Combination chemotherapy for advanced urothelial-tract carcinoma

Between December 1982 and November 1990, 31 patients with advanced urothelial carcinoma were treated with one of two combination chemotherapy regimens. A total of 20 patients were treated with 3 mg/m² mitomycin C and 300 mg/m² cyclophosphamide given intravenously every 10–14 days and with 180 mg/m² 5-fluorouracil (5-FU) given intravenously every day for as long as possible (CF-Mito regimen). After the patient had been discharged from the hospital, the same treatment with CF-Mito was performed except that 180 mg/m² 5-FU was replaced by 400 mg/m² UFT (a mixture of tegafur and uracil) given orally. A total of 11 patients whose tumor had relapsed during the first-line treatment were given 60 mg/m² cisplatin, 40 mg/m² Adriamycin, and 40 mg/m² methotrexate intravenously every 28 days (PAM regimen). In all, 20 patients received 4–44 (mean, 9.7) courses of CF-Mito over a period of 1.5–24 (mean, 5.3) months. The results obtained in these 20 patients with evaluable lesions included no complete remission (CR), 4 partial remissions (PRs), 9 cases of stable disease (SD), and 7 cases of progressive disease (PD). The PR duration was 1.5–22 (mean, 7.5) months. The side effects encountered in this group included anorexia, nausea, vomiting, myelosuppression, diarrhea, stomatitis, liver damage, and heart failure. In all, 11 patients received 3–7 (mean, 4.1) courses of PAM over a period of 3–14.5 (mean, 5.2) months. All 11 patients had evaluable lesions, and their responses included no CR, 5 PRs, 3 cases of SD, and 3 cases of PD. The Pr duration was 1–3 (mean, 1.6) months. The side effects encountered in this group included anorexia, nausea, vomiting, myelosuppression, heart failure, and hair loss.Presented at the 4th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 16–17 November 1990, Osaka, Japan     

A phase I/II study of high-dose megestrol acetate in the treatment of metastatic breast cancer

Summary Thirty four patients treated with mastectomy and axillary node dissection for potentially curable breast cancer received a seven month combined adjuvant chemotherapy and radiation therapy program. These patients were considered to be at high risk for recurrence because they had either three or more positive axillary lymph nodes or their primary tumor was greater than 5 cm in diameter. The chemotherapy given at 3-week intervals consisted of cyclophosphamide, 600 mg/m², Adriamycin 40mg/m², and methotrexate 40 mg/m² during cycles 1 through 3 and 7 through 9. Radiation therapy was administered during cycles 4 through 6 with concomitant administration of 5-fluorouracil 600 mg/m², vincristine 1.4 mg/m², and prednisone 40 mg/m² for 7 days. Median follow up time from initiation of study is 60 months (range 36–93). Seventeen of 34 patients (50%) remain free of recurrent breast cancer. Distant metastases and local-regional recurrence have occurred in 16 (47%) and 4 (12%) patients, respectively. Significant myelosuppression and infections requiring hospitalization were seen in 4 patients, with 1 treatment-related death. Adriamycincontaining chemotherapy and post-operative radiotherapy can thus be combined in an adjuvant treatment program with acceptable toxicity.     

A randomized trial of two regimens of cyclophosphamide,methotrexate, 5-fluorouracil,and prednisone in advanced breast cancer

Summary One-hundred evaluable patients with progressive advanced breast carcinoma untreated by cytotoxic chemotherapy but resistant to hormone therapy and irradiation were randomly allocated to receive either a combination of cyclophosphamide (600 mg/m²), methotrexate (40 mg/m²), 5-fluorouracil (600 mg/m²) IV every 3 weeks and prednisone 20 mg/m² PO daily, with diminishing doses (intermittent group), or a combination of cyclophosphamide (100 mg/m² PO on days 1–15, alternating with a 15-day rest period), methotrexate 20 mg/m² IV, 5-fluorouracil 500 mg/m² IV weekly for 20 weeks and prednisone 20 mg/m² PO daily, with diminishing doses in the remission induction period, followed by a maintenance regimen of cyclophosphamide 100 mg/m² PO on days 1–15, methotrexate 20 mg/m² IV on days 1, 8, and 15, 5-fluorouracil 500 mg/m² IV on days 1, 8, and 15, and prednisone 20 mg/m² PO on days 1–15, with a 3-week rest period between the courses (intensive group). Entry was from 1 December 1982 to 30 November 1983. Objective responses were seen in 20/49 (41%) patients in the intermittent group and 34/51 (67%) in the intensive group (²=6.72; P<0.01). The estimated median duration of response was 11 months in the intermittent group and 14 months in the intensive group. The estimated median survival was greater in the intensive group, but the difference was not statistically significant, although this parameter can be influenced with alternative additional chemotherapy. Toxicity was similar in both groups. These data suggest there are no therapeutic and survival advantages to the 3-weekly IV protocol compared with our previous regimen CMFP.     

Alternating six-drug combination chemotherapy induction for intermediate and high-grade non-Hodgkin's lymphoma

Summary 31 patients with intermediate and high-grade non-Hodgkin lymphomas were treated by a six-drug alternating regime comprising four cycles of 200 mg/m² i.v. methotrexate on days 8, 15, 28 and 35, 50 mg/m² i.v. Adriamycin on day 1, 40 mg/m² oral prednisolone on days 1–7 and 21–27, 120 mg/m² i.v. etoposide on days 21–23, 600 mg/m² i.v. cyclophosphamide on day 21 and 1.4 mg/m² i.v. vincristine on day 1 (MAPECO). In all, 3 patients had stage I disease, 12 stage II, 6 stage III and 10 stage IV. Of 28 evaluable patients, 19 were complete responders (68%) and 9 were partial responders (32%); at 2 years, the actuarial relapse-free survival of the 19 patients achieving complete remission is 80%, and 5 patients remain in complete remission at 3 years. This is a preliminary report of an effective intensive regime with acceptable toxicity.     

Prednimustine in combination with methotrexate and 5-fluorouracil in advanced breast cancer: A phase I–II study

Summary Forty-seven patients with advanced breast cancer were treated with a combination of prednimustine (P), methotrexate (M), 5-fluorouracil (F), and tamoxifen (TAM). Twenty-six patients received P, 80 mg/m² day 1–5 (series I) and 21 patients received P, 100 mg/m² day 1–5 (series II). Both series of patients received M, 40 mg/m² day 1 and 8 and F, 600 mg/m² day 1 and 8 with a cycle duration of 4 weeks. All patients received TAM 20 mg twice daily. As concerns the haematologic toxicity, WBC were depressed significantly more often than platelet counts, and during the first 3 cycles 70% of the patients had a WBC nadir corresponding to toxicity grade II or more. No signs of cumulative haematologic toxicity were observed. Nausea and vomiting were registered in 40 out of 47 patients but in 35 of these only of grade I–II. Only one patient developed alopecia requiring a wig. The response to treatment could be evaluated in 28 patients, 21 of whom experienced response (CR or PR) of a median duration of 13 months.In conclusion, it seems that prednimustine can be safely used in combination with methotrexate and 5-fluorouracil. The frequency of alopecia is definitely lower than with CMF. Whether this relates also to subjective side effects will require a randomized study, as will a final conclusion concerning the efficacy compared to that of CMF.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphon-acetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma

Purpose: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma.Patients and methods: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m² i.v. 15-minute infusion followed by methotrexate 200 mg/m² i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m² i.v. push on day 2. Folinic acid was given at 15 mg/m² p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks.Results: Thirty patients with advanced chemotherapy-naive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27–72); median PS 1 (0–2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients.Conclusions: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.     

Phase II trial of 5-fluorouracil,adriamycin and cisplatin (FAP) in advanced gastric cancer

Summary Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m² IV on days 1–5, adriamycin 50 mg/m² IV on day 1, cisplatin 20 mg/m² IV on day 1–5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patients showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2×10⁹/l (range 0.7–4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).     

Etoposide,leucovorin, 5-fluorouracil and interferon alpha-2b in elderly gastric cancer patients: a pilot study

A total of 23 advanced gastric cancer patients older than 65 years received 500 mg/m² 5-fluorouracil i.v. on days 2–4, 120 mg/m² vepesid i.v. on days 2–4, 150 mg/m² 6S-leucovorin on days 2–4, and 5 MU/m² interferon alpha-2b on days 1–5, with cycles being repeated every 3 weeks. Toxicity was severe at an interferon (IFN) dose of 5 MU/m²; only one patient tolerated this dose. In 18 patients an IFN dose of 3 MU/m² and in 3 other patients a dose of 4 MU/m² could be given withoutproducing toxicity. At an IFN dose of 5 MU/m² the most common toxicities encountered were stomatitis (grade 4 in 1 patient and grade 3 in 12 patients), leukopenia (grade 4 in 1 patient and grade 3 in 5 patients), and thrombocytopenia (grade 3 in 3 patients). Two patients achieved a complete response and eight showed a partial response, resulting in an overall response rate of 45% [95% confidence interval (CI), 25%–64%]. The median survival was 7 months for all patients and 9 months for responding patients. In conclusion, without substantially increasing the toxicity, IFN can be added to the etoposide/leucovorin/5-fluorouracil combination, at a dose of 3 MU/m². To verify the possible enhancement by IFN of the activity of this combination, a randomized trial is under way.     

Adjuvant six cycles of high-dose adriamycin,cyclophosphamide, methotrexate, 5-fluorouracil (ACMF) vs. 12 cycles of low-dose acmf with tamoxifen for premenopausal,node-positive breast cancer patients: Results of a prospective randomized study

A prospective randomized study was conducted to compare the adjuvant efficacy of six cycles of high-dose ACMF (Adriamycin, ADM; cyclophosphamide, CPA; methotrexate, MTX; 5-fluorouracil, 5-FU) with that of 12 cycles of low-dose ACMF in premenopausal, node-positive breast cancer patients. The six-cycle ACMF group (93 patients) received, intravenously (iv), 130 mg/m² CPA, 26 mg/m² MTX, and 600 mg/m² 5-FU on days 1 and 8, and 26 mg/m² ADM on day 1 of each cycle. The 12-cycle ACMF group (97 patients) received, iv, 65 mg/m² CPA, 13 mg/m² MTX, and 300 mg/m² 5-FU on days 1 and 8, and 13 mg/m² ADM on day 1 of each cycle. These treatments were repeated every 4 weeks, and all the patients took tamoxifen (30 mg/day) for 2 years. The background factors of the two groups were comparable. There were non-significant trends toward better disease-free and overall survival rates in the high-dose, six-cycle ACMF group. Both treatments were well tolerated, but more patients in the low-dose, 12-cycle group refused to continue to receive chemotherapy. These data suggest that escalating doses of ACMF over a shorter period, even with doses within the conventional range, are superior to low-dose, prolonged therapy. © 1995 Wiley-Liss, Inc.     

Phase-I trial of combination therapy with continuous-infusion MMPR and continuous-infusion 5-FU

Summary Fourty-four evaluable patients were treated with 6-methylmercaptopurine riboside (MMPR) at a dose of 20 mg/m²/day x 5 by continuous IV infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–1519 mg/m²/day x 5 by continuous IV infusion (days 2–6). Dose-limiting oral mucositis occured at a 5-FU dose of 1,381 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and occasional myelosuppression. A partial and a complete response were observed in two previously untreated patients with metastatic colon carcinoma given the highest 5-FU doses (1,381 and 1,519 mg/m²/day). Bone marrow phosphoribosyl pyrophosphate (PRPP) levels monitored after 24 h of MMPR treatment indicated increases of 7.8- and 9.2-fold those found prior to therapy.     

Vinorelbine, bleomycin and methotrexate as a salvage therapy for patients with head and neck squamous carcinoma in relapse after cisplatin/fluorouracil

Background: Cisplatin (CDDP) and 5-fluorouracil (5-FU) represent the standard chemotherapy for advanced/recurrent head and neck squamous carcinoma (HNSC); however, the duration of response is often short, with a median survival of only five to six months.Patients and methods: Patients with HNSC were treated with vinorelbine 20 mg/m² and methotrexate 50 mg/m² every week and bleomycin 15 mg/m² every two weeks. All patients were previously treated with a CDDP/5-FU regimen.Results: Forty-eight patients were evaluable for response and toxicity. After a median follow-up of 15 months, 16 patients are still alive and 32 have died. We had one complete response (2%), 12 partial responses (25%) (overall response rate 27%; 95% CI: 14%–39%), 11 stabilizations (23%) and 24 progressions (50%) of disease. Neutropenia grade 3–4 was seen in 12 patients; peripheral neurotoxicity in two patients. There were no toxic deaths.Conclusions: This regimen, administered in an outpatient setting, revealed some activity as a second-line treatment in patients with HNSC, with acceptable toxicity.     

An EORTC phase I study of epirubicin in combination with fixed doses of cyclophosphamide and infusional 5-fu (CEF-infu) as primary treatment of large operable or locally advanced/inflammatory breast cancer

Purpose. The association of continuous infusion 5-fluorouracil, epirubicin (50mg/m² q 3weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50mg/m² [1, 2, 3] or 60mg/m²/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. Patients and methods. Eligible patients had LO or LA/I BC, a performance status 0–1, adequate organ function and were 65 years old. Cyclophosphamide was administered at the dose of 400mg/m² day 1 & 8, q 4weeks and infusional 5-fluorouracil 200mg/m²/day was given day 1–28, q 4weeks. Epirubicin was escalated from 30 to 45 and to 60mg/m² day 1&8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for 7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade 3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). Results. A total of 21 patients, median age 44 years (range 29–63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4–6). DLTs on cycles 1 and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. Conclusions. This study establishes that epirubicin 60mg/m² day 1&8, cyclophosphamide 400mg/m² day 1&8 and infusional 5-fluorouracil 200mg/m²/day day 1-21, q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study.     

Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background:To determine the dose-limiting toxicity of CPT-11 incombination with oxaliplatin, and the maximal tolerated dose (MTD) and therecommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods:The study was designed to evaluate escalateddoses of CPT-11 starting at 100 mg/m² with a fixedclinically-relevant dose of 85 mg/m² oxaliplatin given every twoweeks. Results:Twenty-three patients and 186 cycles were evaluable fortoxicity (median per patient: 7, range: 1–13). Grade 3oxaliplatin-induced neurotoxicity was cumulative and limiting in 39%(9 of 23) of patients. The MTD of CPT-11 was 200 mg/m², withincomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175mg/m² of CPT-11): no grade 4 neutropenia was seen in the two firstcycles; 30% of patients experienced grade 3–4 diarrhea. Febrileneutropenia (3.2% of all cycles) was 3-fold more frequent inperformance status (PS) 2 than in PS 0–1 patients. Among elevencolorectal cancer (CRC) patients, three complete and four partial responseswere documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion:To combine CPT-11 175 mg/m² and oxaliplatin85 mg/m² every two weeks is feasible in an outpatient setting, andvery active in 5-FU resistant CRC patients. A dose of 150 mg/m²CPT-11 is recommended in PS 2 patients.     

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU

Summary Thirty-four patients were treated with N-(phosphonacetyl)-l-aspartate (PALA) at a dose of 850 mg/m²/dayx5 by continuous intravenous infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–630 mg/m²/dayx5 by continuous intravenous infusion (days 2–6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 g/ml.     

Relationship between 5-fluorouracil disposition, toxicity and dihydropyrimidine dehydrogenase activity in cancer patients

Background:Previous work demonstrated that 5-fluorouracil(5-FU) metabolism is a critical factor for treatment tolerability. Inorder to study the predictivity of pharmacokinetics with respect to theoccurrence of 5-FU toxicity, this study investigates the relationshipbetween the pharmacokinetics of 5-FU and its metabolite5-fluoro-5,6-dihydrouracil (5-FDHU), dihydropyrimidine dehydrogenase(DPD) activity in peripheral blood mononuclear cells (PBMNC) andtreatment tolerability. Patients and methods:Pharmacokinetics and metabolismof 5-FU and activity of DPD in PBMNC were examined in110 colorectal cancer patients given adjuvant 5-FU 370mg/m² plus L-folinic acid 100 mg/m² for five daysevery four weeks. Drug levels were examined by HPLC, while toxicitieswere graded according to WHO criteria. Results:DPD activity in patients with mild toxicities (WHOgrade 1) was 197.22 ± 11.34 pmol of 5-FDHU/min/mg of protein,while in five patients with grade 3–4 gastrointestinal toxicity,DPD ranged from low to normal values (range 31.12–182.37pmol/min/mg of protein). In these patients, 5-FU clearance (CL) waslower (range 14.12–25.17 l/h/m²), and the area underthe curve (AUC) was higher (range 14.70–26.20 h×µg/ml)than those observed in 84 patients with mild toxicities (CL, 56.30± 3.60 l/h/m²; AUC, 7.91 ± 0.44h×µg/ml). The severity of adverse events was associated withincreased 5-FU/5-FDHU AUC ratio and reduced 5-FU CL, while 5-FU and5-FDHU pharmacokinetics were not related to DPD activity. Conclusion:This study shows that DPD activity in PBMNC isunrelated to 5-FU/5-FDHU disposition and patients with severe toxicitydisplay marked pharmacokinetic alterations while a reduction of DPDactivity may not occur.     

A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer

Background:Gemcitabine (Gemzar®) and 5-fluorouracil (5-FU)plus folinic acid (FA) both have proven activity in the treatment of patientswith advanced pancreatic cancer. The present study was initiated toinvestigate the efficacy of gemcitabine in combination with 5-FU–FA. Patients and methods:Thirty-eight patients, median age 60 years(range 34–70) with inoperable, stage IV, pancreatic cancer were enrolledinto the study and treated on an outpatient basis. All except one patientreceived at least one cycle of treatment with gemcitabine (1000mg/m²), followed by FA (200 mg/m²) and 5-FU (750mg/m²) administered as a 24-hour continuous infusion on days 1, 8,15 and 22 of a 42-day schedule. No patient had received prior chemotherapy orradiotherapy. All 38 patients were assessed for efficacy, toxicity and timeto progressive disease. Results:Two patients (5%), achieved a partial response andthirty-four patients (89%) achieved stable disease. There were twoearly deaths (4 weeks). The median time to progression was 7.1 months(range 0.4–18.1+; 95% confidence interval (95% CI):5.3–7.9 months). Three patients had a progression-free interval ofgreater than 12 months and 12 of 38 patients (32%) survived longer than12 months. The median overall survival was 9.3 months (range 0.5–26.5;95% CI: 7.3–13.0 months). The incidence of grade 3 and 4toxicities was low. Conclusions:The combination of gemcitabine and 5-FU–FA isactive and well tolerated and seems to offer an improvement inprogression-free interval over both gemcitabine monotherapy and 5-FU–FAtherapy.     

A phase II study of 5-fluorouracil plus folinic acid in malignant gliomas in adults

Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300–370 mg/m² plus folinic acid 200 mg/m² × 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.     

A pharmacokinetic and pharmacodynamic study of the new anthracycline pirarubicin in breast cancer patients

Summary We evaluated the pharmacokinetics of pirarubicin during 16 courses of therapy in 4 patients suffering from breast cancer who were treated with an association of pirarubicin (30–60 mg/m² according to the hematologic tolerance to the previous course, the first course being given at a dose of 40 mg/m²) and continuous infusions of 5-fluorouracil (750 mg/m² daily for 5 days). Pirarubicin's pharmacokinetics and metabolism were linear within this dose range; the metabolites identified were pirarubicinol, doxorubicin and doxorubicinol (AUC ratios of metabolite/pirarubicin were 0.6, 0.64 and 0.57 respectively). Pirarubicin's decay from plasma followed a twocompartmental pattern, showing half-lives of 15.6 min and 16.6 h: the total plasma clearance of the drug was 140 l/h^–1/m^–2, and the total volume of distribution was 2,830 l/m². A relationship was observed between some pharmacokinetic parameters and the toxic effects of the drug: the percentage of survival of granulocytes was significantly correlated with the AUC values for doxorubicin and doxorubicinol, whereas that of platelets was significantly correlated with the AUC values for pirarubicin and pirarubicinol. This is the first study to demonstrate a pharmacokinetic/pharmacodynamic relationship for pirarubicin.     

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults

The prognosis of patients with incompletely resected malignant brain tumors is almost fatal. In an attempt to improve the outcome of children and young adults with unfavorable brain tumors an intensive multimodal therapeutic strategy was developed combining simultaneous (hyper)fractionated external beam irradiation and conventional adjuvant chemotherapy after initial surgery. 17 patients aged between 2.10 and 25.11 years were entered into the study. 16/17 patients were treated according to the German/Austrian Pediatric Brain Tumor Study Group multicenter trial HIT '91. They are not protocol patients of this HIT '91 trial. Induction chemotherapy consisted of 2 courses of ifosfamide (3 g/m²/d) on days 1–3, etoposide (150 mg/m²/d) on days 4–6, methotrexate (5 g/m²) on days 15 and 22, cisplatin (40 mg/m²/d) and cytarabine (400 mg/m²/d) on days 29–31. Three weeks after the last dose of cisplatin/cytarabine the second course of chemotherapy was started. The last patient entered into the study received a modified therapy containing ifosfamide, cisplatin and etoposide. Synchronously at a median of 12 days after initiation of chemotherapy 12/17 patients received local radiotherapy (6000–7040 cGy) to the brain and 5/17 patients craniospinal irradiation (3520 cGy with a tumor boost of 1400–2000 cGy). 4–6 weeks after completion of the second course of chemotherapy maintenance therapy was started with carmustine (CCNU) (75 mg/m²) and carboplatin (400 mg/m²) each on day 1 and vincristine (1.5 mg/m²) on day 1, 8, 15. This course was repeated eight times every six weeks. 9/17 patients are alive at a median follow-up of 25 months (range 5–50) with 4 complete remissions, 2 partial remissions and 1 stable disease lasting 42 + months. Two patients, who initially had stable disease, progressed, but are still alive at 31 + and 41 + months after diagnosis. Median progression-free survival and median overall survival is 19 and 36 months, respectively. Hematologic and methotrexate-induced toxicity were severe and resulted in one therapy-related death. However, radiotherapy concomitant to chemotherapy appears to be an effective method of treatment for brain tumors with poor prognosis, though toxicity is severe in some cases.     

High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma

The German Society of Pediatric Oncology (GPO) has studied the efficacy of high-dose ifosfamide with mesna uroprotection in patients with Ewing's sarcoma. A phase II trial of ifosfamide (IFO) (2 g/m² per day, days 1–5) in eight patients with recurrent evaluable disease resulted in three partial and two complete responses lasting from 3 to 12 months (median, 6 months). In a second phase II trial in 15 patients, the combination of IFO and cisplatin (20 mg/m² per day, days 1–5) resulted in 7 partial and 2 complete responses lasting from 3 to 32 months (median, 6 months). Consequently, in 1985 IFO was incorporated into first-line chemotherapy for newly diagnosed patients (replacing cyclophosphamide) and given in combination with vincristine, actinomycin D, and Adriamycin (VAIA) in patients considered to be at high risk for relapse. IFO was given at a dose of 3 g/m per day on days 1 and 2 as a 48-h continuous infusion, in combination with actinomycin D (0.5 mg/m² per day on days 1–3) or Adriamycin (30 mg/m² per day on days 1 and 2). The study was piloted from March to December 1985 and has been open since January 1986; 37 patients were entered during the pilot phase and 65 have been entered in the ongoing main trial since January 1986. At present, Kaplan-Meier disease-free survival projects that disease-free survival in patients with large primary tumors has improved compared with that reported for the previous CESS 81 trial. The toxicity of the VAIA regimen was comparable with that of the conventional vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) regimen used in the previous CESS 81 trial.Presented in part at the 4th European Conference on Clinical Oncology and Cancer Nursing (ECCO-4), Madrid, Spain, November 1–4, 1987