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To assess the efficacy and safety of ramucirumab in combination with FOLFIRI in patients with unresectable metastatic colorectal cancer under clinical practice in Japan, we reviewed manuscripts reporting clinical research, including case reports, of Japanese patients with FOLFIRI plus ramucirumab therapy published starting from 2016, when ramucirumab was approved as a treatment for metastatic colorectal cancer in Japan, to June 2020. We also reviewed an interim report of post-marketing surveillance study. The efficacy of ramucirumab in combination with FOLFIRI including irinotecan 150 mg/m2, which is the recommended dose in Japan and is used as initial dose in Japanese clinical practice, was similar to that of the global, phase 3 RAISE study with irinotecan 180 mg/m2. The desirable effect of FOLFIRI plus ramucirumab was observed in patients with wild-type RAS, primary tumors on the left sides(descending, sigmoid, or rectum colons), or who received anti-epidermal growth factor receptor agents, including panitumumab or cetuximab, as previous treatment. Also, the effectiveness of FOLFIRI plus ramucirumab as a late-line treatment was suggested. Several patients were reported to have nephrosis syndrome after starting ramucirumab, but they recovered with discontinuation of ramucirumab and appropriate treatment. No new safety concerns were observed from the literature or the interim report of post-marketing surveillance study.

A 71-year-old man with predialysis terminal renal insufficiency experienced peritoneal dissemination 1.5 years after low anterior resection for advanced rectal cancer. He received FOLFIRI therapy (70% dose); he achieved partial response (PR) under computed tomography and stable disease (SD) was maintained over a long term. Although Grade 3 myelosuppression was occasionally noted, he was treated with FOLFIRI for 2 years without other severe complications and without requiring the initiation of hemodialysis. After the initiation of hemodialysis, FOLFIRI treatment was continued for 1 year until progressive disease (PD). He received mFOLFOX6 as second-line therapy for 6 months, followed by LV-5-FU and a molecular targeting agent. These treatments prolonged his survival for 1 year and 8 months. FOLFIRI can be administered as an effective first-line therapy even for patients with predialysis terminal renal impairment without major renal damage. FOLFOX and molecular targeting agents should be made available and prolonged survival can be expected for advanced colorectal cancer patients with terminal renal disease after the initiation of hemodialysis.

Oxaliplatin is a platinum salt that is particularly effective for treating gastrointestinal tumors. However, some reports state that oxaliplatin-based chemotherapy triggers fatal thrombocytopenia. Myelosuppression is recognized as the main cause of oxaliplatin-related thrombocytopenia, and other mechanisms for this side effect have been suggested, including splenic sequestration of platelets related to oxaliplatin-induced liver damage and immune thrombocytopenia. Other causes of thrombocytopenia such as thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura, heparin-induced thrombocytopenia, and pseudothrombocytopenia should also be considered. We encountered 3 patients who developed fatal thrombocytopenia after oxaliplatin-based chemotherapy and describe the differential diagnosis of fatal thrombocytopenia here.

We report a case of advanced rectal cancer treated with chemotherapy, for which laparoscopic splenectomy had been effective for thrombocytopenia. A 56-year-old man suffered from advanced rectal cancer with multiple lung metastases. He underwent Hartmann's procedure and received chemotherapy with FOLFOX and FOLFIRI with bevacizumab. After 3 years and 2 months, he also suffered from splenomegaly and thrombocytopenia. Laparoscopic splenectomy produced and increased the thrombocyte count, allowing for a restart of chemotherapy. Oxaliplatin-based chemotherapy might produce hepatic sinusoid injury and induce splenomegaly owing to portal hypertension. Laparoscopic splenectomy seemed to be useful for treating thrombocytopenia, and allowed the continuation of chemotherapy.

A 70-year-old woman was referred to our hospital because of abdominal pain. Abdominal computed tomography(CT)and colonoscopy revealed transverse colon cancer with multiple liver metastases, with involvement of the hepatic pedicle and superior mesenteric artery lymph nodes. The patient received eight courses of XELOX plus bevacizumab, and CT showed a decrease in the size of the liver metastases and hepatic pedicle lymphadenopathy. Right hemicolectomy, partial hepatectomy, and hepatic pedicle lymph node resection were performed. Histopathological examination of the resected tissue revealed no residual cancer cells, suggesting a pathological complete response. The patient remains well 7 months after operation, without any signs of recurrence. Surgical resection should be considered for patients with initially unresectable colon cancer with liver metastases and hepatic pedicle lymph nodes involvement if systemic chemotherapy is effective.

Mutation of the KRAS gene in patients with metastatic colorectal cancer(mCRC)has been established as a predictive marker of poor response to anti-EGFR cetuximab. The Japanese Society of Medical Oncology recommends that the KRAS mutation status at codon 12 and codon 13 should be genotyped by direct-sequencing or allele-specific PCR. In this study, we tested the point mutation of codon 12 and 13 in the KRAS gene by Luminex(xMAP)flow cytometry with sequence-specific oligonucleotide probes for 39 out of 64 unresectable mCRC patients enrolled from Sep 2008 to Oct 2009, who were administered cetuximab in combination with irinotecan(CPT-11)as third-line therapy. We retrospectively analyzed the relationship between KRAS mutation status and responses to combination therapy. Mutations in the KRAS gene were detected in 38. 5% of cases(codon12: 73%, codon 13: 27%), and the median follow-up time was 8. 2 months(range, 1. 4-15. 2 months). The response rates for patients with KRAS wild-type and patients with KRAS mutations were 33. 3%(95%CI 14. 5-52. 2%)and 0%(p=0. 015); the disease control rates were 75%(95%CI 57. 7-92. 3%)and 40%(95%CI, 15. 2-64. 8%; p=0. 044); the median TTF was 7 months(95%CI 4. 6-9. 3)and 2. 3 months(95%CI 1. 3-3. 2; p=0. 0007), and the median OS was 12. 9 months(95%CI 6. 7-19. 1)and 10. 8 months(95%CI 5. 0-16. 7; p=0. 15), respectively. Therefore, we concluded that the KRAS mutation in mCRC is a predictive factor for the lack of response to combination therapy with cetuximab plus CPT- 11, as reported in previous clinical studies.

Unlabelled: Most colorectal cancer patients with liver metastases are not resectable upon initial diagnosis. Recently, chemotherapy improves overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. We report a FOLFOX-refractory rectal cancer patient with unresectable multiple liver metastases, whose tumors could be downstaged and completely resected after initiation of FOLFIRI with cetuximab., Case: A 41-year-old male demonstrated rectal cancer with unresectable multiple liver metastases. He was treated by FOLFOX4 therapy as first-line chemotherapy. After initiating 14 courses, he was treated by FOLFIRI with cetuximab because of disease progression. After initiation of chemotherapy, radiographic examination demonstrated remarkable reduction of primary rectal tumor and metastatic liver tumors. He underwent complete rectal tumor resection after 13 courses of chemotherapy, and metastatic liver tumor resection after 18 courses of chemotherapy.

Unlabelled: The incidence of gastrointestinal bleeding, thromboembolic events and gastrointestinal perforation during chemotherapy with metastatic or unresectable gastric cancer has been unknown. To clarify the incidence of these events, we reviewed the clinical records of our hospital., Patients and Methods: We investigated metastatic or unresectable gastric cancer patients who received chemotherapy during January 2002 to December 2006. Grade≥3 (CTCAE v3.0) adverse events from the first day of chemotherapy to 1 month after the last day of chemotherapy were investigated., Results: A total of 292 patients received chemotherapy. Patient characteristics were as follows: median age 63.5 years (range, 28 to 87); performance status 0/1/2/3: 129/129/31/3; male: female, 206:86, histopathological type intestinal/diffuse/unclassified-adenocarcinoma/others: 91/139/58/4. We found the incidence of Grade≥3 gastrointestinal bleeding in 7 patients (2.4%), thromboembolic events in 5 patients (1.7%) and gastrointestinal perforation in 3 patients (1.0%). Thromboembolic events in patients under 55 years of age were associated with a higher incidence (p=0. 0046)., Conclusion: The incidence was not so high as expected. We should be aware of the frequency of these toxicities in the treatment of gastric cancer.

The revised version of the Japanese colorectal cancer treatment guidelines by the Japanese Society for Cancer of the Colon and Rectum published in July 2009 showed remarkable changes in the field of systemic chemotherapy compared with the 2005 edition. Bevacizumab was approved in 2004 in United States, in 2005 in Europe, and in 2007 in Japan. On the other hand, cetuximab was approved in 2004 in Europe and United States, and in July 2008 in Japan. Besides, capecitabine was approved in September 2009 in Japan for not only adjuvant chemotherapy but also unresectable advanced colorectal cancer. Thus, we had one more treatment option of capecitabine with Oxaliplatin as CapeOx (XELOX). Therefore, most of the standard chemotherapy regimens in Western countries then became available in Japan. There has been no major difference in the drug treatment strategy except for the approval of panitumumab in Europe and the US, but this was not true in Japan. Now KRAS testing is recommended, and the indication for cetuximab is limited to KRAS wild type. Cetuximab can not be administered as the first-line treatment in Japan because KRAS testing is not covered by health insurance. This article deals with the difference in the anti EGFR antibody indication between the Japanese and overseas guidelines.

Purpose: Oxaliplatin (L-OHP) is one of the key drugs against advanced, recurrent colorectal cancer, and FOLFOX4 regimen combination of l-leucovorin (l-LV)and 5-fluorouracil (5-FU)with oxaliplatin is a standard therapy in colorectal cancer. We performed a retrospective study that researched adverse events and relative dose intensity(RDI)to evaluate safety and feasibility of FOLFOX4 regimen., Patients and Methods: We administered 188 patients a FOLFOX4 regimen. To evaluate RDI, this study research dose modification and delay treatment procedure was done for 1 to 13 cycles., Results: RDI of oxaliplatin is 89.1% (1-4 cycles), 81.4% (4-7 cycles), 78.2% (7-10 cycles), 69.0% (10-13 cycles). The factors of RDI decrease were hematologic toxicity(leucopenia, neutropenia, thrombocytopenia), peripheral neuropathy and allergic reaction. Moreover, peripheral neuropathy and allergic reaction often require therapy to be discontinued (peripheral neuropathy: 15.2%, allergic reaction: 20.3%)., Conclusion: Feasibility of FOLFOX4 regimen is related to incidents of hematologic toxicity, peripheral neuropathy and allergic reaction. We should pay sufficient attention to these adverse events of FOLFOX4.

We have retrospectively been collecting data on adverse reactions to FOLFIRI chemotherapy in our hospital from September 2005 to August 2006, by electronic medical records. The retrospective study was of 67 patients who received FOLFIRI for advanced colorectal cancer. Survey results showed high incidences of vomiting(58.2%), anorexia(91.4%), constipation (47.8%), diarrhea (61.2%) and alopecia(71.6%). The first cycle using FOLFIRI therapy, vomiting (20.9%), anorexia(53.7%), constipation ( 14.9%), and diarrhea (23.9%)were observed. We sought to minimize inter-individual differences in pharmaceutical care and drug consultation by clinical pharmacists and to ensure the accurate understanding of patients. We are sure that this kind of activity will help us to provide better pharmaceutical care for patients.

The number of elderly patients with colorectal cancer is increasing in Japan. They have the opportunity to receive chemotherapy similar to non-elderly patients because of the development of new drug agents and improvement of supportive therapy. We analyzed retrospectively 184 patients (32 aged >or= 70, 75 or= 3 adverse events. The FOLFOX4 regimen maintains its efficacy/safety ratio in elderly patients with good performance status with colorectal cancer in Japan.

We have been collecting data on the adverse reaction of FOLFOX 4 chemotherapy in our hospital from April 2005 to October retrospectively, by electronic clinical records. A retrospective study of 123 patients receiving FOLFOX 4 for advanced colorectal cancer was conducted. Survey results showed high incidences of hemotoxicity (52.8%), chronic sensory neuropathy (16.2%) and allergic reactions (15.4%). In the initial FOLFOX 4 therapy, appetite loss (60.1%), vomiting (19.5%) and acute sensory neuropathy (33.3%) were observed. We prepared a brochure in order to minimize inter-individual differences in pharmaceutical care and drug consultation by clinical pharmacists and to ensure the accurate understanding of patients. We feel sure that this kind of activity will help us to provide better pharmaceutical care for patients.

A 40-year-old man suffering from right cheek swelling was first diagnosed with ameloblastoma or anaplastic poorly-differentiated carcinoma of the head and neck region. He received 2 courses of CDDP/TXT chemotherapy (cisplatin 75 mg/m2, docetaxel 80 mg/m2) and achieved a partial response, but his carcinoma of the pancreas recurred. He also achieved a partial response with 2 courses of CBDCA/TXL regimen (carboplatin AUC=6, paclitaxel 200 mg/m2), but later died from his progressive disease. The autopsy revealed a pathological diagnosis of metastatic endocrine carcinoma of the pancreas. This case was close to a cancer with an unknown primary (CUP) site, and several favorable sub-sets of CUP have been identified, which are responsive to systemic chemotherapy. Poorly-differentiated neuroendocrine carcinomas like this case are highly sensitive to chemotherapy, and a careful pathological diagnosis may clarify its sensitivity to chemotherapy and the prognosis.

We report a case on hemodialysis with metastatic rectal cancer who was introduced to CPT-11. Although the expected pharmacokinetics was shown 24 hours post-dialysis with the infusion of dose-reduced CPT-11, grade 4 neutropenia was observed. Considering the chronic renal failure status with latent lower function of multiple organs, the dose escalation method was recommended while watching the pharmacokinetics. CPT-11 is not only the key compound for metastatic colorectal cancer, but is also effective with several other cancers. It is important for cancer patients with chronic renal failure that the feasibility and efficacy of CPT-11 should be determined by future study.

A 55-year-old woman underwent breast-conserving surgery with irradiation for Stage IIB (T2 N1 M0) breast cancer of her right breast. Thereafter, she was treated orally with oral UFT and tamoxifen. Three years following surgery, she was diagnosed as having a non-Hodgkin's lymphoma. She underwent 6 cycles of EPOCH-G (etoposide, vincristine, adriamycin, cyclophosphamide, prednisolone, G-CSF) therapy, and obtained complete remission. Two years later, her neck and inguinal lymph nodes were swollen. Biopsy confirmed the relapse of NHL. She underwent salvage chemotherapies of MST-16, carboplatin, IVAC, and CPT-11, but the disease was refractory. In May 2000, bilateral pleural effusion was detected. Cytomorphologically, the pleural fluid specimen showed both atypical lymphoid cells and adenocarcinoma cells simultaneously. Existence of double cancer in the pleural effusion has not been reported, suggesting that this case is rare.