Search

Although the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL) are similar, few studies have compared its outcomes for T-ALL/LBL and Ph-negative B-ALL. The clinical data of 28 patients with T-ALL, 16 with T-LBL, and 99 with Ph-negative B-ALL who underwent the first allo-HSCT from 2000 to 2019 were retrospectively analyzed. Complete remission (CR) rates at allo-HSCT were 79 %, 63 %, and 75 % for T-ALL, T-LBL, and B-ALL, respectively; the 3-year overall survival (OS) rates were 55.7 %, 56.2 %, and 58.6 %, respectively (p = 0.92). Univariate analysis revealed that disease subtypes were not significantly associated with OS (B-ALL vs. T-ALL: hazard ratio [HR]=0.89, p = 0.70; T-LBL vs. T-ALL: HR=0.87, p = 0.75), and CR at allo-HSCT was the only prognostic factor for OS (HR=0.25, p < 0.001). Multivariate analysis demonstrated that CR at allo-HSCT was the only predictor of OS (HR=0.24, p < 0.001). In all three disease subtypes, patients in CR at allo-HSCT tended to have a lower cumulative incidence of relapse than did those in non-CR (T-ALL: 13.6 % vs. 50.0 %, p = 0.10; T-LBL: 20.0 % vs. 50.0 %, p = 0.21; B-ALL: 10.0 % vs. 56.0 %, p < 0.01). Thus, the outcomes of allo-HSCT for T-ALL/LBL were comparable to those of Ph-negative B-ALL. Irrespective of the disease subtypes, achieving CR before allo-HSCT was associated with a favorable OS. Further advances in chemotherapy before allo-HSCT and defining the optimal timing of allo-HSCT would improve the prognosis of patients with T-ALL/LBL., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A 60-year-old man underwent distal pancreatectomy with splenectomy and combined resection partially of the stomach, jejunum, and left renal vein. We administered S-1 adjuvant chemotherapy for 1 year. After its completion, the patient showed no evidence of recurrence. However, his carbohydrate antigen(CA)19-9 level was elevated for 1 year and 8 months postoperatively. We administered gemcitabine chemotherapy. He was admitted for bowel obstruction 3 years and 10 months postoperatively. Conservative treatment with an ileus tube did not improve the bowel obstruction. Therefore, we performed the surgery. Intraoperative findings revealed peritoneal nodules invading the small intestine. We performed a small bowel bypass. Pathological examination revealed the peritoneal nodule of pancreatic cancer. Although we administered FOLFIRINOX chemotherapy postoperatively, his CA19-9 level remained elevated for 4 years and 8 months after the first surgery. Therefore, chemotherapy was changed to gemcitabine and nab-paclitaxel. Six years and 11 months after the first surgery and 5 years and 3 months after the diagnosis of peritoneal dissemination, he survives with recurrence. Herein, there were 2 contributors to long-term survival; the patient not only showed positive responses to each chemotherapy regimen but could also continue chemotherapy without developing significant adverse effects.

Background: Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection., Methods: We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed., Results: A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration., Conclusions: Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.

Purpose: The aim of this study is to evaluate the safety and efficacy of induction modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab followed by S- 1-based chemoradiotherapy in magnetic resonance imaging (MRI)-defined poor-risk locally advanced low rectal cancer., Patients and Methods: This was a prospective phase II trial at a single comprehensive cancer center. The primary endpoint was the pathological complete response (pCR) rate. Eligible patients had clinical stage II-III low rectal adenocarcinoma with any of the following MRI-defined poor-risk features: circumferential resection margin (CRM) ≤ 1 mm, cT4, positive lateral nodes, mesorectal N2 disease, and/or requiring abdominoperineal resection. Patients received six cycles of mFOLFOX6 with 5 mg/kg bevacizumab followed by oral S-1 (80 mg/m 2 /day on days 1-14 and 22-35) plus radiotherapy (50.4 Gy). Surgery was conducted through a laparoscopic approach. Lateral node dissection was selectively added when the patient had enlarged lateral nodes., Results: A total of 43 patients were enrolled. Grade 3-4 adverse events occurred in nine patients during induction chemotherapy and in five patients during chemoradiotherapy. One patient declined surgery with a clinical complete response. Forty-two patients underwent surgery, and 16 had pCR [37.2%, 95% confidence interval (CI) 24.4-52.1%]. All underwent R0 resection without conversion, including combined resection of adjacent structures (n = 14) and lateral node dissection (n = 30). Clavien-Dindo grade 3-4 complications occurred in six patients (14.3%). With median follow-up of 52 months, six developed recurrences (lung n = 5, local n = 1; 3-year relapse-free survival 86.0%)., Conclusions: This study achieved a high pCR rate with favorable toxicity and postoperative complications in poor-risk locally advanced low rectal cancer. Multicenter study is warranted to evaluate this regimen.

Background: Disseminated adenovirus (ADV) infection is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, it is rare following autologous peripheral blood stem cell transplantation (auto-PBSCT) or chemotherapy alone., Case: A 66-year-old Japanese female with relapsed and refractory multiple myeloma (RRMM) received auto-PBSCT, achieving partial response. To obtain a greater response, pomalidomide/dexamethasone was started on day 28 after auto-PBSCT, but was stopped on day 41 due to thrombocytopenia, fever, and gross hematuria. Additionally, she complained of abdominal pain on day 46. Blood tests revealed elevation of transaminases and alkaline phosphatase. There was no evidence of bacterial or fungal infections or progression of MM. ADV titer in urine and serum were 3.41 × 10 5 copies/mL and 6.76 × 10 3 copies/mL, respectively. CT scans revealed cystitis, urethritis, and peritonitis. Since more than two organs were infected with ADV, she was diagnosed with disseminated ADV disease. After 5 weeks of supportive care, all symptoms resolved. ADV titer decreased to 5.90 × 10 2 copies/mL in urine and became negative in serum on day 80. However, she succumbed to the MM a little more than a month later., Conclusion: Disseminated ADV infection can occur even in non-allogeneic transplant settings, such as in severely immunocompromised patients with MM who receive auto-PBSCT and repeated salvage therapies. Although it is a rare event, the mortality rate of this disease is very high, and hence, early diagnosis and interventions are needed in suspected cases., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Past studies have suggested that adjuvant capecitabine and oxaliplatin (CAPOX) provides decreased tumor relapse and longer survival in patients with curatively resected colon cancer. We report the first evidence of the feasibility of adjuvant CAPOX in Japanese patients with early colon cancer., Patients and Methods: Eligible patients had histologically-confirmed stage II/III colon cancer and received curative resection. The primary endpoint was completion rate of treatment after 8 cycles of adjuvant CAPOX., Results: Thirty-six patients were enrolled in this study. The completion rate of CAPOX and oxaliplatin were 77.8% and 61.1%, respectively. The incidence of grade ≥3 adverse events was neutropenia (n=6), thrombocytopenia (n=3), nausea (n=5), hand-foot syndrome (n=1) and peripheral sensory neuropathy (n=1). Three-year disease-free survival for stage II patients and stage III patients were 100% and 79.3%, respectively., Conclusion: Adjuvant CAPOX can be safely administered to Japanese patients with stage II/III colon cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The patient was a 65-year-old man who underwent colonoscopy for melena. Following a biopsy, the patient was diagnosed with anal canal squamous cell carcinoma. A computed tomography (CT) scan revealed metastasis to the regional lymph nodes. The proposed treatment regimen comprised radiotherapy combined with S-1 and mitomycin C (MMC). Dur- ing radiotherapy (59.6 Gy in 32 fractions), 10mg/m² MMC was administered, as an intravenous bolus injection, on days 1 and 29. S-1 was administered orally, at a dose of 80 mg/m², on days 1-14 and 29-42. No serious adverse events were observed during chemoradiotherapy; the observed adverse events were leukemia (Grade 2), diarrhea (Grade 1), anorexia (Grade 1), and radiation dermatitis (Grade 1). After 8 weeks of treatment, no tumors, only scar tissue could be detected by using colonoscopy, and a CT scan revealed a remarkable reduction in regional lymph node metastases. The patient achieved a complete response.

Background: The significance of lateral pelvic lymph node (LPLN) metastasis in advanced low rectal cancer treated with preoperative chemoradiotherapy (CRT) remains unclear. The objective of this study was to evaluate the outcomes of selective LPLN dissection (LPLD) based on the pretreatment imaging in patients with advanced low rectal cancer treated with preoperative CRT., Methods: We reviewed 127 consecutive patients with clinical stage II-III low rectal cancer below the peritoneal reflection who underwent preoperative CRT and curative resection. LPLD was performed in patients with suspected LPLN metastasis based on MDCT or MRI before CRT (LPLD group, N = 38), and only total mesorectal excision (TME) was performed in patients without suspected LPLN metastasis (TME group, N = 89). Clinical characteristics and the oncological outcome were compared between groups., Results: The median tumor-to-anal verge distance was 40 mm in both groups. The median maximum long-axis LPLN diameter before CRT was 0 mm in the TME group and 10.5 mm in the LPLD group. Pathological LPLN metastasis was confirmed in 25 patients (66 %) in the LPLD group. Local recurrence at LPLN developed in 3 patients (3.4 %) in the TME group and in none (0 %) of the LPLD group. Multivariate analysis showed that only ypN was an independent prognostic factor for relapse-free survival (RFS), but LPLN metastasis was not associated with poor RFS., Conclusions: The incidence of LPLN metastasis is high even after preoperative CRT, and LPLD might improve local control and survival of patients with LPLN metastasis in advanced low rectal cancer treated with preoperative CRT.

We report a case of consciousness disorder following the fourth course of chemotherapy with cisplatin (CDDP) and 5- fluorouracil (5-FU) in a patient with esophageal cancer. A 74-year-old man was admitted to our hospital to receive chemotherapy for esophageal cancer. Six days after chemotherapy, the patient showed impaired consciousness and his serum sodium concentration was found to be 125 mEq/L, but no edema or dehydration was noted. This hyponatremic state was diagnosed as CDDP-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) on the basis of serum and urine hypo-osmolality. Accordingly, fluid intake was restricted and sodium supplements were administered, resulting in an appropriate increase in the serum sodium concentration to 132 mEq/L in 4 days.

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.

A 60-year-old man underwent sigmoid loop colostomy for obstructive rectal cancer. Computed tomography (CT) showed a circumferential thickening of the lower rectal wall caused by a tumor invading the posterior and side pelvic wall. As we considered R0 resection too difficult, we gave the patient bevacizumab plus FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil). After eight courses, CT showed improvement in the rectal wall thickening but linear thickening of the mesorectal fascia remained. We therefore gave the patient chemoradiotherapy (CRT), and then 10 weeks later performed Hartmann's operation laparoscopically. Microscopic examination revealed that the tumor had been almost replaced by fibrous tissue, with only a few cancer cells left in the subserosa. The circumferential resection margin was free of cancer cells. The patient is doing well after 27 months of follow-up. This case suggests that systemic chemotherapy with FOLFOX4 plus bevacizumab prior to conventional preoperative CRT is a promising strategy for patients with initially unresectable locally advanced rectal cancer.

Purpose: FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples., Patients and Methods: Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method., Results: We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively., Conclusion: The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis.

We report a patient with locally advanced gastric carcinoma successfully treated with S-1/CDDP. The patient was a 77-year-old woman who had gastric cancer surgically diagnosed as T4N2, invading the pancreas and mesocolon. After the firsts exploratory laparotomy, chemotherapy was begun as follows. S-1(80 mg/day)was orally administered for 3 weeks followed by 2 weeks' rest as a course, and CDDP(75 mg/body)was administered by intravenous drip on day 8. Because of severe anorexia and nausea, however, the CDDP administration had to be discontinued. Therefore, we changed the procedure to S-1 single treatments, 2 weeks' administration followed by 2 weeks' rest. The total 9 courses of this procedure proved successful. Subsequently, she underwent curative surgery consisting of total gastrectomy with D2 lymph node dissection, combined with distal pancreatectomy and splenectomy, and obtained pathological CR. S-1/CDDP appears to be an effective treatment modality for advanced gastric cancer.

A 50-year-old man was referred to our department with esophageal cancer. He had past history of small cell lung cancer treated with chemoradiation therapy 10 years prior. The disease was evaluated as complete remission after chemoradiation therapy and no recurrence had been observed. Esophagectomy accompanying postoperative chemotherapy was applied, but he died of secondary myelodysplastic syndrome with its acute myeloblastic transformation. Risk evaluation revealed a high incidence of esophageal cancer after radiation therapy and hematological malignancies after chemoradiation therapy in usual regimen with topoisomerase inhibitor or alkylating agents. Chemoradiation therapy is thought to be one of a few highly effective therapeutic alternatives and many complete remission cases have been reported in small cell lung cancer or esophageal cancer. In post-therapeutic follow up of patients with such past therapeutic histories, we should be cautious about secondary malignancies even if primary malignant disease was evaluated as complete remission in long past history., (Copyright 2005 Blackwell Publishing Asia Pty Ltd.)

The patient was a 73-year-old man with unresectable advanced gastric cancer and celiac and supraclavicular lymph node metastases. Neoadjuvant chemotherapy consisting of paclitaxel (TXL) and CDDP was administered. TXL (80 mg/m2) and CDDP (25 mg/m2) was administered weekly on day 1, 8 and 15 as 1 cycle. After 4 cycles of TXL/CDDP administration, the lymph node metastases and gastric tumor had decreased almost completely in size and distal partial gastrectomy was performed. After surgery, the patient was treated with 4 courses of TXL/CDDP and has survived without recurrence to the present. TXL/CDDP is associated with few adverse events in hospital visits, and is thought to be an effective chemotherapy against advanced gastric cancer.

Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents have been widely used in both registered and non registered indications and are frequently combined with other cytotoxics. In Japan, cisplatin has been used successfully at low doses in combination with 5-FU based regimens and appears to achieve a synergistic effect, but controlled data are not yet available. More recently oxaliplatin (Europe) and nedaplatin (in Japan) have been introduced, but their clinical roles in therapy have yet to be established. One of the limiting features of the first generation of platinum compounds is that a significant proportion of tumours develop cross resistance to platins due to either changes in uptake or excretion, intracellular detoxification or accelerated DNA repair. The forum discussed the possibility for the development of better new platinum compounds, A new platin agent which had lower toxicity and higher efficacy across a wide range of cancers without the development of resistance would be a significant step forward. If the tolerability profile was suitable, an oral formulation may improve the quality of life for patients but this must not be at the expense of efficacy. Even after the introduction of new target based drugs, platinum cytotoxics are likely to be used to reduce the tumour mass and in some cases can be expected to potentiate the effects of the new agents. In preclinical studies, ZD0473 has been shown to by-pass some major mechanisms of resistance and has the potential to achieve these objectives and is now being evaluated in clinical studies in both Japan and the West.

Background: A combination of chemotherapy and radiotherapy (chemoradiation therapy; CRT) has recently been developed to improve the survival of esophageal cancer patients. However, the optimal choice of chemotherapeutic agents and their doses, as well as chemotherapy and radiotherapy regimens, remain unclear., Methods: Based on recent advances in knowledge on the radiosensitizing and biochemical modulation effects of chemotherapeutic agents, we have recently developed concurrent CRT which consisted of continuous 5-fluorouracil (5FU) administration (600 mg/m2/day, days 1-5) combined with a low dose of daily cisplatin administration (10 mg/m2/day, days 1-5, and 5 or 10 mg/m2/day, days 8-12 and 15-19) before each fraction of radiation (2 Gy each). To evaluate the efficacy and safety of our concurrent CRT, 10 esophageal cancer patients received one or one and a half courses of the CRT., Results: All patients tolerated and completed a full course of the CRT. The effectiveness of the CRT on the primary tumor included pathologically or endoscopically complete responses in three patients (30%), partial response in five (50%), no response in two (20%) and tumoral downstaging (T-classification) in five (50%). Grade 2 and Grade 3 toxicity, seen in six patients, did not affect surgical operation. No patients showed CRT-related deaths. Eight patients (80%) underwent resection with no operative mortality. Of these, two patients (25%) showed pathologically or endoscopically complete responses, and four (50%) showed partial response. Three patients died of cancer after resection. The two inoperable patients showed a pathologically complete response and partial response, respectively. They were relieved of their cancer-related complaints and were living without hospitalization at the time of this analysis., Conclusions: These results suggest that the concurrent CRT based on the theoretical backgrounds is effective and has acceptable toxicities with maintaining its efficacy for the treatment of esophageal cancer patients.

The first clinical application of biochemical modulation (BCM) of 5-fluorouracil (5-FU) was the sequential MTX/5-FU regimen proposed in 1977 by Bertino for the treatment of colorectal cancer. In Japan, sequential MTX/5-FU therapy was mainly used as a new method of treating gastric cancer, and attracted a great deal of attention because it proved effective in many cases of advanced gastric cancer that had been unresponsive to the previous chemotherapy, particularly scirrhous gastric cancer with poor prognosis. Its therapeutic efficacy varied according to histologic type, it was effective in cases of peritoneal dissemination and disseminated intravascular coagulopathy (DIC), it was associated with fewer adverse effects, and it was a multidrug chemotherapy based on a clear rationale. With sequential MTX/5-FU therapy as a starting point, fundamental studies of BCM and its clinical applications have expanded rapidly in Japan. This paper provides an outline of sequential MTX/5-FU therapy from the aspects of its mechanism of action, indications, therapeutic efficacy, relevance to adjuvant therapy, counter-measures to adverse effects, and emergence of resistance to the drugs involved. The high therapeutic efficacy of this therapy in certain histologic types is also discussed, and its combined use with other forms of BCM, as in triple BCM (LV/5-FU + CDDP/5-FU + MTX/5-FU), is introduced.

In Japan, long-term oral therapy with tegafur in combination with immunopotentiators is commonly used as adjuvant therapy after curative resection of gastric or colorectal can for gastric and colorectal cancer. When the outcome was analyzed in terms of the relative performance (R.P.) and the individual dose intensity (I.D.I.) of OK-432, gastric cancer patients with a R.P. of 0.5 or higher tended to have a better survival curve. There were no marked differences in lymphocytes subsets, except that the Leu 7 level at 3 months after gastric cancer resection was significantly higher (p < 0.05) in group B than in group A. Thus, no inhibition of the anticancer effect of UFT was noted during long term combination therapy with UFT and an immunopotentiator as postoperative adjuvant therapy for patients who underwent curative resection of gastric or colorectal cancer. The results suggest that UFT combined with long-term OK-432 maintenance therapy may contribute to improve survival rates in gastric cancer patients.

At present curative resection is the only radical treatment for gastric cancer, although recently developed combination chemotherapy shows increased activity in treating locally advanced and metastatic disease. Among several combination regimens, those based on biochemical modulation, such as sequential methotrexate/5-fluorouracil or low-dose CDDP/5-fluorouracil, are thought to provide increased efficacy with decreasing adverse reactions in unresectable gastric cancer. Therefore, a prospective randomized clinical trial comparing the prognosis of patients receiving adjuvant multi-agent chemotherapy with those treated only surgically should be pursued for estimation of the clinical benefit of these agents.

To improve the survival rate of patients with esophageal cancer, several protocols of a preoperative combination of chemotherapy and radiotherapy, known as chemoradiation therapy, have been developed, recently characterized by the combination of 5-fluorouracil (5-FU), cisplatin, and radiation. Although some of these combinations have been demonstrated to be effective, the optimal chemoradiation dose and schedule are not yet precisely established. Recent investigations have elucidated that the radiosensitizing effects of cisplatin are able to be achieved more effectively by the daily administration of cisplatin before each fraction of radiation. Based on these investigations, we report herein the case of a patient with esophageal cancer with direct invasion to the trachea, in whom a complete response was achieved by the continuous administration of 5-FU, 600 mg/m2 per day, from days 1-5 combined with the daily administration of low-dose cisplatin, 10 mg/m2 per day before each fraction of radiation, given as 2Gy each time, throughout the entire treatment period of 3 weeks beginning on day 1. The benefits of our preoperative chemoradiation therapy included no severe side effects, down-staging and resectability of the tumor, as well as a pathological complete response, which could prolong the survival time. Our experience of this case prompts us to recommend the concurrent daily preoperative chemoradiation therapy for patients with locally advanced esophageal cancer.

A 47-year-old woman was admitted to our hospital with a mass shadow in the upper lobe of the right lung. Undifferentiated carcinoma was diagnosed after transbronchial biopsy. Combination chemotherapy consisting of cisplatin and etoposide was given. After two cycles of chemotherapy, partial response was obtained, and surgery was done because there was no evidence of lymph node metastasis or distant metastasis. After successful surgery, malignant fibrous histiocytoma was diagnosed because histological examination revealed the typical storiform pattern and most tumor cells showed positive cytoplasmic staining for alpha 1-antitrypsin, alpha 1-antichymotrypsin, and CD68. No evidence of another primary lesion was found, so this tumor was thought to be a pulmonary malignant fibrous histiocytoma. Cisplatin and etoposide have synergistic effect in vivo, and this combination is widely used as a standard regimen for small cell lung cancer and other malignancies. It might also be effective against pulmonary malignant fibrous histiocytoma.

Sequential MTX/5-FU therapy was performed on 64 patients with unresectable or recurrent gastric cancer. The therapy was most effective in patients with poorly differentiated type gastric cancer. We adopted the intermediate (MTX: 100mg/m2, 5-FU: 800mg/m2) and low (MTX: 30mg/m2, 5-FU: 600 mg/m2) dose regimens. The latter was performed at the outpatient clinic every 2 weeks. This therapy was used for patients with Borrmann type 4 gastric cancer or advanced gastric cancer of poorly differentiated type as postoperative adjuvant chemotherapy. The response rate was 25% in 44 evaluable patients, and 33% in patients with poorly differentiated type cancer. As an adverse effect, leukopenia (grade 3, 4) was observed in 4 patients (9%). The 5-year cumulative survival rate of the sequential MTX/5-FU therapy group (52.6%) was much better than the conventional adjuvant chemotherapy group (32.1%) in patients who underwent curative resection with Borrmann type 4 gastric cancer. One patient survived more than 900 days after non-curative resection with peritoneal dissemination (P 3) after low dose therapy of sequential MTX/5-FU. For the patients who did not respond to the MTX/5-FU therapy, MTX/CDDP/LV/5-FU therapy was adopted. This protocol consisted of MTX (30 mg/m2 iv; day 1), CDDP (60 mg/m2 div; day 2 and day 9), Leucovorin (30 mg iv; day 2-9) and 5-FU (250 mg/m2 div; day 2-9). We also performed MTX/CDDP/LV/5-FU therapy for the treatment of differentiated type gastric cancer.

A multicenter cooperative study was conducted from Dec. 1992 to April 1994 to evaluate the clinical efficacy of high-dose l-leucovorin (l-LV) and 5-fluorouracil (5-FU) treatment in 76 patients with advanced colorectal carcinoma. Treatment consisted of intravenous bolus injection of 5-FU (600 mg/m2) 1-hour after the initiation of a 2-hour infusion l-LV (250 mg/m2), 6 weekly treatments were administered followed by a two-week rest. These treatment were repeated until progressive disease or intolerable toxicity. Seventy patients were evaluated for response. Responses were the following: PR 21, NC 29, PD 20 and the overall response rate was 30%. Grade 4 hematological side-effect was observed in three cases, and severe diarrhea in one case. These data suggested that high-dose l-LV and 5-FU was effective for advanced colorectal carcinoma but showed some hematological toxicity, and a further investigation should be carried out.

We report the results of a multicenter clinical trial comparing three combination chemotherapeutic regimens including 5-fluorouracil (5-FU) and l-leucovorin (l-LV). One hundred and twenty-two patients were randomized to three regimens comprising 5-FU (600 mg/m2) plus high-dose l-LV (250 mg/m2) in six doses given weekly by i.v. injection midway during a 2-hr infusion of l-LV (regimen A), 5-FU (370 mg/m2) plus high-dose l-LV (100 mg/m2) given simultaneously for 5 consecutive days and a 23-day interval between treatments (regimen B) and 5-FU (370 mg/m2) plus low-dose l-LV (10 mg/m2) with the same dose administration schedule as regimen B (regimen C). The response rates were 32.4% (12/37 cases) in Regimen A, 20.0% (8/40) in regimen B and 11.1% (4/36) in regimen C. The most prominent side effects observed in regimen A were diarrhea (53.8%) and leukopenia (53.8%); however, they were within permissible levels. The combinations of high-dose l-LV and 5-FU (regimen A and B) had higher response rates than that of low dose l-LV and 5-FU (regimen C). Weekly administration of high-dose l-LV and 5-FU (regimen A) is now being expanded to late phase II trials.

A randomized early phase II study using l-leucovorin (l-LV) and 5-fluorouracil (5-FU) in gastric cancer was conducted. The administration schedules: Arm A was 250 mg/m2 of l-LV and 600 mg/m2 of 5-FU weekly, arm B was 100 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days, and arm C was 10 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days. PR was obtained in 10/28 (35.7%) of arm A, 7/28 (25.0%) of arm B and 0/17 (0%) of arm C, in complete cases. In eligible cases, 30.3%, 21.9% and 0%, respectively. Because there was no responder in arm C, the entry to arm C was stopped by controller at the point where 17 patients were treated with arm C. Median survival time was 9.6 months in arm A, 8.0 months in arm B and 5.9 months in arm C. Major toxicities were stomatitis, diarrhea and neutropenia. Stomatitis was seen more in arm B and C than in arm A. These data suggest that the high dose of l-LV and 5-FU seems to be a very promising combination, but there was no responder using low-dose l-LV schedule against gastric cancer. We thus selected arm A for the next late phase II study against gastric cancer.

The effects of preoperative chemotherapy on gastric and colonic cancers have yet to be evaluated fully. In this study, its effects were assessed by studying DNA ploidy patterns, cell cycles, and histological findings in such patients. Thirty-nine patients with gastric or colonic cancer were given preoperative chemotherapy with UFT (an admixture of tegafur and uracil). Biopsy specimens for analysis were obtained before chemotherapy through a gastroscope or colonoscope and after chemotherapy from resected tumors. The DNA ploidy patterns and cell cycles were evaluated using a flow cytometer and the tissues were examined histologically. The DNA ploidy pattern was diploid (D) in 12 gastric and 13 colonic cancer patients and aneuploid (A) in 10 and 4 patients, respectively. After chemotherapy, the pattern changed in nine gastric (A-->D: 7, D-->A: 2) and six colonic cancer patients (A-->D: 3, D-->A: 3) and was unchanged in the remaining patients. Cell cyclic analysis showed decreased G1- and increased S-phase fractions in 10 of 12 patients with gastric and 6 of 10 patients with colonic cancer. Histologically, decreased tumor cellularity, increased fibrosis, and/or cytological changes were observed in both cancers after chemotherapy. Gastric and colonic cancers in which the DNA ploidy pattern changed from aneuploid to diploid, G1- decreased and S-phase increased, and/or histological changes were observed, were considered to have responded to preoperative UFT administration.

The therapeutic efficacy and toxicity of sequential methotrexate and 5-fluorouracil in 64 inoperable gastric cancer patients are reported. An intermediate-dose treatment was given to 48 patients, and a low-dose treatment to 16 patients. In the intermediate-dose treatment, leukopenia was observed in 11 patients, nausea and vomiting in six patients and diarrhea and stomatitis in two patients each. In the low-dose treatment, no patient developed toxic symptoms of grade 3 or 4. All 9 responders had adenocarcinoma of the poorly differentiated type and the response rate in patients who belonged to this type was 32.1%.

Mechanism of synergism and clinical results of methotrexate and 5-fluorouracil (MTX/5-FU) combination therapy for gastric cancer were studied. The response rate against poorly differentiated gastric cancers was 35% in this treatment. This treatment also showed a remarkable effect against cases with pleural and abdominal effusion caused by cancerous disseminations. A promising result was obtained by this treatment as neoadjuvant and postoperative chemotherapy against Borrmann type 4 gastric cancer. A greater dependence on the de novo pathway of pyrimidine synthesis against poorly differentiated gastric carcinoma, which was estimated by the fact that the thymidylate synthetase/thymidine kinase ratio was significantly higher in poorly differentiated gastric cancer than in well differentiated cancer, may potentiate therapeutic results of this treatment.

This report describes the clinical use of MMC localized intra-arterial infusion therapy in combination with Angiotensin II for advanced gastric carcinoma which is not surgically treatable, along with some basic considerations. Since blood vessels regenerated within a tumor no longer have automatic adjustment of blood flow, there is no vascular contraction mechanism operation even when Angiotensin II is administered. The blood flow within the tumor shows a relative increase so the amount of the carcinostatic substance reaching the tumor is considered to increase. Using MMC intra-arterial infusion together with Angiotensin II, the authors were able to increase the antitumorigenic effect of the carcinostatic agent in patients with advanced gastric carcinoma. In an experiment using VX2 tumor transplanted into domesticated rabbits, the group treated with angiotensin II showed a marked reduction in the tumor. At the clinical level, differentiated gastric carcinoma patients with liver metastases very often evidenced favorable effects when treated with Angiotensin II in combination with the MMC intra-arterial infusion method. A randomized clinical study of 30 patients using either Angiotensin II together or without intraarterial infusion revealed that in 4 advanced gastric carcinoma patients could PR be obtained by the combination therapy, the non-combination treated group showed no favorable effects. In Borrmann type IV gastric carcinoma, the present combination therapy displayed no effect, while a switch to MTX-5FU sequential therapy yielded very often good results. Since the ability of the agent to reach the tumor is markedly enhanced in the Angiotensin II-intraarterial infusion approach to chemotherapy, progress in the latter science is anticipated.

Fifteen patients with advanced gastric carcinoma were treated by intraaortic infusion therapy with sequential MTX and 5-FU. Intraaortic bolus injection with 50-100 mg/body MTX was followed 3 hours later with 500-750 mg/body 5-FU and 24 hours later with 30 mg/body leucovorin. Treatment was repeated weekly. Of these 15 patients who were evaluated, 4 had PR and 3 had MR. Response rate was 27%. Two patients had WBC nadir of less than 3,000 cells/mm and other two had a platelet count nadir of less than 10/mm. Gastrointestinal symptoms such as nausea and vomiting were mild. Three patients had diarrhea and 3 had mucositis. No other toxicity was seen. This regimen has been well tolerated for long periods.

The concentration of 1-(2-tetrahydrofuryl)-5-fluorouracil (FT), 5-fluorouracil (5-FU) and uracil in blood, the bladder tumor tissue and the bladder mucosa after oral administration of 600 mg per day of UFT for 7 consecutive days was examined in 10 cases of bladder tumors. The concentration of FT and uracil in the tumor tissue did not significantly increase as compared with that in the blood and the bladder mucosa. However, the concentration of 5-FU in the tumor tissue remarkably increased and was 10.7 and 4 times as much as that in the blood and the bladder mucosa, respectively. These results show that administration of UFT meaningfully increases the 5-FU content in bladder tumors and enhances the antitumor activity.

The VPM-CisA (vincristine (VCR), peplomycin (PLM), methotrexate (MTX), cisplatin (CDDP) and doxorubicin (ADM), regimen was used to treat 33 patients with urothelial tract tumors. Twenty-two patients had bi-dimensionally measurable disease parameters and 11 patients with locally advanced tumors were given postoperative adjuvant chemotherapy. The protocol consisted of 0.6 mg/m2 VCR on days 1 and 3, 3 mg/m2 PLM on days 1 to 4, 3 mg/m2 MTX on days 2 and 4, 35 mg/m2 CDDP on day 4, and 20 mg/m2 ADM on day 5. These doses were adjusted for each case: the above mentioned dose x [(80/(40+Age]2 +[(Karnofsky's performance status/100)2]. Of these patients, 28 (86 percent) were treated adequately, including 8 (36 per cent) who achieved a complete (2) or partial (6) remission. The mean duration of survival was 65.2 weeks for complete and partial responders, and 48.8 weeks for non-responders, which was not a statistically significant difference. Of 11, who were given post-operative adjuvant chemotherapy (mean observation period: 83.5 weeks) 9 were alive without evidence of disease, 1 had a recurrence 8 months after first chemotherapy, 1 died due to pulmonary and liver metastasis 2 years after the chemotherapy. Toxicity included mild myelosupression, moderate anorexia, vomiting, and severe gastric ulcer, pulmonary fibrosis.