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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., (© The Author(s) 2022. Published by Oxford University Press.)

Background: The efficacy of irinotecan plus continuous trastuzumab beyond progression in patients with gastric cancer previously treated with trastuzumab plus standard first-line chemotherapy has not been reported., Methods: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer who were previously treated with trastuzumab received trastuzumab every 3 weeks and irinotecan every 2 weeks. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), 6-month survival rates, safety, and subgroup analysis by HER2 status., Results: Sixteen patients were enrolled in a 3-year pre-planned registration period. This study was prematurely closed due to poor patient accrual. The ORR and disease control rate were 6.7% (95% CI, 0.2-32.0) and 53.3% (95% CI, 26.6-78.7). The median PFS and overall survival (OS) were 2.4 months (95% CI, 0.0-5.2) and 9.7 months (95% CI, 8.2-11.2), respectively. The most frequently reported grades 3-4 adverse events were neutropenia (40%), anemia (27%), anorexia (33%), and fatigue (33%)., Conclusion: With only 16 patients enrolled, the present study has very low power to detect any clinical benefit of trastuzumab plus irinotecan beyond disease progression in patients with HER2-positive advanced gastric cancer who previously received trastuzumab.Trial Identifier: UMIN000007636., (© The Author(s) 2022. Published by Oxford University Press.)

Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3-weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety., (© The Author 2014. Published by Oxford University Press.)

Objective: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system., Methods: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy., Results: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days)., Conclusions: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients., (© The Author 2014. Published by Oxford University Press.)

Objective: Infusion reactions are common adverse reactions associated with antibody preparations. However, no studies have examined the time to onset of serious infusion reactions after administering cetuximab. We aimed to investigate the timing and severity of IRs affecting Japanese patients after administration of cetuximab., Methods: Study subjects were identified from a nationwide prospective registry of 2126 metastatic colorectal cancer patients scheduled to receive cetuximab. Infusion reactions were examined in 2006 patients with adequate safety data., Results: Infusion reactions of any grade occurred in 114 patients (5.7%), including Grade 3-4 infusion reactions in 22 patients (1.1%). Premedications were antihistamine plus corticosteroid (88.9% of patients with infusion reactions), antihistamine alone (9.2%) or corticosteroid alone (1.1%). In 95 patients (83.3%), infusion reactions occurred after the first dose. Twenty of the 22 Grade 3-4 infusion reactions occurred within 1 h of the first dose (the timing of the infusion reaction was unknown in one patient while another infusion reaction occurred after the fourth dose). Infusion reactions resolved in 111/114 patients (97.4%) while one patient recovered with sequelae, one patient died and one patient failed to recover within the follow-up period. Thirteen patients (15.7% of patients with infusion reactions) with Grade 1-2 infusion reactions showed recurrence after readministration of cetuximab; the recurrent infusion reactions were less severe than the initial reactions., Conclusions: Grade 3-4 infusion reactions occurred in 1.1% of colorectal cancer patients, and most occurred within 1 h of receiving the first dose of cetuximab. Therefore, patients should be carefully observed following cetuximab infusion, especially during the first hour after the first infusion., (© The Author 2014. Published by Oxford University Press.)

Objective: Cetuximab (Erbitux(®)) was approved for the treatment of metastatic colorectal cancer in Japan in 2008. To verify information on the safety in practical use of cetuximab, we conducted post-marketing surveillance in accordance with the conditions for approval., Methods: All patients to be treated with cetuximab were enrolled by the central enrolment method. Data on treatment status, and incidence and severity of adverse drug reactions were collected. The target number of patients was 1800., Results: A total of 2126 patients were enrolled from 637 institutions. Among 2006 patients analysed, 93.2% received cetuximab as third-line or later treatment. The median duration of treatment was 15.3 weeks, and 11.1% of patients received treatment for >48 weeks. The incidence of adverse drug reactions was 89.6%, of which ≥grade 3 was 21.5%. The incidence of infusion reactions was 5.7% (any grade), with 83.3% of them occurring at the first administration. The incidence of skin disorders was 83.7% (any grade), and the time to event varied for each skin disorder. The incidence of interstitial lung diseases was 1.2% (any grade). Diarrhoea and haematotoxicity scarcely occurred with cetuximab alone., Conclusions: In this surveillance, the incidence and categories of adverse drug reactions are not distinct from previous reports. Although most patients received cetuximab as third-line or later treatment, treatment was maintained with a median duration of 15 weeks. Cetuximab treatment in practical use is considered to be well tolerated and clinically useful in Japanese patients with metastatic colorectal cancer.

Objective: The actual condition of drug utilization and the adverse drug reactions profile of irinotecan hydrochloride hydrate (irinotecan), an antitumor drug, were examined on the basis of all the case survey results from April 1995 to January 2000., Methods: Drug utilization and the adverse drug reactions profile of irinotecan were figured out by checking of the patient conditions at the start of therapy and monitoring during on-therapy period in this survey., Results: Among the 13 935 patients investigated, 32% had non-small cell lung cancer, 16% had colorectal cancer, 15% had ovarian cancer and 14% had small cell lung cancer, all principal cancers in which irinotecan was domestically approved for use. Most frequent regimens of each cancer were concomitant use with cisplatin for non-small cell lung cancer and small cell lung cancer (38 and 46%, respectively), concomitant use with cisplatin or mitomycin for ovarian cancer (each 30%) and irinotecan alone for colorectal cancer (51%). The major (grade 3 or more) adverse drug reactions were myelosuppressions such as leukopenia (23.8 and 38.3% for lone and concomitant use, respectively) thrombocytopenia (6.5 and 14.3%) and gastrointestinal tract disorders such as diarrhea (10.2 and 10.0%)., Conclusions: It was reconfirmed that the incidences of serious leukopenia, thrombocytopenia and diarrhea were high among the patients with contraindication or careful administration of its use prescribed in the drug package insert. Therefore, for proper use of irinotecan, it is important to discriminate the patient on the basis of risk status.

Objective: After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice., Methods: All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate., Results: A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively., Conclusions: The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

A 42-year-old man was found to have an adenocarcinoma arising from ectopic gastric mucosa in Meckel's diverticulum, as diagnosed with surgical pathology. Recurrence was recognized with massive ascites at 1 year and 6 months after surgery. Chemotherapy in the first and second lines was not effective. In the third line of chemotherapy, pemetrexed and carboplatin were both administered and this resulted in a good response for massive ascites. This palliative therapy was effective and safe.

Objective: Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients., Methods: We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis., Results: The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T(3) and T(4)) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated., Conclusions: The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.

Objective: Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. We evaluated the efficacy and safety of cetuximab in combination with irinotecan in patients with metastatic colorectal cancer (CRC) refractory to irinotecan, oxaliplatin and fluoropyrimidines., Methods: Cetuximab was administered initially at a dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Irinotecan was administered either weekly at a dose of 100 mg/m(2) or every 2 weeks at 150 mg/m(2)., Results: Between October 2005 and February 2006, 39 consecutive patients were enrolled. The response and disease control rates (complete or partial response, or stable disease) were 30.8% (95% CI, 17.0-47.6) and 64.1% (95% CI, 47.2-78.8), respectively. With a median follow-up of 14.4 months, median time to progression was 4.1 months (95% CI, 2.7-5.1) and median survival time was 8.8 months (95% CI, 5.9-12.8). Patients (5.1%) developed Grade 3 acne-like rash., Conclusions: Combination therapy of cetuximab and irinotecan is effective and well-tolerated in patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.

A 61-year-old female with surgically treated rectal cancer that had metastasized to lung and lymph nodes was treated with bevacizumab (BV) plus 5-fluorouracil (5-FU) and leucovorin (LV) as third-line chemotherapy after treatment failures with infusional 5-FU, LV and oxaliplatin (FOLFOX regimen); and infusional 5-FU, LV and irinotecan (FOLFIRI regimen). After four cycles of treatment, a computed tomography scan revealed reduced sizes of the lung and lymph node metastases. Tumor response has still been maintained after six cycles of treatment, and the chemotherapeutic response was evaluated as partial response according to the Response Evaluation Criteria In Solid Tumor guidelines. Manageable toxicity included grade 2 hypertension, grade 1 epistaxis and grade 1 stomatitis. Although there are no clinical trial results supporting the use of BV-containing therapy as third-line chemotherapy for advanced colorectal cancer, BV plus 5-FU and LV was effective and feasible in our patient with colon cancer that had progressed after treatment with 5-FU, irinotecan and oxaliplatin.

There has been no previous report of oxaliplatin administration in patients undergoing hemodialysis. A 65-year-old female with end-stage renal disease who was undergoing hemodialysis presented with anemia in August 2005. She was diagnosed with colon cancer with multiple liver metastases. After colectomy, hepatic arterial infusion chemotherapy of 5-fluorouracil was initiated and systemic administration of irinotecan was later added. After 3 months of treatment, liver metastases were strikingly reduced in size, and the carcinoembryonic antigen level decreased from 336 to 14.2 ng/ml. Eight months after treatment initiation, liver metastases increased in size with higher levels of carcinoembryonic antigen, therefore hepatic arterial infusion of oxaliplatin 60 mg was initiated. Hepatic arterial infusion was performed biweekly during hemodialysis and blood platinum concentrations were assessed. At the first cycle, the area under the curve of total platinum was 19.39 microg h/ml and that of free platinum was 5.51 microg h/ml. After six treatment cycles, the carcinoembryonic antigen level declined from 335 to 123 ng/ml. After eight treatment cycles, she experienced transient fever and impaired consciousness as a result of cholangitis, which improved following administration of antibiotics. We propose that limited cycles of hepatic arterial infusion of oxaliplatin are feasible in patients undergoing hemodialysis and this may become a strategy for treating hepatic metastases from colon cancer in patients undergoing hemodialysis.

Background: Benefits of chemotherapy have generally been modest in gastric cancer, although those regimens developed more recently have produced higher response rates. Paclitaxel plus cisplatin is one such regimen and divided administration of paclitaxel has been suggested to be associated with lower neurological and hematologic toxicities and be able to achieve higher paclitaxel dose intensities than paclitaxel administration at 175 mg/m2 every 3 weeks. This study was undertaked to assess the efficacy and toxicity of a biweekly paclitaxel and cisplatin combination treatment in advanced gastric cancer., Methods: Twenty-five patients from Japan and Korea, 50 patients in total, were entered into this trial which was conducted from October 2004 to June 2005. Median age of the patients was 57 years (range: 26-78). Paclitaxel 140 mg/m2 was administered intravenously on days 1 and 15 of each 4-week cycle. Cisplatin 30 mg/m2 was also administered on days 1 and 15 with standard hydration. A total of 278 courses of treatment (two treatment courses per cycle) were conducted for 50 patients. The median number of treatment cycles per patient was two with a range of one to six., Results: Nine of the 50 patients responded to the treatment, with an overall objective response rate of 18% (95% CI, 12-41), which included one complete response. Two patients were not evaluable and 14 patients had stable disease as best response. The median survival duration of the 50 patients was 333 days (range: 52-637+ days). The main toxicity was neutropenia. Significant toxicity (NCI-CTC grade 3 or 4) included neutropenia in 19 patients (38%), anorexia in four (8%), infection in three (6%), anemia in three (6%), and abdominal pain in three (6%)., Conclusions: Biweekly paclitaxel and cisplatin combination chemotherapy showed modest activity in advanced gastric carcinoma with a favorable toxicity pattern.