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.

Long-Term Follow-up Data of a Multi-Institutional Phase-2 Study of S-1/oxaliplatin and Bevacizumab Therapy in Patients with Advanced Colorectal Cancer: The HiSCO-02 Study.

Oral fluoropyrimidines (FUs) have certain advantages over intravenous FUs, such as longer intervals between outpatient visits, no requirement for central venous port (CVP) implantation, and lower incidence of neutropenia. We previously reported the efficacy of S-1/oxaliplatin (SOX) with bevacizumab therapy as a first-line treatment for advanced colorectal cancer (CRC) in a prospective phase-II multi-institutional clinical trial (HiSCO-02 study). However, our prognostic data at the time lacked a sufficient observation period. Herein, we analyze the longer-term follow-up data, focusing on the status of eventual CVP implantation via an open-label, non-randomized, multicenter study. This study enrolled 55 patients (mean age, 64 years), of whom 43 died (41 of primary cancer). The median overall survival was 22.7 months (95% CI: 20.1-34.7 months). Post-treatment regimens after failure of first-line treatment were initiated in 43 patients; CPT11-based regimens were selected in most cases, and other oral FU combinations in nine. CVP was implanted in 35 patients prior to first-line treatment; eleven of the remaining 20 patients did not require CVP implantation. In conclusion, we report here the final prognostic update of the Phase II clinical trial examining the efficacy of SOX plus bevacizumab therapy, the results of which confirm the clinical efficacy of this regimen.

Poor association between dihydropyrimidine dehydrogenase (DPYD) genotype and fluoropyrimidine-induced toxicity in an Asian population.

OBJECTIVE: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)-induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype-based FP dosing strategy. PATIENTS AND METHODS: The current study aimed to investigate their impact on FP-related toxicities in an Asian population using genome-wide association study (GWAS) data set from 1364 patients with colon cancer. RESULTS: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP-related toxicities; however, none of these variants revealed a significant correlation with FP-related toxicities. CONCLUSION: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP-related toxicities in an Asian population.

Primary tumor location as a predictor of survival in patients with RAS wild-type colorectal cancer who receive molecularly targeted drugs as first-line therapy: a multicenter real-world observational study by the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. METHODS: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. RESULTS: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07). CONCLUSION: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.

Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report.

BACKGROUND: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

Clinical implications of using both fluoropyrimidine and paclitaxel in patients with severe peritoneal metastasis of gastric cancer: A post hoc study of JCOG1108/WJOG7312G.

BACKGROUND: In the JCOG1108/WJOG7312G trial, a combination (FLTAX) of 5-fluorouracil (FU) /leucovorin (FL) and paclitaxel (PTX) did not show superiority in overall survival (OS) to FL in untreated patients with severe peritoneal metastasis of gastric cancer (GC-SPM), some of whom received second-line chemotherapy with PTX after FL. This post hoc study aimed to investigate the clinical implications of using both FU and PTX either sequentially or in combination for patients with GC-SPM. METHODS: A total of 94 patients were enrolled and categorized into the following three subgroups: patients treated with (1) FL followed by PTX (FL/PTX, N = 25), (2) FL followed by best supportive care (BSC) (FL/BSC, N = 21), and (3) FLTAX (N = 48). OS was compared between the subgroups. By comparing baseline factors between the FL/PTX and FL/BSC subgroups, factors preventing the sequential use of PTX (SUP) were explored using logistic regression model. The efficacy of FL and FLTAX was compared according to the presence of risk factors preventing SUP. RESULTS: The FL/PTX subgroup showed better and equivalent OS compared to the FL/BSC (median 7.8 vs. 2.0 months, p < 0.01) and FLTAX (median 7.8 vs. 8.0, p = 0.49) subgroups, respectively. Glasgow Prognostic Score 2 and initially unresectable disease were identified as risk factors preventing SUP. Absence of both risks predicted SUP with a sensitivity of 13% and a specificity of 100%, whereas absence of any risks predicted SUP with a sensitivity of 67% and a specificity of 62%. FLTAX showed better OS than FL in patients with one or two of these risks but worse OS in those with none. CONCLUSIONS: Although sequential use of FU and PTX showed equivalent survival to FLTAX in patients with GC-SPM, FLTAX might be preferable given the difficulty in selecting patients likely to receive sequential use at the initiation of first-line chemotherapy.

Safety and efficacy of S-1 plus oxaliplatin 130 mg/m2 combination therapy in patients with previously untreated HER2-negative unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: a phase II trial (KSCC1501A).

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI).

PURPOSE: FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. METHODS: Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). RESULTS: Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8-77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. CONCLUSIONS: FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.

Capecitabine Plus Bevacizumab for Cardiac Metastasis of Sigmoid Colon Cancer: Case Report and Literature Review.

BACKGROUND/AIM: Right ventricular cardiac metastasis from colorectal cancer (CRC) is rare and clinically silent. There is no standardised treatment. To date, only twelve cases have been reported in the literature. This is a case report and literature review of right ventricular cardiac metastasis from CRC. CASE REPORT: A 75-year-old woman with a history of CRC treated with sigmoidectomy followed by liver and lung metastasectomy presented with a right ventricle tumour. Biopsy showed metastatic adenocarcinoma not suitable for resection because multiple lung metastases coexisted. The metastases were controlled for a prolonged duration by chemotherapy with capecitabine plus bevacizumab. According to the review of 13 cases, the median age of metastatic CRC that involves the right ventricle is 71 years and the primary site is half the colon and rectum. Half of cases have non-cardiac metastases at cardiac metastasis diagnosis. Chemotherapy is more suitable than resection in cases with metastases other than heart because resection of the right ventricle has a high risk. CONCLUSION: Cardiac right ventricular metastasis from CRC can be controlled by capecitabine plus bevacizumab.

Morphologic response to chemotherapy containing bevacizumab in patients with colorectal liver metastases: A post hoc analysis of the WJOG4407G phase III study.

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

A placebo-controlled, double-blind, randomized study of recombinant thrombomodulin (ART-123) to prevent oxaliplatin-induced peripheral neuropathy.

PURPOSE: The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators. RESULTS: Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred. CONCLUSION: ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.

Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G).

BACKGROUND: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study. PATIENTS AND METHODS: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety. RESULTS: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%). CONCLUSION: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.

Occurrence of Immunoglobulin G4-related Disease during Chemotherapy for Advanced Breast Cancer.

Immunoglobulin G4-related disease (IgG4-RD) is defined as an inflammatory lymphoproliferative disorder. The relationship between malignancies and IgG4-RD remains unclear. We herein present a case of IgG4-RD that occurred during chemotherapy for advanced breast cancer. In this case, it was challenging to determine which of these diseases was responsible for the patient's mediastinal lymphadenopathy. Lymphadenopathy with IgG4-RD was diagnosed by assessing the reactivity to corticosteroids, which were used as premedication in chemotherapy, over time. The administration of prednisolone, which was initiated to treat active IgG4-RD, led to stable systemic therapy for malignancy. It is imperative to assess the disease activity and consider each treatment.

Randomized, Phase II Study of Trastuzumab Beyond Progression in Patients With HER2-Positive Advanced Gastric or Gastroesophageal Junction Cancer: WJOG7112G (T-ACT Study).

PURPOSE: This study evaluated the continuous use of trastuzumab beyond progression (TBP) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. PATIENTS AND METHODS: Patients with HER2-positive advanced G/GEJ cancer refractory to first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Patients were randomly assigned to the paclitaxel (80 mg/m2, days 1, 8, and 15, every 4 weeks) or paclitaxel with trastuzumab (PT; initially 8 mg/kg followed by 6 mg/kg, every 3 weeks) arms. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate, and safety. Biomarkers such as HER2 expression status in tumor tissue after first-line treatment, HER2 amplification evaluated in serum cell-free DNA, and soluble HER2 levels were analyzed. RESULTS: Overall, 91 patients were allocated to the paclitaxel (n = 46) and PT (n = 45) arms. The median PFS in the paclitaxel and PT arms was 3.2 and 3.7 months, respectively (hazard ratio [HR], 0.91; 80% CI, 0.67 to 1.22; P = .33), and the median OS in both arms was 10 months (HR, 1.2; 95% CI, 0.75 to 2.0; P = .20). The overall response rates in the paclitaxel and PT arms were 32% and 33%, respectively (P = 1.00), and safety was comparable between the 2 arms. On exploratory analyses, HER2 positivity of tumor tissues was lost after first-line chemotherapy in 11 (69%) of 16 patients whose tumor tissues were available, and circulating HER2 DNA amplification was detected in 41 (60%) of 68 patients. However, no biomarkers associated with efficacy of TBP were found. CONCLUSION: The TBP strategy failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer, and no beneficial biomarkers were found.

Randomized phase II/III study of 5-fluorouracil/l-leucovorin versus 5-fluorouracil/l-leucovorin plus paclitaxel administered to patients with severe peritoneal metastases of gastric cancer (JCOG1108/WJOG7312G).

BACKGROUND: Oral fluoropyrimidine plus cisplatin is often not tolerated by patients with severe peritoneal metastases of gastric cancer. Combination of 5-fluorouracil (5-FU), l-leucovorin (l-LV), and paclitaxel (FLTAX) has promising activity for such patients. We conducted a phase II/III study comparing FLTAX with 5-FU/l-LV. METHODS: Eligibility criteria included: unresectable or recurrent gastric adenocarcinoma; 20-75 years; performance status (PS) 0-2; peritoneal metastases + ; massive ascites and/or inadequate oral intake; no prior chemotherapy. Patients were randomly assigned to receive 5-FU/l-LV or FLTAX. The primary endpoint of phase III was overall survival: UMIN000010949. RESULTS: We enrolled 101 patients. Early deaths occurred in patients with PS 2 having massive ascites and inadequate oral intake simultaneously; the protocol was amended to exclude such patients. Median survival times were 6.1 and 7.3 months for the 5-FU/l-LV and the FLTAX arms, respectively (HR 0.792; 80% CI 0.596-1.053; one-sided p = 0.1445). FLTAX arm had longer progression-free survival (PFS) [1.9 vs 5.4 months (HR 0.64; 95% CI, 0.43-0.96; p = 0.029)]. Grade 3/4 adverse events such as leucopenia and anorexia were more frequently observed in the 5-FU/l-LV arm. In the 5-FU/l-LV arm, two deaths were treatment-related. In the 5-FU/l-LV and FLTAX arms, 12 and 3 deaths occurred within 30 days after the last protocol treatment, respectively. CONCLUSIONS: Chemotherapy was indicated for patients with severe peritoneal metastases excluding patients with PS 2 having massive ascites and inadequate oral intake simultaneously. FLTAX did not confer a significant survival benefit but may be preferred because of longer PFS and acceptable toxicity.

Sinusoidal obstruction syndrome post-treatment with trastuzumab emtansine (T-DM1) in advanced breast cancer.

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Here, we present the cases of two patients with metastatic breast cancer who received T-DM1 monotherapy and developed noncirrhotic portal hypertension (NCPH). Patient 1 presented with ruptured gastric varices at 2 years and 5 months after T-DM1 treatment. Patient 2 presented with intrahepatic portal-hepatic venous shunt at 2 years and 6 months and portal-systemic shunt encephalopathy at 4 years and 11 months after T-DM1 treatment. In both the patients, liver biopsies revealed sinusoidal obstruction syndrome (SOS). T-DM1-induced hepatotoxicity can result from SOS. In long-term administration of T-DM1 the unfavorable events associated with chronic liver circulatory disorder due to SOS, such as NCPH, are concerning.

Multicenter phase II study of SOX plus trastuzumab for patients with HER2+ metastatic or recurrent gastric cancer: KSCC/HGCSG/CCOG/PerSeUS 1501B.

BACKGROUND: Trastuzumab (T-mab) combined with cisplatin and fluoropyrimidines is a standard first-line treatment for HER2+ advanced gastric cancer (AGC). We conducted the first phase II trial among four Japanese study groups to assess the efficacy and safety of T-mab + S-1 and oxaliplatin (T-SOX130) for HER2+ AGC or recurrent gastric cancer. METHODS: Patients with IHC 3+ or IHC 2+/FISH+ tumors received 80 mg/m2 (80-120 mg/day) oral S-1 on days 1-14, 130 mg/m2 intravenous oxaliplatin on day 1, and intravenous T-mab (8 mg/kg loading dose, 6 mg/kg thereafter) on day 1 of a 21-day cycle. The primary endpoint was centrally assessed response rate (RR). Adverse events were based on the Common Terminology Criteria for Adverse Events (CTCAE) Ver.4.0. RESULTS: We enrolled 42 patients from June 2015 to May 2016. Efficacy and safety analyses were conducted for 39 patients. The data cutoff was May 31, 2018. The confirmed RR was 82.1% (32/39; 90% CI 70.0-90.0); the disease control rate was 87.2% (34/39; 95% CI 73.3-94.4). Nine patients underwent curative surgery after T-SOX130. Median Time to treatment failure (TTF), Progression-free survival (PFS) and Overall survival (OS) was 5.7 (95% CI 4.6-7.0), 7.0 (95% CI 5.5-14.1), and 27.6 (95% CI 15.6-Not reached) months, respectively. Incidences of grade 3-4 adverse events > 10% were thrombocytopenia (17.9%), anorexia (17.9%), anemia (12.8%), neutropenia (10.3%), and hyponatremia (10.3%). CONCLUSIONS: T-SOX130 showed promising response and survival with a favorable safety profile and should be considered for patients with HER2+ AGC.

A single institution experience of the treatment of pancreatic ductal carcinoma: The demand and the role of radiation therapy.

We aimed to demonstrate a single institution experience of treatment of pancreatic ductal carcinoma and to identify the role of radiation therapy. We assessed all patients who were diagnosed with pancreatic ductal carcinoma from January 2011 to December 2017. A total of 342 patients were enrolled. Thirteen, 131, 36, and 162 patients had stage I, II, III, and IV disease, respectively (UICC TNM, 7th edition). Among the patients with stages I-III disease, 94 underwent surgery, and the median overall survival (OS) was 33 months. Of patients with stages I-III disease who were not suitable for surgery, 58 patients received chemotherapy, and the median OS was 12 months. Among them, 17 patients received chemoradiotherapy added on chemotherapy and their OS was significantly better than that of patients who received chemotherapy alone. Of patients with stage IV disease, 111 received chemotherapy, and the median OS was 6 months. This study evaluated the demand, role, and outcome of each treatment modality and demonstrated a single institution experience of treatment of pancreatic ductal carcinoma. The demand and role of radiation therapy remained small; however, radiation therapy might have some importance as a local treatment.