[Clinical development of oral chemotherapeutic agents for advanced gastric cancer].

5-fluorouracil (5-FU) has been the mainstay of systemic therapy since its initial development 50 years ago for gastrointestinal cancer. In Japan, the development of orally administered fluoropyrimidines that maintain or improve the effectiveness of intravenous 5-FU, has been advanced. In the JCOG9912 trial, S-1 demonstrated significant non-inferiority to 5-FU. In the SPIRITS trial, S-1+CDDP combined chemotherapy showed significant statistical superiority to S-1 monotherapy. On the basis of these results, S-1+CDDP combination therapy was adopted as the standard cancer chemotherapy regimen for inoperable and recurrent gastric cancer. The ACTS-GC trial suggested that adjuvant chemotherapy with S-1 should be adopted as the standard treatment for stage II/III gastric cancer after curative D2 gastric dissection. This manuscript describes the clinical development of oral fluoropyrimidines (S-1, capecitabine) and their modulators for gastric cancer.

[First/second/third-line chemotherapy with molecular targeted drugs for colorectal cancer].

According to the Japanese Colorectal Cancer Treatment Guideline by the Japanese Society for Cancer of the Colon and Rectum, the recommendation for recurrent colorectal cancer consists of 2 options according to the number of metastatic organs and surgical curability. In Japan, oxaliplatin was approved for patients with metastatic colorectal cancer in 2005, bevacizumab was approved in 2007, cetuximab was approved in 2008. Then most of the standard regimens in western countries became available in Japan. Therefore, Japanese standard regimens in patients with recurrent colorectal cancer are considered according to the standard western regimen. This review paper introduce the major regimens in the first-, second-, and third-line settings in patients with recurrent colorectal cancer in Japan, and comments on several chemotherapy issues in Japan.

[Gastric cancer].

The prognostic significance of histologic type is unclear in patients with gastric cancer. However, the regimen has been actually selected by histologic type from clinical reports and clinical experiences. The differentiated type is related to metastasis in the liver and the undifferentiated type to the peritoneum metastasis. The S-1+CDDP combined therapy that is standard treatment has no difference in antitumor effect by the histologic type factor. CPT-11 and CPT-11+ CDDP combined therapy, which is the second-line therapy, can be expected to be effective in a gastric cancer patient with target lesion like liver metastasis. With paclitaxel and docetaxel, the second-line therapy, the effect is expected in a gastric cancer patient without a target lesion like peritoneal metastasis.

[Clinical development of chemotherapy for advanced gastric cancer].

The ACTS-GC trial suggested that adjuvant chemotherapy with S-1 should be adopted as the standard treatment for stage II/III gastric cancer after curative D2 gastric dissection. In the JCOG9912 trial (5-FU vs CPT-11+CDDP (CP), 5-FU and vs S-1), the MSTs were 9.0, 12.1, and 10.5 months for 5-FU, CP, and S-1, respectively, with S-1 demonstrating significant non-inferiority to 5-FU, while CP did not show statistically significant superiority to 5-FU. In the SPIRITS trial comparing S-1 alone with S-1+CDDP, the MSTs were 11.0 and 12.0 months for S-1 and S-1+CDDP, respectively, and S-1+CDDP showed statistically significant superiority to S-1 monotherapy. The GC0301/TOP-002 trial compared CPT-11+S-1(IRI-S)to S-1 alone in advanced gastric cancer patients. An analysis revealed an ORR of 26.9% for the S-1 monotherapy arm and 41.5% for the IRI-S arm (p=0.035). However, IRI-S did not show statistically significant superiority to S-1 alone in OS. On the basis of these results, S-1+CDDP was adopted as the standard cancer chemotherapy regimen for inoperable and recurrent gastric cancer in Japan. Thus, in the next revision, the contents of the description of the Japanese Guidelines for Treatment of Gastric Cancer (2nd Edition) will be changed. Now, the second-line treatment and the biological molecular targeting agents-based drug medicine treatment development are continued with an eye to the future.

[Pilot-testing of the Japanese version of the EORTC QLQ-STO22 gastric cancer module].

The pilot testing of the Japanese translation of the European Organization for Research and Treatment of Cancer (EORTC) gastric cancer module (QLQ-STO22) was done for 10 patients (6 men; 4 women) with gastric cancer. Age ranged from 23 to 73. Five patients had a performance status (PS) of 0, 4 had a PS of 2, and 1 had a PS of 4. Five had stage IV gastric cancer. It took 20 to 40 minutes for the patients to complete the questionnaire. All stated that it did not take long a time to complete, and that each question was easy to understand as a whole. They also mentioned that the questionnaire appropriately described and represented their health condition. However, it was revealed that some linguistic revisions should be made for 5 of the 22 questions to clarify their meanings by adding examples or replacing unclear words with clearer ones. The Japanese version of the QLQ-STO22 was finalized via those revisions. We are waiting for the result of the validation study in an international field (EORTC protocol number 15001/40003) with a larger number of gastric cancer patients using standardized psychometric testing.

Effectiveness of doxifluridine (5'-DFUR)/docetaxel against advanced/recurrent gastric cancer showing resistance to various anticancer drug regimens.

A 58-year-old man was diagnosed as having type 3 gastric cancer (poorly differentiated adenocarcinoma). He underwent total gastrectomy with splenectomy, as well as D3 dissection, and received postoperative chemotherapy combining oral uracil and futrafur (UFT) with cisplatin (CDDP), but results showed recurrence of multiple abdominal lymph node metastases around the aorta. He therefore received various anticancer drug regimens (irinotecan [CPT-11]/CDDP; 1 M tegafur-0.4 M gimeracil-1 M oteracil potassium [TS-1], methotrexate (MTX)/5-fluorouracil); however, final results showed growth of lymph node metastasis and simultaneous worsening of his general condition. The patient then received combined administration of doxifluridine (5'-DFUR)/docetaxel (5'-DFUR, 1000 mg/body [666.7 mg/m(2)], given by consecutive daily administration, orally, for days 1-14; and docetaxel, 80 mg/body [60 mg/m(2)], on day 8, by venous drip, every 3 weeks). Three courses of this regimen resulted in approximately 90% reduction of the abdominal lymph node size, disappearance of the right cervical lymph node metastasis, reductions of the levels of two tumor markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA]19-9), and improvement of his general condition. In total, seven courses of the regimen were carried out. The patient died on day 298 after starting this combined regimen and showed a response period of 126 days. The primary toxicity identified was neutropenia (grade 4), as well as other low-grade (grade 1, 2) hematological and nonhematological toxicities. In the field of gastric cancer treatment, especially for patients showing multiple resistance to anticancer drugs, an effective therapy is critically needed.

[Development of a Japanese version of the FLIE].

Nausea and vomiting induced by chemotherapy have an impact on cancer patients' quality of life (QOL). The Functional Living Index-Emesis (FLIE), which is designed to assess the change in QOL from the influence of nausea and vomiting is rarely used in Japan, regardless of its utility, because it is written in English. We investigated the use by cancer patients with the main object of designing a reliable and valid Japanese version of the FLIE. We also verified the validity of a Japanese translation and improved part to design a highly precise Japanese version FLIE. Consequently, we found a correlation between the FLIE Japanese version and the QOL questionnaire Quality of Life Assessment of Cancer Patients Receiving Chemotherapy (QOL-ACPRC), which was the external standard. Furthermore, we improved the questionnaire to raise the rate of patient response, and improve reliability and validity. We think that this FLIE Japanese version will become useful in assessing the change in patient QOL due to the influence of nausea and vomiting.