Phase II of doxorubicin/taxol in metastatic breast cancer

Purpose. To assess the response rate, survival, and toxicity of Taxol®(paclitaxel) as 1h infusion plus doxorubicin as firstline treatment for patients with metastatic breast cancer (MBC).Patients and methods. Seventysix patients with untreated MBC were recruited. All of them had measurable disease and were evaluable for toxicity. Fiftyfive percent of the patients had visceral involvement. The dose of doxorubicin was fixed at 50mg/m² as a short intravenous infusion, followed by 200mg/m² of Taxol as a 1h intravenous infusion. Doxorubicin was administered during the first seven cycles, continuing with Taxol only up to a maximum of ten cycles.Results. Neutropenia was the most important toxicity: 30% grade 3 and 18% grade 4. Only 2 patients showed a decrease in the left ventricular ejection fraction (LVEF) which caused discontinuing the treatment. No clinical congestive heart failure (CHF) was observed. Seventyfour patients were eligible for response evaluation: 10 (14%) achieved complete response (CR) and 46 (62%) achieved partial response (PR). The mean duration of response was 13.47± 1.35 months (95% confidence interval (CI): 10.82; 16.12) and the mean survival was 21.50± 1.42 months (95% CI: 18.72; 24.29).Conclusion. The overall response (OR) rate was 76%. No CHF was assessed and 2 patients stopped treatment due to LVEF decrease. Although doxorubicin 50mg/m² followed by Taxol 200mg/m² in 1h intravenous infusion presents a toxicity profile which demands a close followup, it represents a convenient outpatient schedule with similar activity rate compared to longer Taxol infusions.     

Prolonged Infusional Topotecan and Accelerated Hyperfractionated 3d-conformal Radiation in Patients with Newly Diagnosed Glioblastoma – A Phase I Study

Purpose: Topotecan has demonstrated exceptional central nervous system penetration as well as radiosensitizing properties in glioblastoma xenografts [Chastagner et al., Int J Radiat Oncol Biol Phy 50: 777–782, 2001]. This phase I trial was performed to determine the maximum tolerated dose and the recommended dose of topotecan continuous infusion administered together with concomitant radiotherapy in patients with glioblastoma. Patients and methods: A total of 20 patients were treated in this trial. Twenty one day topotecan continuous infusion was escalated from 0.3mg/m²/d in increments of 0.1mg/m²/d and cohorts of 3–6 patients until maximum tolerated dose was reached; Three-dimensional (3d) conformal radiotherapy was applied concurrently twice daily with a fraction size of 1.75Gy up to 57.75Gy total dose. Three additional cycles of maintenance topotecan chemotherapy were scheduled. Results: Fifty-three courses were performed in 5 dose levels (0.3mg/m²/d: 12 cycles, 0.4mg/m²/d: 6 cycles, 0.5mg/m²/d: 10 cycles, 0.6mg/m²/d: 6 cycles, 0.7mg/m²/d: 19 cycles). Maximum tolerated dose was reached at dose level 5 (0.7mg/m²/d), because 3/7 patients suffered from dose limiting toxicity. These were febrile sinusitis, bacterial sepsis and grade 4 thrombocytopenia. Neutropenia of grade 4 was encountered in 2 cycles (0.5 and 0.7mg/m²/d). Response data were available in 17 patients, 3 of which (18%) achieved partial remission, 12 (71%) stable disease throughout the observation period and 2 (11%) progressive disease. Conclusion: The recommended dose for further trials will be 0.6mg/m²/d topotecan administered as 21 days continuous infusion in combination with accelerated 3d conformal radiation.     

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4mg/kg/day, orally over 4days in 6-hourly divided doses and melphalan at a dose of 140mg/m²/day by intravenous infusion over 5min on day –1. Three patients additionally received thiotepa 250mg/m²/day intravenously over 2days and four patients additionally received topotecan 2mg/m²/day over 5days by intravenous infusion over 30min. The other seven patients received busulfan and thiotepa at the same doses.Patients stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12g/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48h after completion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.     

High complete pathological response in locally advanced breast cancer using paclitaxel and cisplatin

Background.In an earlier study, we have demonstrated a high response rate in metastatic breast cancer using paclitaxel (P) and cisplatin (C). A phase II study using the same regimen (PC) has been conducted in locally advanced breast cancer (LABC). Methods.A total of 72 consecutive patients with non-inflammatory LABC (T24cm, T3 or T4, N0–N2, M0). Patients were scheduled to receive 3–4 cycles of the neoadjuvant PC (paclitaxel 135mg/m² and cisplatin 75mg/m² on day 1) every 21 days. Patients were then subjected to surgery and subsequently received 6 cycles of FAC (5-fluorouracil 500mg/m², doxorubicin 50mg/m², and cyclophosphamide 500mg/m²) or 4 cycles of AC (doxorubicin 60mg/m², and cyclophosphamide 600mg/m²). Patients then received radiation therapy, and those with hormone receptor positive tumors were given adjuvant tamoxifen intended for 5 years. Results.The median age was 39 years (range, 24–78). Clinically, 7%, 58%, and 35% of patients had T24cm, T3, and T4, respectively. Disease stage at diagnosis was IIB (33%), IIIA (27%), and IIIB (40%). Complete and partial clinical response to PC was demonstrated in 13 (18%), and 52 (72%) patients, respectively. Of those patients with evaluable pathologic response (68 patients), complete pathologic response (pCR) was achieved in 15 (22%) patients. At a median follow-up of 22 (±3.5) months, 58 (81%) were alive with no recurrence, nine (12%) were alive with evidence of disease, and five (7%) were dead. None of the patients achieving pCR has developed any relapse. The median overall survival has not been reached for all 72 patients with a projected 3-year survival (±SE) of 90% (±4%). The median progression-free survival (PFS) was 42.1 (±4.8) months with a projected PFS of 74%±7% at 3-years (for 68 patients). Conclusions.PC regimen in LABC produced a high pCR. The contribution of the other added modalities to survival could not be assessed.     

A Randomized Phase II and Pharmacokinetic Study of Dacarbazine in Patients with Recurrent Glioma

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750mg/m²IV day 1 every 28 days (Arm A) or DTIC 200mg/m²IV days 1–5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27–67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1–2 nausea (33%), lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazeno] imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15mMmin, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29mMmin, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.     

Ultrastructural Changes of the Vascular Endothelium after Intra-arterial Administration of Tumor Necrosis Factor-alpha (TNFα) in Rat Gliomas

The ensuing ultrastructural changes in tumor vascular endothelial cells following intra-arterial administration of tumor necrosis factor- (TNF) were studied in an experimental rat glioma model. C6 glioma cells were implanted in Wistar rats and then after 14 days, 5×10³U of human natural-type TNF (1.7×10⁵U/m²) was administered through the carotid artery. The animals were sacrificed at 3 or 24h after TNF treatment. A detailed examination with transmission electron microscope revealed swelling of the tumor vascular endothelial cell nuclei and mitochondria with matrix densities at 3h. At 24h, these cells demonstrated the presence of high amplitude mitochondrial swelling or the violent blebbing characteristic of damaged mitochondria; the cytoplasm was swollen enormously and there were dissolution of cytoplasmic organelles and rupture of the plasma membrane. The observed findings were typical of cell necrosis and confirms yet another mechanism by which TNF exerts its anti-tumor effects, that is, necrotizing effects on tumor vascular endothelium. The information appears to be important in the context of clinical application of intra-arterial TNF in the treatment of malignant gliomas.     

Instructions for Authors

We conducted a pilot study of dose dense doxorubicin and cyclophosphamide (AC) combination chemotherapy followed by infusional paclitaxel (T) in primary breast cancer to determine its safety and feasibility. Twenty-two subjects (10 with stage II and 4 positive lymph nodes, and 12 with stage III disease) were treated with AC (A 60mg/m² and C 2000mg/m²) with filgrastim every 14 days for three cycles followed by infusional paclitaxel (140mg/m² over 96h) every 14 days for three cycles. Mean overall cycle length was 15.3 days and mean duration of therapy was 92 days. Dose reductions of C or T were required in 7/132 (5.3%) cycles for mucositis, diarrhea, or failure to recover platelets by day 15. Ninety-five percent of subjects had grade 4 neutropenia and 1 subject had a platelet nadir of <20,000. Actual delivered dose intensity (DI) over six cycles was: A 27mg/m² per week; C 892mg/m² per week; T 64mg/m² per week (90.6, 89.2, and 91.4% of planned DI, respectively). Average total dose administered was: A 180mg/m²; C 5880mg/m²; T 403mg/m² (100, 98, and 96% of planned total doses, respectively). Clinical response rate in 10 subjects receiving neoadjuvant therapy was 100% (4 complete response, 6 partial response). Four subjects had a pathologic complete response (three subjects without evidence of malignancy and one subject with ductal carcinoma in situ.) Administration of dose dense AC followed by infusional paclitaxel in 14-day cycles is feasible and this regimen is active in breast cancer.     

Repetitive 5-aminolevulinic acid-mediated photodynamic therapy on human glioma spheroids

The response of human glioma spheroids to repetitive 5-aminolevulinic acid-mediated photodynamic therapy (PDT) was investigated. In all cases, light fluences were kept below toxic thresholds to simulate conditions typically found at 1–2cm depths in brain adjacent to tumor. Significant inhibition of spheroid growth was observed following multiple PDT treatments at sub-threshold light fluences. The effect appears to be insensitive to the treatment intervals investigated (weekly or bi-monthly). In all cases, suppression of growth was observed for the duration of treatment. Low fluence rates (5mWcm^–2) appear to be more effective than high fluence rates (25mWcm^–2). No evidence of PDT resistance was found in this investigation.     

Is salvage chemotherapy for metastatic breast cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus 5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus leucovorin

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A – 30mg/m² i.v. weekly; Arm B – leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 15, q 28days; Arm C – mitoxantrone 12mg/m² i.v. only day 1+leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 13, q 28days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3–4 toxicities.Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.     

Phase I/II trial of high dose mitoxantrone in metastatic breast cancer: the M.D. Anderson Cancer Center experience

Anthracyclines are among the most active agents in metastatic breast cancer. Mitoxantrone demonstrated a different toxicity profile when compared to doxorubicin. We performed a phase I/II study of singleagent highdose mitoxantrone therapy for advanced breast cancer. Nineteen patients who had a diagnosis of metastatic breast cancer received treatment at the M.D. Anderson Cancer Center between June 1986 and December 1987. The patients received escalating doses of mitoxantrone until a maximum tolerated dose (MTD), defined as grade 3 or 4 nonhematologic toxicity or infection, was obtained. The starting dose of 25 mg/m², given by short intravenous infusion, was escalated by 25% in each fivepatient cohort if each patient in the previous cohort tolerated the initial course and 2 or fewer patients reached the MTD. The median cumulative dose of mitoxantrone was 93 mg/m² (range, 25–205) and the maximum single dose was 39mg/m². Myelosuppression was the dose limiting toxicity. The median duration of granulocyte count 250/l was 5–7 days. Four patients (22%) had infections that required hospitalization, 3 patients (17%) had cardiac toxicity. One patient (6%) achieved a complete response, and 3 (17%) had a partial response, with an overall response rate of 22.3%. No apparent doseresponse relationship was observed in our study. The mitoxantrone dosage recommended for phase II studies is 25mg/m² every 3–4 weeks. We conclude that highdose mitoxantrone therapy for metastatic breast cancer was relatively well tolerated but was not associated with a higher response rate than that of standard dose mitoxantrone.     

Fotemustine Combined with Procarbazine in Recurrent Malignant Gliomas: A Phase I Study with Evaluation of Lymphocyte O6-alkylguanine–DNA Alkyltransferase Activity

The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O ⁶-alkylguanine–DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100mg/day oral PCZ for 12 consecutive days and a 1-h intravenous infusion of fotemustine given 4h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125mg/m²/day). After a 6-week rest period, a maximum of 4 maintenance cycles (PCZ 300mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured on days 1, 5 and 12 over 4h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125mg/m² (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.     

Inflammatory Breast Cancer Survival: The Role of Obesity and Menopausal Status at Diagnosis

No previous studies have evaluated the effect of body size and menopausal status at diagnosis on survival from inflammatory breast cancer (IBC). We evaluated whether obesity and menopausal status had an impact on IBC survival in a cohort of 177 female IBC patients seen from 1974 to 1993 at The University of Texas MD Anderson Cancer Center. Survival time was defined as time from diagnosis until death or censorship at last date of contact. We categorized women by body size by using the National Institutes of Health/National Heart, Lung, and Blood Institute's definitions of obesity as body mass index ((BMI)=weight in kg/(height in m)²)30, overweight as 25BMI <30kg/m², and normal/lean as BMI <25kg/m². Cox proportional hazards analysis, adjusting for axillary lymph node involvement and chemotherapy protocol, revealed a modifying effect of menopausal status at diagnosis on the association between obesity and IBC survival (P=0.02). Relative to postmenopausal women, premenopausal women had significantly worse survival (hazard ratio (HR)=1.51, 95% confidence interval (CI)=1.03–2.22). After stratifying by menopausal status, premenopausal obese women had non-significantly better survival than their leaner premenopausal counterparts (HR=0.63, 95% CI=0.34–1.15) while postmenopausal obese women had significantly worse survival than their leaner counterparts (HR=1.86, 95% CI=1.02–3.40). These findings suggest that factors associated with larger body size at diagnosis may contribute to shorter IBC survival among postmenopausal women but not premenopausal women, who were found to have poorer survival regardless of body size.     

A pilot study of neoadjuvant chemotherapy with mitomycin C,etoposide, cisplatin,and epirubicin for adenocarcinoma of the cervix

Background To evaluate the efficacy and toxicity of the combination of mitomycin C, etoposide, cisplatin, and epirubicin (MEPA) as neoadjuvant therapy for patients with cervical adenocarcinoma.Methods Fourteen patients with cervical adenocarcinoma received neoadjuvant MEPA therapy followed by radical hysterectomy. The International Federation of Gynecology and Obstetrics stage was: IB1 in 2 patients, IB2 in 5, and IIB in 7. The MEPA regimen consisted of mitomycin C (15mg/m²) on day 1, etoposide (70mg/m²) on days 1 to 3, cisplatin (15mg/m²) on days 1 to 5, and epirubicin (30mg/m²) on day 1, with this course being repeated every 4 weeks. After two or three courses of chemotherapy, all patients underwent radical hysterectomy. Postoperative radiotherapy was given to 6 patients who showed risk factors at surgery.Results Of the 14 patients, 7 had complete remission (CR) clinically, 6 had partial remission, and only 1 showed no change. Examination of surgical material revealed no residual disease in 6 patients, and microscopic residual disease (5mm) in 2 patients. The patients who had no residual disease or microscopic disease in their hysterectomy specimens showed a significantly longer survival than those with macroscopic residual disease (P = 0.012). The dose-limiting toxicity was myelosuppression. Of the 33 treatment cycles administered, leukopenia of grade 3 or more occurred in 70%, and thrombocytopenia of grade 3 or more occurred in 79%. There were no therapy-related deaths.Conclusion Although severe myelosuppression was also observed, there was a satisfactory response rate to MEPA therapy, which showed a good pathological CR rate.     

Effect of Dose and Infusion Time on the Delivery of p-boronophenylalanine for Neutron Capture Therapy

Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B) boron concentration ratio would have the potential of significantly improving the therapeutic gain of BNCT. The effects of total dose, infusion time, and route of administration of BPA on tumor and blood boron concentrations were studied in rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to 1000mg/kg, administered intravenously over a 2-h infusion period, resulted in an increase in tumor boron concentration from 30 to 70µg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1. Similarly, extension of the infusion time from 2 to 6h, at a constant dose-rate of 125mg BPA/kg/h, resulted in an increase in tumor boron concentration from 30 to 80µg 10B/g, while, again, maintaining a constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for 1h at a dose rate of 125mg BPA/kg resulted in an increase in the tumor boron concentration from 26 to 38µg 10B/g with a corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these results on the therapeutic gain potentially achievable with BNCT are discussed.     

Phase I/II study of irinotecan, 5-fluorouracil,and <Emphasis Type="Italic">l</Emphasis>-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer

Background A combination of irinotecan 125mg/m², 5-fluorouracil (5-FU) 500mg/m², and leucovorin (LV) 20mg/m² (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.Methods Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100mg/m² was given intravenously over the course of 90min on day 1, followed by l-LV 10mg/m², and then 5-FU. The dose of 5-FU was escalated from 400mg/m² (level 1) to 500mg/m² (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100mg/m² and the dose of 5-FU in the original Saltz regimen was 500mg/m².Results One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2.Conclusion Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100mg/m², 5-FU 500mg/m², and l-LV 10mg/m².     

Biweekly administration regimen of docetaxel combined with CPT-11 in patients with inoperable or recurrent gastric cancer

Background. Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study. Methods. Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30mg/m² and 50mg/m²; level 2, 35 and 50mg/m²; level 3, 40 and 50mg/m²; level 4, 40 and 60mg/m²; and level 5, 50 and 60mg/m². The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. Results. Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages. Conclusion. Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35mg/m² and 50mg/m², respectively.     

Weekly paclitaxel in women age 65 and above with metastatic breast cancer

We evaluated therapy with weekly paclitaxel 80mg/m² in metastatic breast cancer patients age 65. There was a low incidence of serious toxicities, with similar tolerability profiles in younger and older patients. Response rates and overall survival times were comparable in the two age groups (<65 and 65). Weekly paclitaxel therapy is a reasonable option for older patients with metastatic breast cancer.     

Increasing body mass index in Japanese patients with gastric cancer

We studied the body mass index (BMI) of 986 patients who underwent potentially curative gastrectomy for gastric cancer at the National Cancer Center Hospital, Tokyo, in 1971, 1981, 1991, and 2001. The median BMI increased from 20.8kg/m² in 1971 to 22.6kg/m² in 2001 (P, 0.01). The increase was significant in both early and advanced gastric cancers, and in males, but not in females. The proportion of overweight patients (BMI 25.0kg/m²) increased from 9.2% in 1971 to 24.0% in 2001. Obese patients (BMI 30.0kg/m²) were rare. In conclusion, surgeons at the National Cancer Center Hospital, Tokyo, are increasingly having to operate on fat patients, but obese patients are still uncommon compared to the West.     

Phase I study of irinotecan and S-1 combination therapy in patients with metastatic gastric cancer

Background Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1:0.4:1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1.Methods Irinotecan was given intravenously over the course of 90min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80mg/m² per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100mg/m² (level 1; n = 3), to 125mg/m² (level 2; n = 3), and 150mg/m² (level 3; n = 6).Results Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150mg/m² of irinotecan on day 1 and 80mg/m² per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response.Conclusions A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.     

Tolerance of the Normal Canine Brain to Epithermal Neutron Irradiation in the Presence of p-boronophenylalanine

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950mg of ¹⁰B-enriched BPA/kg as its fructose complex. The 5 × 10cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1cm³ of brain at the depth of maximum thermal neutron flux) ranged from 7.6Gy (photon-equivalent dose: 11.8Gy-Eq) to 11.6Gy (17.5Gy-Eq). The average dose to the brain ranged from 3.0Gy (4.5Gy-Eq) to 8.1Gy (11.9Gy-Eq) and to the left hemisphere, 6.6Gy (10.1Gy-Eq) to 10.0Gy (15.0Gy-Eq). Maximum tolerated threshold doses were 6.7Gy (9.8Gy-Eq) to the whole brain and 8.2Gy (12.3Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5Gy (14.3Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.