Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer.

The result of prospective, randomized, controlled, trial, Japan Clinical Oncology Group (JCOG) 0802/ West Japan Oncology Group( WJOG) 4607L, has been published in April 2022. The superiority in overall survival for patients who underwent segmentectomy for small sized peripheral non-small cell lung cancer( NSCLC)( whole tumor size≤2 cm, C/T ratio>0.5) compared with those undergoing lobectomy has been demonstrated for the first time in the world. Segmentectomy might become a standard surgical procedure for such tumors. Consequently, the opportunity to perform segmentectomy will increase. Developing techniques for segmentectomy is an urgent issue for general thoracic surgeons because segmentectomy generally requires more advanced surgical technique than lobectomy. In particular, the radical segmentectomy is an anatomically limited resection with hilar and mediastinal lymph node dissection. That means anatomically accurate resection of the pulmonary segment. There are a lot of points to be mastered in operative indications based on tumor size, phenotype, and location, understandings of anatomy, surgical techniques, transition to lobectomy, and so on. In this article, we would like to share some tips on segmentectomy primarily focusing on the surgical techniques.

In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

We have reported, in a randomized, controlled study, that tegafur-uracil(UFT)and protein-bound polysaccharide K(PSK)combination therapy significantly improves the 5-year disease-free survival rate and reduces the risk of recurrence compared to UFT alone for Stage II or III colorectal cancer. In this study, we examined the efficacy of PSK by stratifying patients according to the preoperative lymphocyte ratio(Lym).

This is a randomized phase II trial to evaluate non-inferiority of progression-free surviva(l PFS) by comparing S-1 and S-1/PSK for advanced or recurrent gastric cancer. Sample size was calculated to be 120. However, the trial was terminated because of slow accrual. This exploratory analysis was done by collecting the minimum data.

Subjects were 239 patients with colorectal cancer who underwent curative resection surgery from December 1994 to March 1997(Stage I-III b). The patients were given 5'-DFUR for postoperative 10 months as scheduled. They had been allocated into either a 1-year group or a 3-year group by dynamic randomization. 5'-DFUR was administered by an intermittent regimen such as 1,200 mg/body/day for five days followed by two days rest. All patients were followed for five years at least.

Randomized phase III study of S-1 alone versus S-1 plus Lentinan (LNT) in advanced or recurrent gastric cancer started in February 2007 conducted by the Japanese Foundation for Multidisciplinary Treatment of Cancer. The objective of this study is to evaluate the superiority of S-1/LNT to S-1 alone. The primary end point is to compare over all survival between both treatment groups. Secondary end points include time to treatment failure, the grade and rate of the adverse events, the evaluation of quality of life (QOL), response rate evaluated by RECIST and immunological parameters. QOL is evaluated by Japanese version of FACT-BRM questionnaire. Immunological parameters include serum complements (CH50, C3) and beta-1, 3 binding monocytes. The sample size is estimated at 150 patients per arm. Registration period is 2 years with 2-year follow-up. This study has a chance to prove the efficacy of the non-specific biological response modifier. We will have to cooperate in order to make this study a success.

Intravesical chemotherapy is performed after transurethral resection of bladder tumor (TURBT) for superficial bladder cancer. We conducted a prospective randomized controlled study on the prophylactic effects of intravesical instillation of epirubicin (EPI) against recurrence to determine the effective administration schedule. Between April 1999 and March 2003, 54 patients with superficial bladder tumor (pTa or pT1, and G1 or G2 cancer) were assigned to two groups (25 in Group A, 29 in Group B) after TURBT. The schedule of instillation (intravesically 40 mg of EPI dissolved in 40 ml saline) was subsequently once every two weeks for 3 months (7 times) starting one week after TURBT (Group A, short period), and subsequently added every two weeks for 3 months starting 6 months after TURBT (Group B, long period). The patients were followed up by cystoscopy and urinary cytology. There was no significant difference in non-recurrence rates after either one year (A; 62.5%, B; 82.8%) or three years (A; 53.6%, B; 67.3%). A univariate analysis demonstrated that tumor grade and staging were significant predictors of high risk for recurrence. A multivariate analysis performed by using the Cox's proportional hazard model showed that the schedule of instillation was an independent prognostic factor for reccurence. In the present study, only 2 patients showed progression and one patient died of UC. There was no adverse event that forced discontinuation of the therapy. In conclusion, epirubicin instillation influenced the prevention of recurrence, but the benefit of long-term period was not confirmed.

To evaluate the chemotherapeutic regimens suitable for the outpatient settings, we conducted a randomized phase II study of carboplatin/paclitaxel followed by gemcitabine versus carboplatin/gemcitabine followed by docetaxel.

The safety of docetaxel (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) every three weeks (TC) as adjuvant therapy for Japanese women with operable breast cancer was evaluated. Ehime TC Study Group initiated the randomized control study,which compared the effects of the TC course number (4 cycles versus 8 cycles) in the adjuvant setting on the treatment outcomes of breast cancer patients. Eight patients were investigated on the side effects of TC therapy, four of them were allocated to 4 cycles of TC, and four to eight cycles from May, 2004 to Feb. 2005. Leukocytopenia and neutropenia of grade 3 or 4 were seen in 50% and 63% of the cases, respectively. No febrile neutropenia was seen. Although the non-hematological side effects of grade 3 or 4 were not observed, alopecia, stomatitis, skin toxicities and edema of grade 2 were seen in 100%, 25%, 25%, 13% of cases, respectively. TC therapy was well tolerated. All anticancer drugs could be administered as scheduled. From these preliminary results, TC therapy seems to be able to be safely prescribed postoperatively for Japanese women operated for breast cancer.

In order to establish a reasonable prophylactic hepatic arterial infusion (HAI) chemotherapy following curative resection of colorectal liver metastases, the authors performed a randomized control study comparing two regimen. A weekly 5 hour-administration of 5-FU (1500 mg) which was repeated for 8 weeks showed a comparable effect to a continuous infusion group with an identical total dosage of 5-FU. Furthermore, adverse events were observed in only several patients of each group with low grade severity, suggesting that this simple regimen with a weekly HAI is promising. We also analyzed the clinical course of patients receiving HAI using a W spiral catheter which has a shape memory alloy in its tip. The catheter was implanted angiographycally without coil fixation to the vascular wall, which allowed us to remove the catheter after cessation of the scheduled chemotherapy. In all of the patients, the catheters were easily removed without any complications. A 3D-CT angiograph revealed that the hepatic arteries were well patent in all of the patients with a 3.3 Fr type catheter. HAI chemotherapy is basically an invasive treatment. In consideration of its efficacies as well as limitations, a reasonable approach is needed from the viewpoint of patients' quality of life.

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.

E-selectin is an adhesion molecule developed as an important material for hematogenous metastasis of cancer cells on vascular endothelial cells. It is expected that if we can restrain a manifestation of E-selectin then hematogenous metastasis can be restrained. We divided gastric cancer and the colorectal cancer patients, who performed chemotherapy, into two groups of cimetidine administrated group and a non-administration group, and reviewed whether cimetidine inhibited an expression of E-selectin on vascular endothelial cells by measuring E-selectin in plasma. We experienced one example that showed an interesting change of E-selectin and the quantity of E-selectin in plasma fell during the cimetidine dosage. However, we report that E-selectin has risen after the cimetidine dosage was cancelled in the cimetidine administrated group.

A randomized controlled trial of intermittent hepatic arterial infusion of weekly high-dose 5-FU (WHF) after resection of hepatic metastases from colorectal cancer was conducted to study the survival benefit of two regimens. Patients were randomly assigned to receive one of two arms after resection of hepatic metastases: the WHF arm (study group), 1000 mg/m2 of 5-FU administered over the course of 5 hr once a week by hepatic arterial infusion; or the CVI arm (control group), 300 mg/m2 of 5-FU administered as a continuous intravenous infusion daily for 5 days followed 2 days' rest. This study is the first randomized trial of hepatic arterial infusion chemotherapy with percutaneous hepatic catheter placement and assessment of liver drug distribution by CT angiography after resection of hepatic metastases from colorectal cancer in the world. Fifty-two centers participated, and 91 patients were enrolled. Although the target number of patients was not enrolled, problems of this study and future prospects for trials of hepatic arterial infusion after resection of hepatic metastases were assessed by questionnaire surveys of the participating centers.

The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.

We conducted a joint study of different duration of drug administration for oral adjuvant chemotherapy using camphor (HCFU) with patients having advanced colorectal cancer who underwent curative resection. The patients were randomly divided into 2 groups, according to length of HCFU administration (6-month group and 2-year group), and followed up for 5 years postoperatively. In total, 239 patients were originally enrolled, out of which 155 were chosen as subjects for this study. There was significant difference in the overall cumulative 5-year survival rate between the short-term group and the long-term group (78.1% vs 89.6%). Between the respective subgroup that was defined by tumor location (colon or rectum), no differences were observed, but there was significant difference in the subgroup that was defined by the presence/absence of lymph node metastasis (59.4% vs 83.9%). It appears that oral adjuvant chemotherapy with HCFU is more effective when administered for 2 years than for 6 months.

The efficacy and safety of preoperative chemotherapy with carmofur (HCFU) for colorectal cancer were evaluated in a randomized controlled study involving 63 institutes in the Kanto area. Patients aged 75 or younger with Dukes' B or C colorectal cancer were eligible if curative surgery was expected. In the end, 326 were eligible from 405 consecutive colorectal cancer patients. Patients in both the control (n = 162) and the new treatment group (n = 164) were given intravenous mitomycin C (MMC) 6 mg/m2 on day 0 and 7 after surgery and HCFU 300 mg/day orally from day 14 for a year. Patients in the new treatment group were also given oral HCFU for 14 days or more prior to surgery. All 326 patients were followed for 5 years or longer. Five-year overall and disease-free survival rates were not significantly different between the two groups (75.4% and 71.6% for the control, and 71.8% and 71.5% for the study group, respectively). In the subset analysis, neither cancer site nor nodal status affected the differences in overall- and disease-free survival rates between the groups. The present findings show no additional efficacy of preoperative chemotherapy with HCFU in survival from advanced colorectal cancer. Further investigations in terms of patient selection, treatment regimen, combined use of radiotherapy, and other factors would be required to determine the significance of preoperative chemotherapy against advanced colorectal cancer.

The purpose of the present multi-center collaborative study was to elucidate the efficacy of intraportal chemotherapy with the combination of 5-FU and MMC for the prevention of liver recurrence after resection for colorectal cancer. A total of 125 patients with Stage II, III, and IV colorectal cancer were enrolled in this study between June 1993 and December 1995. Of them, 45 patients were randomized to a portal group: 10 mg/body of mitomycin one shot portal infusion, before and after 500 mg/m2 of 5-FU per 24 h for 7 days portal infusion followed by administration of oral 5-FU. Fifty-three patients were randomized to a control group: oral administration of 5-FU. Twelve patients suffered from temporary mild liver damage. One patient (2%) in the portal group and 6 patients (11%) in the control group developed liver metastases; there was not a significant difference between these two groups regarding development of liver metastases. There was also no significant difference by tumor stage between the portal and control groups regarding development of liver metastases. The 5-year survival rate and 5-year disease-free survival were 84.3% and 81.9%, respectively, in the portal group, and 70.7% and 72.4%, respectively, in the control group; the difference was not significant. Although there was not a significant difference between the portal and control groups regarding the prognosis in stage II, there was a significant difference between the portal and control groups regarding the 5-year disease free survival in stage III (81.1% vs 54.2%). These results suggest that intraportal chemotherapy is effective for stage III colorectal cancer.

The authors analyzed the histological effect of preoperative chemotherapy for 62 advanced colorectal cancer patients using resected specimens. Thirty-one patients in the 5'-DFUR + LV group received 800 mg/day of 5'-DFUR and 30 mg/day of leucovorin for 10-14 days just before the operations. Thirty-one patients in the 5'-DFUR group received 5'-DFUR 800 mg/day during the same period. None of the patients in either group developed any side effects. The results of the histological examination showed the number of Grade 1a and 1b cases in the 5'-DFUR + LV group was 22 (66.7%) and 5 (15.2%), respectively, and in the 5'-DFUR group 21 (65.6%) and 5 (15.6%). In the 5'-DFUR + LV group, 3 lesions showed Grade 2 histological degeneration, while there were no such lesions in the 5'-DFUR group. However, our results did not demonstrate any statistical difference between the two groups (p = 0.25, U test).