A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.

BACKGROUND: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. OBJECTIVE: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. METHODS: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. RESULTS: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). CONCLUSIONS: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. CLINICAL TRIAL REGISTRATION: jRCTs041190100.

[Case of a Patient with Cancer of Unknown Primary in the Poor Prognosis Group Who Had a Experienced a Beneficial Treatment Course].

A 47-year-old woman with general malaise and abdominal pain presented with multiple liver tumors and lymph node metastasis. She was diagnosed with small cell carcinoma on the basis of a lymph node biopsy; however, the primary lesion was not identified. Finally, we diagnosed her with cancer of unknown primary lesion and placed her in the poor prognosis group. Although her general condition was poor, she experienced a relatively good response to treatment for small cell carcinoma.

Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

Phase II Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 and Cisplatin for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Intraperitoneal chemotherapy is promising for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of intraperitoneal paclitaxel combined with S-1 and intravenous paclitaxel, the sensitivity analysis suggested clinical efficacy. Thus, attempts to combine intraperitoneal paclitaxel with other systemic therapies with higher efficacy have been warranted. We sought to explore the efficacy of intraperitoneal paclitaxel with S-1 and cisplatin. PATIENTS AND METHODS: Gastric cancer patients with peritoneal metastasis were enrolled in the phase II trial. In addition to the established S-1 and cisplatin regimen every 5 weeks, intraperitoneal paclitaxel was administered on days 1, 8, and 22 at a dose of 20 mg/m2. The primary endpoint was overall survival rate at 1 year after treatment initiation. Secondary endpoints were progression-free survival and toxicity. RESULTS: Fifty-three patients were enrolled and fully evaluated for efficacy and toxicity. The 1-year overall survival rate was 73.6% (95% confidence interval 59.5-83.4%), and the primary endpoint was met. The median survival time was 19.4 months (95% confidence interval, 16.1-24.6 months). The 1-year progression-free survival rate was 49.6% (95% confidence interval, 34.6-62.9%). The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (25%), anemia (30%), diarrhea (13%), and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in four patients. There was one treatment-related death. CONCLUSIONS: Intraperitoneal paclitaxel combined with S-1 and cisplatin is well tolerated and active in gastric cancer patients with peritoneal metastasis.

Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Updated Adjuvant Chemotherapy for Gastric Cancer.

Surgical resection is currently the best curative approach for gastric cancer (GC); however, the prognosis of patients with advanced GC remains poor even with curative resection. For this reason, perioperative chemotherapy has been combined with surgery to reduce the risk of postoperative recurrence. Standard perioperative chemotherapy for resectable advanced GC varies from region to region. Postoperative S-1 therapy was standardized via the ACTS-GC study in East Asia, perioperative ECF (Epirubicin + Cisplatin + Fluorouracil) was standardized via the MAGIC study in Europe, and postoperative chemoradiotherapy was standardized via the US intergroup study in North America. Since then, more intensive regimens have been developed. In recent years, perioperative therapy using novel agents, such as molecular-targeted drugs and immune checkpoint inhibitors (ICIs), has also been tested and evaluated in the three major regions (East Asia, Europe, and North America) with promising results. Perioperative chemotherapy has become an integral part of many treatment strategies and requires continued research and evaluation.

Cancer of unknown primary eventually diagnosed as poorly differentiated prostate cancer: a case report.

BACKGROUND: Prostate cancer has been well known to have a high prevalence among middle-aged and older men, with high incidence of metastases to the bone-the main metastatic site. However, prostate cancer among those less than 50 years of age is extremely rare, and neck swelling is seldom the initial symptom. CASE PRESENTATION: We herein report case of a 47-year-old Japanese male with poorly differentiated prostate cancer that had been initially diagnosed as a cancer of unknown primary with multiple lymph node and bone metastases before reaching a definitive diagnosis. The patient has been started on endocrine therapy and is currently alive without progression. DISCUSSION AND CONCLUSION: When locating the primary lesion in men with cancer of unknown primary, it is important to consider the possibility of prostate cancer, confirm serum prostate-specific antigen levels, and perform local prostate evaluation.

Early prediction of treatment outcome for lenvatinib using 18F-FDG PET/CT in patients with unresectable or advanced thyroid carcinoma refractory to radioiodine treatment: a prospective, multicentre, non-randomised study.

BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.

Genomic characterization between HER2-positive and negative gastric cancer patients in a prospective trial.

BACKGROUND: We aimed to clarify the genomic characteristics of HER2-positive and negative gastric cancer cases that potentially affect tumor progression and treatment response in a prospective trial. METHODS: We collected 80 formalin-fixed paraffin-embedded (FFPE) samples (49 HER2+ and 31 HER2-) from gastric cancer patients who participated in the TROX-A1 trial (UMIN000036865). We queried a 435-gene panel (CANCERPLEX-JP) to generate comprehensive genomic profiling data, including the tumor mutation burden, somatic mutations, and copy number variations. In addition, the genomic differences between HER2+ and HER2- gastric cancer patients were analyzed. RESULTS: Mutational analyses showed that TP53 was the most frequently mutated gene regardless of HER2 status. ARID1A mutation was significantly enriched in HER2-negative patients. The number of total mutations in HER2-negative patients with ARID1A mutation was remarkably higher than that in HER2-positive patients. Next, copy number variation analyses showed that the number of amplified genes (such as CCNE1, PGAP3, and CDK12) in HER2-positive cases was significantly higher than that in HER2-negative cases. Moreover, PTEN deletion was more common in HER2-positive cases. Finally, we found that, compared with HER2-positive patients, HER2-negative patients tended to have a higher tumor mutation burden, particularly in patients with ARID1A mutation. Pathway analyses of the gene alterations showed an enrichment of several immune-related pathways in HER2-negative patients. CONCLUSIONS: According to the genomic profiling of HER2-positive and negative gastric cancer, several gene alterations in the HER2 pathway may be the potential mechanism underlying trastuzumab resistance. Relative to HER2-positive gastric cancer, HER2-negative gastric tumors with ARID1A mutation may be sensitive to immune checkpoint inhibitors.

Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

Background: The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. Methods: FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. Discussion: There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. Clinical trial registration: Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.

Study protocol of the HGCSG1803: a phase II multicentre, non-randomised, single-arm, prospective trial of combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) as first-line treatment for metastatic or relapsed pancreatic cancer.

INTRODUCTION: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) has become one of the standard treatments for metastatic pancreatic cancer. However, the use of FOLFIRINOX requires prolonged infusion. Therefore, we planned to develop a new combination chemotherapy regimen with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. In the phase Ⅰ study that was conducted previously, the safety and recommended dose of OX-IRIS were assessed. In this study, we will evaluate the efficacy and safety of OX-IRIS. METHODS AND ANALYSIS: The HGCSG1803 study started as a multicentre, non-randomised, single-arm, prospective, phase II study in December 2019. Eligible subjects were patients with untreated metastatic or relapsed pancreatic cancer. OX-IRIS is administered as follows: 30 min infusion of antiemetic; 2-hour infusion of oxaliplatin (65 mg/m2); 1.5-hour infusion of irinotecan (100 mg/m2) on day 1 and 15 of each 4-week cycle; and oral S-1 (40 mg/m2) twice daily from after dinner on day one to after breakfast on day 15, followed by a 14-day rest, to be repeated every 2 weeks until disease progression, unacceptable toxicity or patient refusal. The primary endpoint is response rate. The secondary endpoints are overall and progression-free survival, safety and dose for each drug. Using a binomial test, a sample size of 40 patients was set with a threshold value of 10% and expected value of 30%. Registration of 40 cases is planned from 18 institutions in Japan. ETHICS AND DISSEMINATION: All the procedures will be conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1964 and its later versions. All the patients will receive written information about the trial and will provide informed consent before enrolment. This trial was approved by the Hokkaido University Certified Review Board (approval No: 018-037). TRIAL REGISTRATION NUMBER: jRCTs011190008.

Phase II Study of Ramucirumab Plus Irinotecan Combination Therapy as Second-Line Treatment in Patients with Advanced Gastric Cancer: HGCSG1603.

BACKGROUND: Ramucirumab is a human IgG1 monoclonal vascular endothelial growth factor receptor-2 antibody that inhibits tumor cell growth and affects the tumor cell microenvironment. We assessed the efficacy and safety of ramucirumab plus irinotecan combination therapy as second-line treatment in patients with previously treated advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer refractory or intolerant to primary chemotherapy were included. Ramucirumab 8 mg/kg plus irinotecan 150 mg/m2 combination therapy was administered every 2 weeks. The primary endpoint was progression-free survival rate at 6 months and secondary endpoints were overall survival, progression-free survival, response rate, safety, and dose intensity for each drug. RESULTS: Thirty-five patients were enrolled between January 2018 and September 2019. The progression-free survival rate at 6 months was 26.5% [95%CI, 13.2%-41.8%, P = .1353)]. Median progression-free and overall survivals were 4.2 months (95%CI, 2.5-5.4 months) and 9.6 months (95%CI, 6.4-16.6 months), respectively. The overall response rate was 25.9% (95%CI, 11.1-36.3%) and disease control rate was 85.2% (95%CI, 66.3-95.8%). Grade ≥3 adverse events that occurred in >10% of patients included neutropenia, leucopenia, anemia, anorexia, and febrile neutropenia. No death or new safety signals with a causal relation to the study treatment were observed. CONCLUSION: Although the primary endpoint was not achieved statistically, combination therapy of ramucirumab plus irinotecan showed anticancer activity and a manageable safety profile for second-line treatment of patients with advanced gastric cancer.

Synopsis of a clinical practice guideline for pancreatic ductal adenocarcinoma with peritoneal dissemination in Japan; Japan Peritoneal Malignancy Study Group.

Patients with pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination have a dismal prognosis because discontinuation of systemic chemotherapy is required for massive ascites or poor performance status. The natural history, diagnosis and treatment of PDAC with peritoneal dissemination have not been fully investigated. We systematically reviewed published information on the clinical diagnosis and treatment of PDAC with peritoneal dissemination using the PubMed database (2000-2020) and provided recommendations in response to clinical questions. This guideline was created according to the "Minds Clinical Practice Guideline Development Guide 2017". The literature quality and body of evidence were evaluated with the GRADE System and classified into four levels ("strong", "medium", "weak", "very weak"). The strength of each final recommendation was decided by a vote of committee members based on the GRADE Grid method. These guidelines address three subjects: diagnostic, chemotherapeutic, and surgical approaches. They include nine clinical questions and statements with recommendation strengths, evidence levels, and agreement rates, in addition to one "column". This is the English synopsis of the 2021 Japanese clinical practice guideline for PDAC with peritoneal dissemination. It summarizes the clinical evidence for the diagnosis and treatment of PDAC with peritoneal dissemination and provides future perspectives.

Intraperitoneal Chemotherapy as Adjuvant or Perioperative Chemotherapy for Patients with Type 4 Scirrhous Gastric Cancer: PHOENIX-GC2 Trial.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer.

BACKGROUND: The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. METHODS: The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis. RESULTS: Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0-1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46-1.34], p = 0.373, adjusted HR: 0.87 [0.41-1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38-1.12], p = 0.125, adjusted HR 0.53 [0.27-1.07], p = 0.078). CONCLUSION: In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents.

Pooled analysis of combination antiemetic therapy for chemotherapy-induced nausea and vomiting in patients with colorectal cancer treated with oxaliplatin-based chemotherapy of moderate emetic risk.

BACKGROUND: Among patients with colorectal cancer (CRC) treated with oxaliplatin (L-OHP)-based chemotherapy, delayed chemotherapy-induced nausea and vomiting (CINV) have not been well controlled. METHODS: We pooled data from two prospective observational studies in Japan and one phase III clinical trial to assess whether delayed CINV could be controlled with a combination of three antiemetics adding a neurokinin-1 receptor antagonist and identified individual risk factors, using an inverse probability treatment-weighted analysis. RESULTS: A total of 661 patients were evaluable in this study (median age: 64 years; 391 male, and 270 female). 3 antiemetics controlled delayed nausea (33.18% vs. 42.25%; p = 0.0510) and vomiting (4.15% vs. 16.08%; p < 0.0001) better than with 2 antiemetics. Female and 2 antiemetics were risk factors for both delayed nausea (female-odds ratio [OR]: 1.918; 95% confidence interval [CI]: 1.292-2.848; p = 0.0012; 2 antiemetics-OR: 1.485; 95% CI: 1.000-2.204; p = 0.0498) and delayed vomiting (female-OR: 2.735; 95% CI: 1.410-5.304; p = 0.0029; 2 antiemetics-OR: 4.551; 95% CI: 2.116-9.785; p = 0.0001). CONCLUSIONS: Identifying individual risk factors can facilitate personalized treatments for delayed CINV. We recommend a 3-antiemetic combination prophylaxis for CRC patients treated with L-OHP-based chemotherapy, especially for female patients.

Phase II study of trifluridine/tipiracil (TAS-102) therapy in elderly patients with colorectal cancer (T-CORE1401): geriatric assessment tools and plasma drug concentrations as possible predictive biomarkers.

PURPOSE: The current study aimed to determine the efficacy of trifluridine/tipiracil for elderly patients with advanced colorectal cancer. METHODS: This single-arm, open-label, multicenter, phase II study included elderly patients aged 65 years or more who had fluoropyrimidine-refractory advanced colorectal cancer and received trifluridine/tipiracil (70 mg/m2, days 1-5 and 8-12, every 4 weeks). The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), overall response rate (ORR), toxicities, association between efficacy and geriatric assessment scores, and association between toxicity and plasma drug concentrations. RESULTS: A total of 30 patients with a mean age of 73 years were enrolled. Median PFS was 2.3 months (95% confidence interval, 1.9-4.3 months), while median OS was 5.7 months (95% confidence interval, 3.7-8.9 months). Patients had an ORR of 0%, with 57% having stable disease. Grade 4 neutropenia was observed in 13% of the patients. Patients with a higher G8 score (15 or more) showed longer PFS than those with a lower G8 score (median 4.6 vs. 2.0 months; p = 0.047). Moreover, patients with grade 3 or 4 neutropenia showed higher maximum trifluridine concentrations than those with grade 1 or 2 neutropenia (mean 2945 vs. 2107 ng/mL; p = 0.036). DISCUSSION: The current phase II trial demonstrated that trifluridine/tipiracil was an effective and well-tolerated option for elderly patients with advanced colorectal cancer. Moreover, geriatric assessment tools and/or plasma drug concentration monitoring might be helpful in predicting the efficacy and toxicities in elderly patients receiving this drug. TRIAL REGISTRATION NUMBER: UMIN000017589, 15/May/2015 (The University Hospital Medical Information Network).

Phase II study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study).

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. METHODS: Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. RESULTS: A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3-16.0), the median OS was 45.4 months (95% CI 37.4-NA), and the RR was 56.0% (95% CI 42.3-68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). CONCLUSIONS: First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.