophylactic antiemetic therapy were 20.8% and 10.5%, respectively. Prophylactic antiemetics were given to 24% of patients, of whom 70% received D2 antagonists. Multivariate Cox proportional hazards analysis showed that experience of CINV in previous treatment tended to be associated with vomiting (hazard ratio [HR]: 7.13, 95% confidence interval [CI]: 0.87-58.5, P = 0.07), whereas prophylactic antiemetic administration was not (HR: 1.61, 95 CI: 0.50-5.21, P = 0.43). With regard to patient satisfaction, the proportion of patients who were "very satisfied," "satisfied," "slightly satisfied" or "somewhat satisfied" was 81.8%. CONCLUSIONS: The low incidence of vomiting and high patient satisfaction suggest that TAS-102 does not require the use of uniform prophylactic antiemetic treatments. However, patients with the experience of CINV in previous treatment might require prophylactic antiemetic treatment.

Randomized phase II study of SOX+B-mab versus SOX+C-mab in patients with previously untreated recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study).

BACKGROUND: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. METHODS: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. RESULTS: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). CONCLUSIONS: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. TRIAL REGISTRATION: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920.

Multicentre cohort study of the impact of percutaneous coronary intervention on patients with concurrent cancer and ischaemic heart disease.

BACKGROUND: The incidence of concurrent cancer and ischaemic heart disease (IHD) is increasing; however, the long-term patient prognoses remain unclear. METHODS: Five-year all-cause mortality data pertaining to patients in the Osaka Cancer Registry, who were diagnosed with colorectal, lung, prostate, and gastric cancers between 2010 and 2015, were retrieved and analysed together with linked patient administrative data. Patient characteristics (cancer type, stage, and treatment; coronary risk factors; medications; and time from cancer diagnosis to index admission for percutaneous coronary intervention [PCI] or IHD diagnosis) were adjusted for propensity score matching. Three groups were identified: patients who underwent PCI within 3 years of cancer diagnosis (n = 564, PCI + group), patients diagnosed with IHD within 3 years of cancer diagnosis who did not undergo PCI (n = 3058, PCI-/IHD + group), and patients without IHD (n = 27,392, PCI-/IHD- group). Kaplan-Meier analysis was used for comparisons. RESULTS: After propensity score matching, the PCI + group had better prognosis (n = 489 in both groups, hazard ratio 0.64, 95% confidence interval 0.51-0.81, P < 0.001) than the PCI-/IHD + group. PCI + patients (n = 282) had significantly higher mortality than those without IHD (n = 280 in each group, hazard ratio 2.88, 95% confidence interval 1.90-4.38, P < 0.001). CONCLUSIONS: PCI might improve the long-term prognosis in cancer patients with IHD. However, these patients could have significantly worse long-term prognosis than cancer patients without IHD. Since the present study has some limitations, further research will be needed on this important topic in cardio-oncology.

Efficacy and safety of tolvaptan in patients with malignant ascites: a phase 2, multicenter, open-label, dose-escalation study.

OBJECTIVE: This phase 2 study examined the efficacy and safety of tolvaptan, an aquaretic drug, in the treatment of ascites associated with cancer. METHODS: In the dose-escalation phase, oral tolvaptan was initiated at a dose of 3.75 mg/day, and the dose was increased daily to 7.5, 15 and 30 mg/day. Dose escalation was terminated once the increase from baseline in the daily urine volume reached 500 ml, at which point the patient proceeded to the maintenance phase of 5-7 days. Improvement of ascites was determined primarily by reduction in body weight and ascitic fluid volume. RESULTS: The mean change from baseline in body weight was maintained below 0 kg throughout the study. The mean change (±standard deviation) from baseline in ascitic fluid volume at the end of treatment (EOT) was 237.45 ± 868.14 ml in 33 evaluable patients. Although an increase from baseline in ascitic fluid volume at the EOT was observed in 23 of 33 patients (maximum: 1589.3 ml, minimum: 3.83 ml), a reduction in ascitic fluid volume was observed in the remaining 10 patients (maximum: -2304.3 ml, minimum: -27.5 ml). The common treatment-emergent adverse events included vomiting (5 of 43 patients, 11.6%), abdominal distension, constipation, thirst, blood osmolarity increased and renal impairment (3 of 43 patients, 7.0% each). CONCLUSIONS: Tolvaptan seemed to have no definitive effect on reducing ascites; however, it might be effective in at least some cancer patients. No new safety concerns were identified at doses of 3.75-30 mg/day.

Long-term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer.

The long-term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment-refractory advanced esophageal cancer who participated in an open-label, single-arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand-1 (PD-L1) and CD8+ status of tumors and tumor-infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end-points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long-term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD-L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.

Correction: A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Practical guidance for the evaluation of disease progression and the decision to change treatment in patients with advanced gastric cancer receiving chemotherapy.

After failure of first-line chemotherapy with fluoropyrimidines and platinum compounds for advanced gastric cancer, second-line chemotherapy with ramucirumab plus paclitaxel, which elicits a durable response, and third-line or later chemotherapy with nivolumab have been shown to lead to a more favorable prognosis in advanced gastric cancer patients. As new and more effective drugs are now available, sequential chemotherapy would contribute to prolonged survival. From this point of view, the patient's disease course should be frequently monitored in order to adapt treatment regimens. This review summarizes the points to note in regard to radiological assessment, and discusses the integration of prognostic factors, tumor markers, and clinical symptoms that need to be taken into account to change treatment at an appropriate timing.

Correction to: Practical guidance for the evaluation of disease progression and the decision to change treatment in patients with advanced gastric cancer receiving chemotherapy.

The article Practical guidance for the evaluation of disease progression.

Evaluation of FOLFOX or CAPOX reintroduction with or without bevacizumab in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy (REACT study).

BACKGROUND: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy. METHODS: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m2, and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

Exploration of potential prognostic biomarkers in aflibercept plus FOLFIRI in Japanese patients with metastatic colorectal cancer.

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

A multicentre, prospective study of plasma circulating tumour DNA test for detecting RAS mutation in patients with metastatic colorectal cancer.

BACKGROUND: OncoBEAMTM RAS CRC kit using BEAMing technology is a circulating tumour DNA (ctDNA) test for detecting plasma RAS mutational status in metastatic colorectal cancer (mCRC). We conducted a multicentre, prospective study to investigate the concordance of the RAS mutational status between plasma ctDNA and tumour tissue DNA. METHODS: mCRC patients without prior anti-EGFR antibodies or regorafenib treatment were enroled. Plasma- and tissue-based RAS mutational status were determined by BEAMing, respectively. RESULTS: A total of 280 patients from eight institutions were eligible. The overall agreement between plasma- and tissue-based analyses was 86.4%, with a positive percent agreement of 82.1% and negative percent agreement of 90.4%. From logistic regression analysis, lung metastasis alone indicated the most significant factor associated with discordance. The agreement between plasma- and tissue-based analyses was 64.5% in patients with lung metastasis alone (n = 31) indicating lower amount of ctDNA. Among the cases with lung metastasis alone, all plasma- and tissue-based analyses were perfectly concordant in cases with ≥20 mm of maximum lesion diameter or ≥10 lesions. CONCLUSION: The clinical validity of OncoBEAMTM RAS CRC kit was confirmed. Careful attention should be paid for mCRC patients with lung metastases alone having fewer metastases or smaller diameter lesions.

A Phase I Study of Neoadjuvant Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) in Patients with Locally Advanced Rectal Cancer.

OBJECTIVES: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. METHOD: Patients received irinotecan and oxaliplatin (85 mg/m2) on day 1, and capecitabine (1,000 mg/m2 orally twice daily) on days 1-7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m2, were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. RESULTS: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m2. Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. CONCLUSIONS: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m2.

Phase 1 study of olaratumab plus doxorubicin in Japanese patients with advanced soft-tissue sarcoma.

Olaratumab, a monoclonal antibody targeting human platelet-derived growth factor receptor α, plus doxorubicin significantly improved overall survival in patients with advanced soft-tissue sarcoma (STS) in a prior phase 1b/2 randomized trial. Subsequent exposure-response analysis suggested that higher olaratumab exposures earlier might improve outcomes in patients at risk of early disease progression. This phase 1 study (3 treatment cohorts; minimum 6 patients each) investigated the safety, pharmacokinetics and antitumor activity of olaratumab plus doxorubicin in Japanese patients with STS. Patients received olaratumab 15 mg/kg on Days 1 and 8 during each 21-day cycle until disease progression. Patients in Cohort 3 received a 20 mg/kg loading dose of olaratumab in Cycle 1. Doxorubicin was administered for up to 6 cycles. Patients in Cohort 1 received doxorubicin 25 mg/m2 on Days 1, 2 and 3. Patients in Cohorts 2 and 3 received doxorubicin 75 mg/m2 on Day 1. One patient in Cohort 2 experienced a dose-limiting toxicity of Grade 3 febrile neutropenia. Most treatment-emergent adverse events were of mild and moderate severity, and were known doxorubicin toxicities. Olaratumab serum concentrations in Cohort 3 reached a steady-state exceeding the target level in Cycle 1. Partial response was confirmed in 4 patients (2 each in Cohorts 2 and 3). Olaratumab plus doxorubicin had an acceptable safety profile in patients with STS. A loading dose of olaratumab 20 mg/kg was effective for achieving minimum serum concentrations above the target trough level in Cycle 1.

Prolonged Neoadjuvant Therapy for Locally Advanced Pancreatic Cancer.

PURPOSE: The purpose of this study was to investigate if prolonged neoadjuvant therapy, for locally advanced pancreatic cancer could be used to identify those patients who could benefit from resection surgery. METHODS: Thirty-four patients with locally advanced pancreatic cancer invading the adjacent major arteries underwent chemoradiotherapy, followed by 6 months of systemic chemotherapy, unless their tumor was already resectable. After this combination treatment, surgical resection was performed on those patients with tumors judged to be at least borderline resectable. RESULTS: Reevaluation after chemoradiotherapy revealed that, at that stage, surgery was only possible for one case; resection was successfully performed. Following 6 months of systemic chemotherapy, a further 7 patients were diagnosed with borderline resectable lesions; 4 underwent surgery with no postoperative complications. The median survival time of the patients following surgery was 3.63 years; this was reduced to approximately a third in patients not undergoing surgery (1.01 years; p = 0.0005). CONCLUSIONS: For patients with locally advanced pancreatic cancer, prolonged neoadjuvant therapy was successfully used to select candidates that could benefit from surgical resection of their tumor. Resection significantly increased the long-term survival rate.

Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial.

BACKGROUND: Nivolumab is a human monoclonal IgG4 antibody that inhibits programmed cell death protein 1 (PD-1) expressed on activated T cells. We investigated the safety and activity of nivolumab in patients with treatment-refractory oesophageal cancer. METHODS: We did an open-label, single-arm, multicentre phase 2 study. Eligible patients had advanced squamous-cell carcinoma, adenosquamous-cell carcinoma, or adenocarcinoma of the oesophagus refractory or intolerant to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. Patients were treated with 3 mg/kg nivolumab given intravenously once every 2 weeks in 6-week cycles. The primary endpoint was centrally assessed objective response (the proportion of patients whose best response was complete or partial response), according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Adverse events and treatment-related adverse events (defined as events for which a causal relation to nivolumab could not be ruled out) were monitored throughout the study. The safety analysis was done in patients who received at least one dose of nivolumab, and drug activity was assessed in patients who received at least one dose of nivolumab and had at least one central assessment of tumour response. This study is registered with clinicaltrials.jp, number ONO-4538-07/JapicCTI-No.142422. Follow-up of patients is ongoing. FINDINGS: Between Feb 25 and Nov 14, 2014, 65 patients were enrolled, all with squamous-cell carcinoma. 64 patients were assessable for the primary endpoint as one patient was excluded due to having multiple primary cancers; all patients were assessable for safety. Median follow-up was 10·8 months (IQR 4·9-14·3). 11 (17%, 95% CI 10-28) of 64 patients had a centrally assessed objective response. Of the 65 patients assessed for adverse events, the most common grade 3 or 4 events were grade 4 dyspnoea and hyponatraemia (one [2%) patient each), grade 3 lung infection (five [8%] patients), grade 3 decreased appetite (two [3%] patients), grade 3 increased blood creatinine phosphokinase (two [3%] patients), and grade 3 dehydration (two [3%] patients). Serious adverse events that occurred during the study were lung infection (four [6%] patients), dehydration (two [3%]), interstitial lung disease (two [3%]), and hyponatraemia, dyspnoea, fatigue, abnormal hepatic function, diarrhoea, bile duct stenosis, gastroenteritis, pneumonia, oedema, and back pain (one [2%] patient each). There were no treatment-related deaths. INTERPRETATION: Nivolumab showed promising activity with a manageable safety profile. This drug could offer a potential new treatment approach for patients with treatment-refractory advanced squamous-cell carcinoma. FUNDING: Ono Pharmaceutical, Bristol-Myers Squibb.

Neoadjuvant CapeOx therapy followed by sphincter-preserving surgery for lower rectal cancer.

PURPOSE: This retrospective study investigates the safety of neoadjuvant chemotherapy with oxaliplatin capecitabine (CapeOx), followed by laparoscopic surgery, for lower rectal cancer, and its efficacy in preserving the sphincter. METHODS: Ten patients with diagnosed lower rectal cancer received three or four cycles of neoadjuvant CapeOx chemotherapy, prior to undergoing low anterior resection or intersphincteric resection, with total mesorectal excision. The primary outcomes were R0 resection and the rate of sphincter preservation. RESULTS: Nine patients completed CapeOx as scheduled and a partial response was achieved in four; thus, the overall response rate was 40% (n = 4/10). After surgical intervention, 80% of tumors displayed downstaging. Postoperative anastomosis leakage developed in one patient. The distance from the anal verge to the tumor increased by 60% (median 1.5 cm) after CapeOx treatment. The anal sphincter was preserved in all patients and all pathological distal and radial margins were negative (R0 resections). A pathological complete response was achieved in one patient. CONCLUSIONS: Neoadjuvant CapeOx chemotherapy is a promising approach, because it extended the distance from the anus to the tumor. Subsequent laparoscopic intervention for advanced lower rectal cancer could allow for safe preservation of the sphincter.

[Recurrence of Jejunal Carcinoma in the Ileum and Ovary - A Case Report].

Small bowel carcinoma has poor prognosis. The basis of treatment is surgical resection. There are no established guidelines for chemotherapy. We report a case in which we performed surgical resection of recurrent jejunal carcinoma. A 62-year-old woman underwent laparoscopic partial resection of the small intestine for primary jejunal carcinoma. The final diagnosis was T3N0M0, fStage II A. After 16 months of follow-up, she developed abdominal pain and vomiting. We diagnosed recurrence of jejunal carcinoma in the ileum and right ovary. Single-port laparoscopic small intestinal resection and right ovariectomy were performed. The patient underwent curative resection for recurrent lesions. The type of tumor in the ileum and right ovary was consistent with primary jejunal carcinoma by histopathological examination, and was diagnosed as recurrence of jejunal carcinoma. She is now on adjuvant chemotherapy with XELOX.

Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors.

Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).

Feasibility of Chemotherapy in Patients with Inflammatory Bowel Disease-Related Gastrointestinal Cancer.

BACKGROUND/AIMS: Long-standing inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is a known risk factor for gastrointestinal (GI) cancer, especially colorectal cancer (CRC). However, the feasibility of chemotherapy for IBD-related GI cancer is not well understood in terms of efficacy and adverse events, because there are fewer GI cancer patients with IBD than without IBD. METHODOLOGY: We retrospectively analyzed the medical records of eight IBD patients (CD = 5 and UC = 3) who received chemotherapy for IBD-related GI cancer between April 2003 and March 2013. RESULTS: The most common gastrointestinal adverse event was diarrhea (75%); 38% of patients experienced grade 3 diarrhea. Moreover, all grade 3 diarrhea occurred in patients with CD. The most common hematologic adverse events were anemia (75%), leukopenia (38%), and neutropenia (30%); 25% of patients experienced grade 3 neutropenia. The other severe adverse events were grade 3 AST and ALT elevation (13%). CONCLUSIONS: In this study, the incidence of grade 3 diarrhea was higher in patients with CD. The length and dysfunction of the small intestine is the most likely reason that diarrhea occurred more frequently in patients with CD.

Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.