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Background: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen., Patients and Methods: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m 2 /day), doxorubicin (10 mg/m 2 /day), and vincristine (0.4 mg/m 2 /day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m 2 /day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6., Results: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation., Conclusion: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: We evaluated the efficacy and safety of a modified FOLFIRINOX regimen for chemotherapy-naïve patients with metastatic pancreatic cancer., Methods: Patients with untreated metastatic pancreatic cancer (MPC) received modified FOLFIRINOX (intravenous oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , 5-FU infusion 2400 mg/m 2 over 46 h, no bolus 5-FU). The primary endpoints were overall survival and the incidence of grade 3 or higher neutropenia. No patients received prophylactic pegfilgrastim., Results: Sixty-nine pts. were enrolled from 39 institutions in Japan. The median overall survival was 11.2 months [95% confidence interval (CI) 9.0-]. The median progression-free survival was 5.5 months (95% CI 4.1-6.7). The response rate was 37.7% (95% CI 26.3-50.2), and the disease control rate was 78.3% (95% CI 66.7-87.3). The incidence of grade 3 or higher neutropenia was 47.8%. Serious adverse events occurred in six patients (8.7%). All AE proportions were less than those in the previous Japanese full-dose phase II study. One patient died due to interstitial pneumonia related to treatment., Conclusion: This is the first prospective study of modified FOLFIRINOX in Asia. Modified FOLFIRINOX in this study has an improved safety profile with maintained efficacy in MPC without prophylactic pegfilgrastim.

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS>5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The prognostic implications of infra-diaphragmatic (InD) versus supra-diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression-free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n=35), and without (n=34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P=0.024, HR 0.09)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The MIB-1 labeling index, which is based on Ki67 immunostaining, is widely used to evaluate the proliferation of tumor cells in lymphoma. However, its clinical significance has not been fully assessed. We retrospectively evaluated the prognostic impact of the MIB-1 labeling index at the time of diagnosis, in 98 patients with follicular lymphoma (FL) grade 1-3b who were treated uniformly with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. The 5-year progression-free survival (PFS) for an MIB-1 labeling index of ≥10% (n = 60) and <10% (n = 38) was 35% and 61%, respectively (P = 0.015). The 5-year overall survival (OS) for an MIB-1 labeling index of ≥10% and <10% was 77% and 92%, respectively (P = 0.025). Pathological grading was not correlated with PFS or OS. In multivariate analysis, an MIB-1 labeling index of ≥10% was independently associated with poor PFS and OS. In conclusion, an MIB-1 labeling index of 10% is a useful cut-off level for predicting the prognosis of patients with FL., (© 2013 Japanese Cancer Association.)

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone., (© 2013 Blackwell Publishing Ltd.)

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in living patients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy.

Background: S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC., Patients and Methods: S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1., Results: Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%)., Conclusion: S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

We evaluated the effect of intra-arterial infusion chemotherapy associated with radiotherapy for two cases of local recurrence of rectal cancer. We performed an intra-arterial infusion chemotherapy (5-FU was injected continuously: 250 mg/day/body x 28 days, CDDP was injected weekly: 5 mg/day x 5 days) associated with radiotherapy (2-3 Gy/day x 20-30 days) for local recurrence of rectal cancer with the aim of pain-relief. Both patients markedly tended to feel less pain after the radiotherapy. Radiotherapy has been useful for pain-relief of the localized bone metastasis. The present intra-arterial infusion chemotherapy associated with radiotherapy was a possible local therapy for local recurrence of rectal cancer in the pelvis. Although the survival benefit depends on the presence of other site of recurrence, this procedure is useful for the improvement of QOL by relieving the pain of the patients.

The use of neoadjuvant chemotherapy for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors, especially for patients with Stage IV b (Japan criteria). We report our experience with a six-drug chemotherapeutic regimen that resulted in sufficient downstaging of the tumor in some patients to justify surgical resection. From Jan. 2001 through December 2003, 6 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg), according to the UCLA regimen and gemcitabine weekly (600 mg/m2) and heparin as a continuous infusion (0-3,000 U/day) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response and survival. There were 5 partial responses (83% response rate) and 1 no response. Four of 5 responding patients had sufficient tumor regression to meet clinical criteria for resectability, three of whom underwent a curative resection. All patients who underwent downstage operation were still alive for the follow-up period (4-23 months).

The safety of chemotherapy combining TS-1 and pirarubicin (THP) for treatment of recurrent or locally advanced gastric cancer was evaluated. THP was administered by intravenous drip infusion at a dose of 14 mg/m2 every other week. TS-1 was administered orally at a dose of 40 mg/m2 twice a day for 2 weeks followed by 2 weeks of rest (level 1), for 3 weeks followed by 2 weeks of rest (level 2), and for 4 weeks followed by 2 weeks of rest (level 3). Three patients were treated with the level 1 schedule. One patient with peritoneal dissemination received 22 courses of the treatment, and benefited from a long-term NC. However the remaining 2 cases were diagnosed as PD after 4 courses and were withdrawn from further treatment. Two patients in this group suffered from grade 2 adverse events according to the NCI-CTC. Only 1 patient who had liver metastasis was treated at level 2. Fourteen courses were administered, and a PR was achieved while grade 2 adverse events were observed. One of 3 patients who were treated with level 3 had grade 3 adverse events. Consequently, 3 more cases were added to this dose level, and no additional grade 3 adverse events were observed, while grade 2 adverse events were seen in 4 cases. Urinary urgency had completely disappeared in 1 patient with peritoneal recurrence. Myelosuppression, which was the main observed adverse event, was well controlled and of brief duration. The response, including alleviation of clinical symptoms, was confirmed in 3 of 5 chemo-naive patients.

We performed CHPP with concomitant use of CDDP and etoposide for prevention or treatment of peritoneal dissemination in gastric (10 cases) and colon (1 case) cancers with serosal invasion or peritoneal dissemination. The patients received intra-abdominal perfusion by saline heated to 41.5-42 degrees C dissolving CDDP and etoposide for 40-50 minutes. The blood concentrations of total CDDP and etoposide rapidly increased and reached maximum at the end of perfusion. Post-operative complications were more frequent in the group without STS than with STS. The prognosis of patients with peritoneal dissemination (P3) was poor, but ascites was observed to disappear in four of five cases. All patients with S (+) or P1 have been alive and free from disease for 1 to 12 months after CHPP. These results suggested that CHPP was effective for prevention and treatment of peritoneal dissemination.

Based on our experimental study, which indicated that simultaneous combined administration of MMC and CDDP prolonged life more significantly than individual administration, clinical application was performed on three cases of carcinomatous peritonitis from Borrmann type 4 cancer of the stomach. The dosage was 14 mg/m2 (7 mg/m2 at second and following administrations) of MMC and 35 mg/m2 of CDDP and they were repeatedly administered in the abdominal cavity via the drug delivery system. As the result, no severe toxicities were found except for two cases of leukopenia (Grade 2). Effectiveness was indicated in all cases with the negative change of cytology, whereas no improvements in prognosis were obtained. We concluded that some new devices would be necessary to increase the drug delivery to the carcinomatous wall.

In order to elucidate the effect of tumor vascularity on a various regimens concentration in tumor tissue, correlation among tegafur, 5-fluorouracil (5-FU), uracil concentrations in tissue and the microangiography were examined in 27 patients with colorectal cancer after preoperative administration of UFT (400 mg/day for 7 days). The concentrations of tegafur, 5-FU and uracil in tumor were higher than those in normal tissue (p < 0.01). There was no definite correlation between tissue concentration in each regimen and the extra or intramural vascular changes. A significant high concentration of 5-FU was found in the protuberant cancer and the ulcerative cancer with horizontal growth than that in the ulcerative cancer with vertical growth (p < 0.05). The present study indicates that the vascular changes within a tumor and the vascular pattern of tumor may be a contributing factor affecting the tissue concentration in the regimens.

A 56-year-old man who had undergone curative gastrectomy for Borrmann 2 type gastric cancer 43 months before, had a cancer recurrence (liver metastasis and peritoneal dissemination). Intra-arterial hypertensive chemotherapy with MMC for liver metastasis and intra-arterial sequential MTX/5-FU chemotherapy for peritoneal dissemination were given. He died of lung cancer with brain metastasis 27 months after this therapy. But in autopsy the remarkable effects of chemotherapy were recognized in intra-abdominal recurrent sites, and in fact, microscopically no cancer cells were found in metastatic lesions. We thus concluded that intra-arterial noradrenaline-induced hypertensive MMC therapy for liver metastasis and intra-arterial sequential MTX/5-FU therapy for peritoneal dissemination were useful treatment.

To prevent dissemination to the peritoneum following surgery for gastric cancer, examinations were performed with mouse ascites cancer models and the objective of enhancing the combined effect of MMC, CDDP and 5-FU. Pharmaceutical dosage was set at approximately 30% of the increased life span (ILS) for Meth-A. The dosage was 0.2 mg/kg for MMC, 1 mg/kg for CDDP and 37.5 mg/kg for 5-FU. Results indicated that simultaneous combination of 0.2 mg/kg of MMC and 1 mg/kg of CDDP extended life significantly more than individual administration, and clinical application of this combination was considered to be possible. In contrast, simultaneous combination of 1 mg/kg of CDDP and 37.5 mg/kg of 5-FU had no clear life-extending effect compared to individual administration of each. Some biochemical modulation of the administration method was thus considered necessary.

Three cases of bile duct necrosis owing to hepatic arterial infusion chemotherapy (HAI) were reported. Regarding HAI, transcatheter hepatic arterial embolization (TAE) was applied in two cases (hepatocellular carcinoma: 1; metastasis: 1) and 5-fluorouracil (continuous) combined with leucovorin (one shot) therapy (LV + 5-FU) was given to one metastatic case. In the data of blood biochemistry, serum alkaline phosphatase, gamma-glutamyl transpeptidase, and leucine aminopeptidase values characteristically elevated without the elevation of total bilirubin value. Hepatic tumors degenerated with necrosis in all cases and no viable cells were histologically recognized. Although the destruction of bile ducts was locally detected adjacent to these tumors in TAE cases and was more widespread in the LV + 5-FU case, these lesions were very similar in each case. Therefore, we concluded that both ischemia and drug toxicity induced bile duct necrosis and the necrosis around the bile duct was the secondary change due to the leaked bile juice.

One hundred and thirty-seven cases of stomach cancer given fluoropyrimidines (UFT: 66 cases, Tegafur: 58 cases, 5-FU: 13 cases) after gastrectomy as the adjuvant chemotherapy were examined as to appearance of macrocytic anemia. The mean corpuscular volume (MCV) gradually elevated in all cases but seven after administration. Macrocytic anemia, defined by the elevation over 20% compared with both pre-operative and pre-administrative values of MCV, was developed 30.3% in UFT group, 8.6% in tegafur group and 30.8% in 5-FU group. The incidence was statistically higher in UFT group (p less than 0.01) and 5-FU group (p less than 0.05) than in tegafur group. The cause was attributed to fluoropyrimidine administration because the serum folate and vitamin B12 levels remained normal and the value of MCV normalized after cessation of administration. Each total dose to induce macrocytic anemia was potentially about 70g in UFT. 100g in tegafur and 30 g in 5-FU. In conclusion, periodical hematological examination is necessary for the patients given fluoropyrimidine preparations.

We used treatment with intra-arterial injection in cases of liver and peritoneal metastasis in progressive or recurrent gastric cancer patients. The investigation of the relationship between efficiency of therapy and survival period was evaluated. The effective rate of sequential treatment of peritoneal metastasis with MTX.5-FU in 34 cases was 35.3%, while that of liver metastasis with MMC combined with DSM in 12 cases was 50%. Although the effective rate among 16 cases treated with MMC.5-FU combined with Angiotensin II was 50%, no effect was recognized in the groups treated with AF and MF. In cases of peritoneal metastasis with MTX.5-FU, the prognosis PR cases was significantly better than that of NC.PD. For treatment of liver metastasis with MMC combined with DSM and MMC.5-FU combined with Angiotensin II, the PR prognosis was unsatisfactory and the survival period did not significantly improve compared with that of NC.PD. In future cases of liver metastasis, these results indicate the extreme difficulty in maintaining therapy and controlling the lesion after PR. We speculated that sequential treatment of peritoneal metastasis with MTX.5-FU was useful because it significantly extended the survival period in PR cases.

Fifty-five gastric cancer patients with liver metastasis received arterial infusion chemotherapy. In 14 patients who had lesions in the liver intra-hepatic artery infusion chemotherapy was performed, while in 41 patients who had lesions in the liver and other sites intra-aortic infusion chemotherapy was performed. Methods for inserting the catheter into the aorta or hepatic artery and treatment schedules were reported previously. Between 1975 to 1981, 33 gastric cancer patients with liver metastasis were treated with 5-FU only (4 cases). MMC.5-FU (18 cases) and ADM.5-FU (11 cases). No response was seen, but minor response was seen in two cases. Between 1982 to 1988, 22 gastric cancer patients with liver metastasis were treated using arterial MMC.5-FU therapy combined with angiotensin II (13 cases), arterial MMC therapy combined with degradable starch microsphere (6 cases) and sequential MTX.5-FU (3 cases). The response rate of MMC.5-FU therapy combined with angiotensin II was 5/13 (38%) including one complete response. The responders of MMC-combined DSM therapy were seen in 3 (50%) out of 6 patients. However, no response was seen in sequential MTX.5-FU therapy. In the present study, a 61-year-old patient treated with MMC.5-FU combined with angiotensin II therapy, survived for 49 months after treatment. In order to improve the prognosis of gastric cancer patients with liver metastasis, it is important to increase the delivery of anticancer drugs to the target tissues by using certain drugs like angiotensin II and DSM. In the future, further studies should be done to prolong the duration of remission by arterial chemotherapy.