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Background: Regorafenib(Rego)is the salvage line standard treatment for metastatic colorectal cancer(mCRC), which often causes severe toxicities, such as hand-foot syndrome. Previously, we reported that in phase Ⅱ study, S-1 plus bevacizumab( Bev)(SB)showed favorable anticancer activity and feasibility as a salvage line. The aim of this study was to evaluate 2 treatments for mCRC as salvage line., Patients and Methods: In this multicenter phase Ⅱ study, the patients were randomly assigned(1:1)to the Rego or SB group. In the Rego group, Rego 160 mg/kg body weight was orally administered every 28 days for 21 days. In the SB group, S-1 was orally administered every 42 days for 28 days, according to body surface area, and Bev 5 mg/kg was administered by intravenous infusion on days 1, 15, and 29. Administration of S-1 every 21 days for 14 days and Bev 7.5 mg/kg on day 1 was also permitted. The primary endpoint was overall survival(OS), and the planned sample size was 86., Results: This study was ended prematurely due to poor accrual. Overall, 8 patients were enrolled from 6 institutions between Oct 2013 and May 2015. Although 4 patients were assigned to each group, one patient in the Rego group was excluded after enrollment. The median OS in the Rego and SB groups was 30.2 months and 6.6 months, respectively(hazard ratio: 0.205, p=0.123). The median progression-free survival in the Rego and SB groups was 3.7 months and 1.6 months, respectively. The disease control rate in the Rego and SB groups was 100% and 75%, respectively. The Grade 3 or 4 adverse events were increased, including AST/ALT(n=1, 25%), hyponatremia(n=1, 25%), hand-foot syndrome(n=1, 25%), hypertension(n=1, 25%), and proteinuria(n=1, 25%)in the Rego group and colitis( n=1, 25%)in the SB group; the treatment was discontinued., Conclusion: Despite the fact that data could only be collected from a small number of patients, SB is not recommended as salvage line for mCRC.

Recently, accumulating discoveries in the field of immunology have been applied in clinical settings along with rapid progression of basic and pre-clinical research. Especially, advancement of gene modification technologies has contributed to unlock a way to novel cancer immunotherapy. One representative is chimeric antigen receptor-expressing T(CAR-T)cell therapy which was approved by FDA in August, 2017 as first gene-modified cell therapy. However, such technologies are still work-in-progress and there are many obstacles to be overcome for their full development. So called 4th generation CAR-T cells, in which CAR-T cells are engineered to secrete some kinds of cytokine and/or chemokine, have revealed their prominent potential to eradicate established solid tumors, which are usually resistant to conventional CAR-T cells. Another example of gene-modified cells for cancer immunotherapy is T cell receptor(TCR)-T cells, which are T cells engineered to express tumor antigen-specific TCR. Targeting neoantigens, mutated proteins to be expressed only in cancer cells and scarcely in normal ones, is attracting attempt for TCR-T cell approach. In addition, due to unique immunological functions, other lymphocyte subsets such as natural killer(NK)cells, invariant natural killer T(iNKT)cells, and gd-type T cells gain attention as effector cells to be gene-modified. Furthermore, off-the-shelf cell therapy, in which patients receive cell products made from allogeneic non-self immune cells, is nowunder development. It should be noted that development of "personalized" medicine, which aims to customize drugs to be suitable for each patient and different types of tumor, and "universal" technologies, which are crucial to generate uniform quality of cell products and to decrease manufacturing time and cost, are highly important for further advance of cancer immunotherapy.

Unlabelled: Injectable combination chemotherapy with 5-fluorouracil (5-FU)/Leucovorin (LV), oxaliplatin (OHP), and irinotecan (CPT-11) has been a standard treatment for advanced colorectal cancer (CRC). An oral fluoropyrimidine, S-1 (tegafur, gimeracil, and oteracil), has been developed recently, and a combination of S-1/CPT-11 demonstrated effects comparable to FOLFIRI for the treatment of advanced CRC. Being without continuous infusion lasting for days, combination chemotherapy with oral fluoropyrimidine may limit inconvenience and improve the quality of life (QOL) of patients. There have been few studies evaluating chemotherapy with oral fluoropyrimidine in terms of patient QOL and convenience., Patients and Methods: We assessed the patients' QOL by questionnaire, comparing experiences of those treated with S-1/CPT-11 to those treated with mFOLFOX6 in patients with advanced CRC. The questionnaire, selected from EORTC QLQ, FACT-G, and FACT/GOG-Ntx, consisted of six categories: moving activity, willingness, pain and numbness, gastrointestinal symptoms, daily life, and convenience. The questionnaire had 5 questions in each category and a total of 30 questions., Results: Patients' background and characteristics were similar. No significant difference was observed in response rates and time to progression between the groups. As for adverse effects, there was a case of fatigue (grade 2), five cases of neurotoxicites (grade 1 and 2) in mFOL-FOX6, and a case of diarrhea (grade 3) in S-1/CPT-11. No difference between the two groups was observed in responses to the questionnaire asking about moving activity, willingness, gastrointestinal symptoms, and daily life. As for neurotoxicity and convenience, however, S-1/CPT-11 showed significantly better results than mFOLFOX6., Conclusion: The present results suggest that questionnaires are useful for assessing patients' QOL with advanced CRC treated chemotherapy. Combination chemotherapy with oral fluoropyrimidine S-1 could provide similar response rates, limit inconvenience, and improve QOL.

Unlabelled: In colorectal cancer (CRC), 5-fluorouracil (5-FU) has been a basic chemotherapeutic agent. Orotate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TP) are essential enzymes for activation of 5-FU. Dihydropyrimidine dehydrogenase (DPD) is an enzyme for degradation. The feasibility of individualized chemotherapy was studied using the enzyme expression and drug sensitivity test., Methods: The study included 160 surgical patients (stage II to IV). OPRT, TP, and DPD expressions, assessed with immunohistochemistry, were evaluated in relation to clinicopathological features and patient survival. We assessed 5-FU sensitivity using the collagen gel droplet. Embedded culture-drug sensitivity test(CDDST). The area under the concentration curve (AUC) and growth inhibition curve (IR) were combined in the AUC-IR curve, according to which the individual AUC(IR₅₀) was calculated. Durations to achieve AUC(IR₅₀) were calculated using AUC(₂₄hr) values in UFT and S-1., Results: TP and DPD expression were positively associated with CRC progression and related with poor prognosis, although OPRT expression was negatively associated with CRC progression and related with better prognosis. Patient survival was best in patients with OPRT (+) DPD (-), and worst in those with OPRT (-) DPD (+). Individual AUC(IR₅₀) ranged from less than 100 mg·hr/mL to more than 10,000 mg·hr/mL. In the chemotherapy with UFT, 55% of patients achieved AUC(IR₅₀) within 6 months, 13% of patients achieved it 6 to 12 months, another 13% of patients in 12 to 24 months, and the other 19% after 24 months of chemotherapy. In the chemotherapy with S-1, 31% of patients achieved AUC(IR₅₀) within 1 course, 15% in 1 to 2 courses, another 23% in 2 to 6 courses and the other 31% of patients achieved AUC(IR₅₀) after 6 courses., Conclusions: The present results suggest that patients' prognosis may be improved with selection of an anti-cancer drug based on the 5-FU metabolizing enzyme expressions and prognostic factors. CD-DST may predict the duration of chemotherapy.

We report here two cases of recurrent gastric cancer after post operative adjuvant chemotherapy, in which S-1 has been effective to control the recurrence and provided long-term survival. Case 1: A 75-year-old male presented with malaise. Endoscopy showed an advanced gastric cancer. He underwent total gastrectomy with lymph adenectomy and received adjuvant chemotherapy with 3 courses of weekly paclitaxel and 6 months of UFT. An abdominal tumor developed with elevation of tumor markers 1 year and 2 months after surgery. After 5 courses of S-1(100mg/day), the tumor resolved and a complete response(CR)was obtained with decline of the markers for 2 years. Case 2: A 62-year-old male presented with abdominal pain. Endoscopy showed an advanced gastric cancer. He underwent distal gastrectomy with lymph adenectomy. Peritonitis carcinomatosa developed with ascites though adjuvant chemotherapy with UFT had been continued for 6 months after paclitaxel. After 10 courses of S-1(100 mg/day), ascites disappeared with decline of the markers. He has been well without any sign of recurrence or elevation of tumor markers for 2 years. Differences in the 5-fluorouracil concentration of UFT and that of S-1 may explain the effectiveness of S-1 for recurrence of gastric cancer after adjuvant chemotherapy with UFT.

We report a case of disease-free survival with low-dose of uracil-tegafur (UFT) after reaction of hepatic and pulmonary metastases from rectal cancer. A 58-year-old male had a medical history of low anterior resection of the rectal cancer. Hepatic and pulmonary metastases developed 3 years and 3 months after the primary operation. Image studies including computed tomography, ultrasonography, and angiography showed multiple metastases in the liver and lung. Two surgeries were performed to resect all of them, followed by adjuvant chemotherapy with low-dose UFT due to relatively low platelet counts. After surgery, the patient has been well without any sign of recurrence or elevation of tumor markers for 2 years and 10 months. This case indicated the usefulness of surgical resection of hepatic and pulmonary metastases, followed by low-dose adjuvant chemotherapy.

We report a case in which combination chemotherapy with oral fluoropyrimidine and weekly paclitaxel was effective for gastric cancer with peritoneal dissemination. A 44-year-old woman suffering from advanced gastric cancer with peritoneal dissemination underwent total gastrectomy. After surgery, combination chemotherapy with doxifluridine plus weekly paclitaxel was administered on an outpatient basis, and was effective without any sign of relapse of the disease for a year. However, she complained of dull abdominal pain, and ascites was observed 13 months after surgery. She received combination chemotherapy with S-1 plus weekly paclitaxel. The ascites decreased after 3 courses of the chemotherapy. No major adverse effect was observed except for grade 1 anemia and grade 2 hair loss. She has been well with the chemotherapy on an outpatient basis 18 months after surgery.

Primary chemotherapy for breast cancer (BC) has drawn attention to control of local diseases and enable breast conservative surgery. A 39-year-old woman presented with a large mass with dull pain in the right breast. Physical examination and image studies including ultrasound, mammography, and computed tomography showed a locally advanced BC (T4bN1M0, Stage IIIB). Aspiration cytology revealed class V cells. After obtaining informed consent, a sequential chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC 500/100/500 mg/m2) was given every 3 weeks 4 times, followed by weekly paclitaxel (80 mg/m2) for a consecutive 12 weeks on an outpatient basis. Although a complete clinical response was obtained after the chemotherapy, modified mastectomy and regional lymph adenectomy were performed, since the tumor had been locally advanced. No mass was observed in the surgical specimen without any adhesion to the muscle. Pathological findings revealed only small clusters of cancer cells, most of which were histologically damaged due to chemotherapy (Grade 2). FEC 100 followed by weekly paclitaxel was feasible and effective for primary chemotherapy for locally advanced BC.

Two cases of postoperative brain metastasis of breast cancer were evaluated after chemotherapy using ACNU. Case 1: A 47-year-old female, who had undergone right standard radical mastectomy in 1979 for breast cancer (T2 N0M0, papillo-tubular carcinoma), was treated with ADM, TAM, and 60Co irradiation for bone metastasis in 1983. In 1984, she complained of loss of consciousness and paralysis of the extremities due to brain metastasis. After chemotherapy using ACNU (100 mg X 3), brain metastasis could not be detected on CT. She remained asymptomatic for more than 9 months without recurrence after therapy. Case 2: A 46-year-old-female, who had undergone left standard radical mastectomy in 1980 for breast cancer (T1 N1 M0, medullar tubular carcinoma), complained of headache and vertigo accompanying a hard tumor in the scalp. Chest X-ray and CT demonstrated right lung metastasis and left cerebellar metastasis. After combination chemotherapy using ACNU (100 mg) + MMC (4 mg) i.v. and FT (600 mg/day) p.o., symptoms and tumor on CT disappeared for 10 months after therapy. However, the patient died of aggravation of angina pectoris and D.M. from which she had been suffering for several years previously. These two cases correspond to complete response (CR) according to the response criteria proposed by Koyama-Saitoh.