Incidence Of Severe Toxicity Research Articles

Follow up of a multicenter phase II study of sequential paclitaxel and S-1 (TXL/S1) as postoperative adjuvant chemotherapy for gastric cancer (GC)

15084 Background: Of patients who undergo R0 resection for GC with serosal invasion (T3–4), more than half recur mainly in the peritoneum, while TXL and S1 exhibited efficacy for diffuse type and peritoneal metastases in the phase II studies. Primary analysis of the sequential chemotherapy with TXL/S1 had shown its safety and tolerability, its survival benefit is being tested in a large phase III study (the SAMIT trial) with oral fluoropyrimidines as controls. The analysis for survival of this preceding phase II study is performed. Methods: Eligibility criteria included histologically proven GC; sT3–4; sN0–2; M0 (except peritoneal cytology: CY); post D2–3 gastrectomy and R0–1; ECOG PS 0–1; and 20–80 years old. On postoperative day 14 to 56, patients received 3 courses of weekly TXL (80mg/m2 on day 1, 8 for the 1st course and on day 1, 8, 15 for the 2nd and 3rd courses, repeated every 3 or 4 weeks) followed by 4 courses of S1 (80mg/m2 daily for 2 weeks, repeated every 3 weeks). The primary endpoints were % of patients who completed all 7 courses (compliance) to see whether the lower 95% confidence limit of compliance was greater than 69% and incidence of severe toxicities and the secondary endpoints were 3-year survival and toxicities. Results: 50 patients were accrued from May 2003 to March 2004. The median age was 63 (range 34–74); male/female: 34/16; pT2/T3/T4: 1/44/5; CY0/CY1: 4/46; f-stage2/3a/3b/4: 12/15/16/7. The overall compliance was 84%. Median follow up time was 1063 days for survivors (694–1332) and 1030 days for all. Three-year DFS were 64.6% for all, 66.1% for CY0 and 50.0% for CY1. Conclusions: Sequential TXL/S1 may serve as an active adjuvant for gastric cancer patients especially who are at high risk for peritoneal spread. No significant financial relationships to disclose.

Mutational Status in Genes of Folate Metabolism Is Associated with Toxicity of High-Dose Methotrexate in Patients with Immunocompetent Primary Central Nervous System Lymphoma.

Background: Outcome of patients with immunocompetent primary central nervous system lymphoma (PCNSL) has improved since the introduction of high-dose (HD) methotrexate (MTX). However, treatment may be perturbed by considerable toxicity. Acute toxicity comprises hematologic, renal, hepatic, pulmonary events and mucositis while neurologic impairment is essentially restricted to long-term survivors. MTX acts via inhibition of 5,10-methylentetrahydrofolate reductase (MTHFR) as well as thymidylate synthase (TYMS) in target cells what eventually results in decreased DNA synthesis. Intracellular uptake of folates is mediated by the reduced folate carrier (RFC). Two common MTHFR single nucleotide polymorphisms (SNPs) affect enzyme activity: 677 C→T and 1298A→C. A 28 base pair (bp) tandemly repeated sequence in the TYMS enhancer region (5′-UTR) containing either 2 or 3 repeats alters enzyme activity as does a 6 bp deletion (del) polymorphism in the 3′-UTR of TYMS. An RFC SNP (80G→A) is known to influence folate and MTX transport. We hypothesized that these polymorphisms may be directly linked to toxicity in PCNSL patients receiving high-dose MTX.Patients and methods: Genomic DNA was prospectively collected from patients (pts) with immunocompetent PCNSL who received HD MTX 4 g/m² every 2 weeks after enrolment onto a German multicenter trial. They had to have histological confirmation of their disease as well as adequate organ and bone marrow function. Genotyping of the two MTHFR and the RFC SNPs was performed by melting point analysis using the Light Cycler® technology. Genotyping of the TYMS 28bp polymorphism was performed by conventional PCR followed by agarose gel electrophoresis. The TYMS 6bp del polymorphism was analyzed by PCR, restriction enzyme digest and agarose gel electrophoresis. Hematologic (Hb, WBC, ANC, platelets) and non-hematologic toxicity (renal, hepatic, pulmonary, mucositis) were assessed prospectively and correlated with polymorphisms with respect to presumable functional relevance.Results: 123 pts with a median age of 62 (range, 27 – 80) years received a total of 506 cycles of high-dose MTX. 39 of 119 evaluable pts (33%) experienced any severe (°3/4) toxicity. Incidence of severe toxicity was significantly different for pts with MTHFR 677 TT (95%) when compared to CC/CT genotype (48%; p=.0024). Not considering hematologic parameters, severe toxicity was even more strongly associated with homozygosity for 677TT (p=.0006). A moderate association with lower ANC was found for MTHFR C677T (p=.049) while °3/4 neutropenia was strongly associated with RFC 80 GG vs. AA/GA (p=.0057). In hand, lower WBC nadirs occurred in pts with RFC 80 GG vs. AA/GA (p=.035).Conclusion: We demonstrate for the first time that pharmacogenetic studies might identify PCNSL pts who are at risk for severe acute hematologic and non-hematologic toxicity when treated with HD MTX. Correlation of (late) neurotoxicity with polymorphisms of folate metabolizing genes, however, will require longer follow-up.

Neoadjuvant dose-dense (DD) concurrent doxorubicin (A) and docetaxel (T) for stage III breast cancer (BC)

10721 Background: The addition of taxanes to anthracycline therapy results in improved disease-free survival (DFS) in the adjuvant setting, and increased pathologic complete response rates (pCR) in the neoadjuvant setting. DD chemotherapy improves DFS and overall survival (OS). We evaluated neoadjuvant DD concurrent AT. Methods: Eligible patients (pts) with stage III BC were treated with AT q 14 days at 1 of 3 dose levels; L1 = 60 mg/m2 for both drugs (4 pts), L2 = A 75 mg/m2 and T 60 mg/m2 (6 pts) or L3 = 75 mg/m2 for both drugs (7 pts) × 6 cycles with G-CSF. Dexrazoxane was given after a cumulative dose of 300 mg/m2 of A. Pts were stratified to post-operative moderate risk (ModR) (≥ partial response, ≤ 3 lymph nodes (LN)) and received adjuvant IV cyclophosphamide (C) 600 mg/m2, methotrexate 40 mg/m2, 5FU 600 mg/m2 IV q 21 d × 6 (CMF), or high risk (HiR) (≤ minor response +/or ≥ 4 LN) and received C 3 gm/m2 q 14 d x 3. Primary endpoints were clinical and pathologic response rates of neoadjuvant AT. Sample size was 42 pts to estimate pCR and provide 90% confidence the true incidence of severe toxicity is <10%. Results: 17 pts with stage III BC were enrolled between 2/1999 and 7/2001; accrual was halted after data on pre-operative trastuzumab were presented. Median age was 50 yrs [range: 34–69]. 3/17 pts (17.6%) had a pCR, and 3 pts had near pCR (residual foci ≤ 1mm), 4/17 (23.5%) had path (-) LN, 7/17 (41%) had a lumpectomy, 7/17 (41%) required dose reductions of AT due to grade 4 neutropenia (5 pts) and grade 3 neuropathy (2 pts). 3 pts required treatment cessation; 1 pt (L2) for prolonged neutropenic fever and 2 pts (L3) for decreased ejection fraction and for acute renal failure. 15 pts were ModR and received adjuvant CMF, 1/2 pts stratified to high dose C declined it and received CMF. Median follow-up is 63 months [range: 28–80] with 13/17 (76.5%) pts surviving, and 12/17 (70.5%) pts surviving and free of disease. Conclusion: Neoadjuvant DD AT every 2 weeks is well-tolerated, with promising activity and survival in locally advanced BC. [Table: see text]

A pilot phase II study of consolidation chemotherapy with docetaxel and cisplatin following concurrent chemoradiotherapy (CCRT) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC)

5549 Background: With the improvement seen with CCRT in the management of locoregionally advanced HNSCC, distant failures have become a more relevant problem in terms of survival. As a consequence, more effective strategies including consolidation chemotherapy are warranted. The primary objective of this pilot phase II study was to assess the feasibility and efficacy of docetaxel and cisplatin consolidation following primary CCRT for HNSCC. Methods: Thirty-three patients with previously untreated, stage III/IV HNSCC participated in this study. CCRT consisted of cisplatin 100 mg/m2 on day 1, 22 and 43. Concurrent radiotherapy (70 Gy) to the primary tumor and neck was performed over a period of 7 weeks. After completion of CCRT, patients with no evidence of disease progression received an additional 4 cycles of consolidation chemotherapy with docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks. To minimize the expected accrual into unacceptable treatment, either in terms of clinical response or toxicity, a total of 35 patients would be required in a two-stage design. Results: Baseline characteristics were: male (22), median age (60 years), ECOG performance status 0/1 (15/18), stage III/IV (10/23). Of these, 27 (81%) patients completed CCRT. After CCRT, 3 complete and 19 partial responses were recorded, giving an overall response rate of 67% (95% CI, 51–83%). Of the 19 patients who went to consolidation phase, only 4 (21%) completed all 4 cycles of docetaxel and cisplatin. Failure to consolidation chemotherapy was attributed to the following causes: toxicity (11 including 3 treatment-related deaths), disease progression (4). During consolidation chemotherapy, 13 patients (68%) had grade 3/4 neutropenia and febrile neutropenia occurred in 6 (32%). With consolidation chemotherapy, one patient with initial stable disease achieved a partial response. Median survival in all patients was 11.0 months, and 8.3 months for those treated with consolidation chemotherapy. Conclusions: The poor compliance and the high incidence of severe toxicities, including 3 treatment-related deaths, prompted no further evaluation of this consolidation chemotherapy following CCRT. No significant financial relationships to disclose.

High Complete Remission Rate and Promising Outcome by Combination of Imatinib and Chemotherapy for Newly Diagnosed BCR-ABL–Positive Acute Lymphoblastic Leukemia: A Phase II Study by the Japan Adult Leukemia Study Group

A novel therapeutic approach is urgently needed for BCR-ABL-positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib. A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL-positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005. Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not. Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

Reirradiation of nasopharyngeal carcinoma withintensity-modulated radiotherapy

Background and purpose To evaluate the treatment outcome in patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT). Materials and methods Between October 2001 and May 2004, 31 patients with locally recurrent NPC received reirradiation using IMRT. The rT classification distribution was 3 for rT1, 5 for rT2, 9 for rT3, and 14 for rT4. Median time from first course of radiotherapy to reirradiation was 51 months. IMRT was performed using step-and-shoot method with nine 4–6 MV photon fields and median prescribed dose was 54 Gy (range: 50–60 Gy). Additional treatments included cisplatin-based induction chemotherapy in 68% and radiosurgery boost with a single dose which ranged from 8.5 to 12.5 Gy in 32%. Median follow-up time was 11 months. Results After reirradiation, 58% of patients had complete regression of primary tumor. One-year loco-regional progression-free, distant metastasis-free and overall survival rates were 56, 90, and 63%, respectively. Significantly better 1-year local progression-free rate was observed in rT1–3 than rT4 tumor (100 vs. 35%). Grade 3 late toxicities, mostly ototoxicity/cranial neuropathy, occurred in six patients (19%). One-year actuarial rates of late toxicities were 70% for all grades and 25% for Grade 3. Conclusion Our preliminary results showed that good control of rT1–3 NPC can be achieved using IMRT with a dose between 50 and 60 Gy, whereas the outcome for rT4 tumor remained poor. Late toxicities were common but incidence of severe toxicities was relatively low.

Liver enzymes elevation after HAART in HIV‐HCV co‐infection

Hepatitis C virus (HCV) co-infection is common among human immunodeficiency virus (HIV) patients. The incidence and risk factors associated with hepatotoxicity in this population after high active antiretroviral therapy (HAART) is initiated are still not well-understood. We argued to evaluate the incidence and risk factors associated with liver enzyme elevation (LEE) and their clinical significance. A retrospective chart review of patients who started HAART and had follow up at our centre for at least 1 year was undertaken. The frequency and severity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation after treatment initiation were investigated and searched for clinical manifestations. Between January 1996 and March 2002, 85 HIV-HCV co-infected patients began HAART and continued follow up for at least 1 year. The incidence of severe toxicity [grades 3 + 4 LEE: >5 and >10 times the upper limit of normal (ULN) of ALT or AST] was calculated at 4% per person-years. There were no clinical manifestations of liver toxicity, and patients continued their treatment with a trend towards a decrease of their enzymes. No statistical differences in opportunistic infections or mortality were evident. The variables associated with severe hepatotoxicity were a higher baseline AST, higher international normalized ratio (INR) and lower albumin. A baseline AST < 2.1 ULN had a negative predictive value of 92% of leading to severe hepatotoxicity. In HIV-HCV co-infected patients therefore, the group at a higher risk of developing higher transaminase elevations is the one with a higher baseline AST, higher INR and lower albumin.

A multicenter phase II study of sequential paclitaxel and S-1 (TXL/S-1) as postoperative adjuvant chemotherapy for gastric cancer (GC)

4067 Background: Of patients who undergo R0 resection for GC with serosal invasion (T3–4), more than half recur mainly in the peritoneum (and eventually need palliative chemotherapy). So far compliance of early postoperative chemotherapy was low and it has failed to suppress peritoneal relapse. Since TXL and S1 exhibited efficacy for diffuse type and peritoneal tumors in the phase II studies, we have investigated the safety and feasibility of TXL/S1 as sequential adjuvant chemotherapy following radical resection of T3–4 gastric cancer. Methods: Eligibility criteria included histologically proven GC; sT3–4; sN0–2; M0 (except peritoneal cytology); post D2–3 gastrectomy and R0–1; ECOG PS 0–1; and 20–80 years old. On postoperative day 14 to 56, patients received 3 courses of weekly TXL (80mg/m2 on day 1, 8 for the 1st course and on day 1, 8, 15 for the 2nd and 3rd courses, repeated every 3 or 4 weeks) followed by 4 courses of S1 (80mg/m2 daily for 2 weeks, repeated every 3 weeks). The primary endpoints were % of patients who completed all 7 courses (compliance) and incidence of severe toxicities and the secondary endpoints were survival and toxicities. Primary analysis was to see whether the lower 95% confidence limit of compliance was greater than 69% and sample size of 50 was calculated. Results: 50 patients were accrued from May 2003 to March 2004. The median age was 63 (range 33–74); male/female: 34/16; pT2/T3/T4: 2/41/4; f-stage2/3a/3b/4: 11/13/16/7. In 4 patients treatment was terminated for toxicities, in 2 for refusal, and in one for recurrence; thus compliance of 87.9% (95%CI:81–98%) was achieved. Grade 4 hematological toxicities in 2% and grade 3 non-hematological toxicities in 4% of the patients were observed. The analysis for survival will be performed in 2007. Conclusions: Sequential chemotherapy with TXL/S1 was safe and well tolerated as a postoperative adjuvant treatment for patients with T3 tumors. Its survival benefit will be assessed in a large phase III study (the SAMIT trial). No significant financial relationships to disclose.

Differences in toxicity between men and women treated with 5‐fluorouracil therapy for colorectal carcinoma

Recent explorations suggest that women may experience more severe 5-fluorouracil (5-FU)-related toxicity than men. The patient populations from 4 Southwest Oncology Group colorectal carcinoma trials with 5-FU-containing regimens were examined for toxicity differences between the genders. The current study included 1074 patients from 4 trials. Hypotheses regarding differences in specific toxicities were generated via exploratory analyses on the data from the 2 earlier trials (n = 505 patients), using basic univariate techniques and classification tree methods. Validation of these hypotheses was performed on data from the 2 later trials (n = 569 patients) using logistic regression models for dichotomous toxicity outcomes and rank-sum tests for comparisons of overall toxicity grade. 5-FU toxicity was more extensive in women than in men in terms of average maximum toxicity grade (P = 0.005), number of different types of toxicity experienced (P = 0.009), and incidence of severe toxicities (P = 0.02). The incidence of > or = Grade 2 hematologic toxicity in the 2 later trials was higher in women than in men and women experienced more frequent moderate to severe mucositis compared with men. Differences in 5-FU toxicity profiles between men and women were hypothesized after an exploratory analysis, and then verified by an independent confirmatory analysis using data from the 2 later trials. This process provided substantial evidence for gender differences in specific aspects of 5-FU toxicity that persist across a range of treatment regimens, patient characteristics, and cancer trial settings.

5-fluorouracil–based chemoradiation in unresectable pancreatic carcinoma: phase I-II dose-escalation study

Purpose A Phase I-II dose-escalation study was performed to evaluate the possible impact of the dose on response, toxicity, pain relief, and outcome in patients with unresectable pancreatic carcinoma. Methods and materials A total of 50 patients entered the study. The external beam radiotherapy (RT) dose was 39.6 Gy in the first 15 patients, 50.4 Gy in the next 15 patients, and 59.4 Gy in the remaining 20 patients, at five 1.8-Gy fractions weekly. During external beam RT, patients received concurrent continuous infusion of 5-fluorouracil (1000 mg/m 2 on Days 1–4 and 21–24). Patients were evaluated for toxic reactions, local disease control, survival, and pain relief. Results No treatment-related deaths occurred from acute toxicity. Four patients required a temporary treatment interruption because of acute hematologic (2 patients) or GI (2 patients) toxicity, not correlated with the delivered RT dose. Three patients (6%) developed late toxicity (duodenal ulcer in 2 and duodenal stenosis in 1). All patients who developed late toxicity had received a dose of 59.4 Gy. At univariate analysis, only the RT dose correlated significantly with the incidence of late toxicity (at 2 years, 39.6–50.4 Gy resulted in 0% and 59.4 Gy resulted in 58.2%; p = 0.023). At multivariate analysis, the RT dose also showed a trend with the incidence of late side effects ( p = 0.052). Overall, 6 patients had a partial response (12%) and 44 (88%) had no change. The overall response rate was 8.0% (95% confidence interval, 1.5–20.5%). The rate of response was not different in the three groups. In-field locoregional disease progression was seen in 7 patients (14.0%). Distant relapse was documented in 34 patients (68.0%). None of analyzed variables, in particular, the RT dose delivered, showed a statistically significant correlation with objective response, local control, incidence of metastasis, disease-free survival, or overall incidence of pain symptoms after therapy. The whole group median survival was 9 months. The actuarial survival rate at 1, 2, and 3 years was 31.3%, 2.8%, and 0.0%, respectively. None of analyzed parameters correlated significantly with survival at univariate or multivariate analysis. Conclusion In a Phase I-II study, the association of high RT doses with the incidence of severe toxicity in the treatment of unresectable pancreatic carcinoma was confirmed. Furthermore, this dose-escalation study did not document a clearcut correlation, using 5-fluorouracil–based chemoradiation, between the radiation dose and clinical outcome.

Oxaliplatin plus high-dose leucovorin and 5-fluorouracil in pretreated advanced breast cancer: a phase II study

The purpose of this study was to evaluate the efficacy and toxicity of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Fifty anthracycline- and taxane-pretreated MBC patients were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2)/day as a 2-h infusion followed by bolus 5-FU 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day for 2 consecutive days. Treatment was repeated every 3 weeks. Patients were evaluated for response every two cycles. The median age was 51 years (range 34-75). Twenty patients (40%) had received three or more chemotherapeutic regimens, 64% had three or four metastatic sites and 78% had visceral metastases. All patients had prior exposure to anthracyclines and taxanes. Based on an intention-to-treat analysis, one patient (2%) achieved a complete response and 16 (32%) a partial response, for a 34% overall response rate. Twenty-one patients (42%) had stable disease and 12 (24%) progressive disease. The median time to tumor progression was 5.3 months (range 0.5-12.8) and the median overall survival was 12.3 months (range 0.5-19.2). Toxicity was mild to moderate. Grade 3/4 neutropenia and thrombocytopenia occurred in 32% and 18%, respectively. Febrile neutropenia was experienced by three patients (6%), who were successfully treated. Grade 3/4 neurotoxicity was reported in 14% of the patients and gradually declined after treatment discontinuation. Cycle delays were reported in 28% of patients and dose reductions in 26%. Alopecia, nausea-vomiting, diarrhea and mucositis were not significant. There were no treatment-related deaths. The combination of oxaliplatin plus 5-FU/LV seems to be an active regimen in patients with MBC and prior exposure to anthracyclines and taxanes with a good safety profile. The incidence of severe toxicity was quite low and the compliance of patients to the treatment was satisfactory. The results obtained with this regimen could be considered encouraging in this heavily pretreated group of breast cancer patients with a high incidence of visceral metastases.

Acute and late toxicity of patients with inflammatory bowel disease undergoing irradiation for abdominal and pelvic neoplasms

Purpose: Little data exists in the medical literature describing the response of patients with inflammatory bowel disease (IBD) to abdominal and pelvic irradiation. To clarify the use of this modality in this setting, this study assesses the short- and long-term tolerance of 28 patients with IBD to abdominal and pelvic irradiation. Methods and Materials: From 1970 to 1999, 28 patients with IBD (10 patients—Crohn’s disease, 18 patients—ulcerative colitis) were identified and underwent external beam abdominal or pelvic irradiation. Mean follow-up time after radiation therapy was 32 months. Patients were treated either by specialized techniques (16 patients) to minimize small and large bowel irradiation or by more conventional approaches (12 patients). Acute and late toxicity was scored. Results: The overall incidence of severe toxicity was 46% (13/28 patients). Six of 28 patients (21%) experienced severe acute toxicity necessitating cessation of radiation therapy. Late toxicity requiring hospitalization or surgical intervention was observed in 8 of 28 patients (29%). One patient experienced both an acute as well as late toxicity. For patients undergoing radiation therapy by conventional approaches, the 5-year actuarial rate of late toxicity was 73%. This figure was 23% for patients treated by specialized techniques ( p = 0.02). Conclusions: Because of the potentially severe toxicity experienced by patients with IBD undergoing abdominal and pelvic irradiation, judicious use of this modality must be employed. Definition of IBD location and activity as well as careful attention to irradiation technique may allow treatment of these patients with acceptable rates of morbidity.

Unexpected High Incidence of Severe Toxicities Associated with Alpha Interferon, Low-Dose Cytosine Arabinoside and All-Trans Retinoic Acid in Patients with Chronic Myelogenous Leukemia

Preclinical data have shown that all-trans retinoic acid (ATRA) with interferon-alpha (IFN-α) can exert significant suppressive effects on Philadelphia-chromosome (Ph)-positive cells. The aim of this study combining IFN-α, low-dose cytosine arabinoside (ara-C) and ATRA was to increase the proportion of patients achieving a major cytogenetic response, in comparison with a group of 140 patients previously treated with IFN-α plus low-dose ara-C. Forty three patients with Ph-positive CML in early chronic phase were treated with IFN-α 5 MU/m2 sc daily, low-dose ara-C 10 mg sc daily and ATRA 45 mg/m2orally daily, for 7 consecutive days every other week. Overall, 76% of patients achieved a complete hematologic response (CHR). A cytogenetic response was in observed 59% (major in 38% and complete in 17%). Compared with patients treated with IFN-α and low-dose ara-C, those receiving additional ATRA had a lower CHR rate (p. 014), but other response rates were similar. Severe toxicities were common with the triple regimen (64%), mostly related to ATRA therapy. Two patients experienced pseudotumor cerebri; two patients had leukocytosis during the week on ATRA treatment, decreasing during the week off (one suffered a severe asthma-like reaction followed by pulmonary edema, resembling ATRA syndrome). Six patients had other unusual side-effects: aseptic necrosis of the hip (1 patient), ataxic syndrome (1 patient), paranoid syndrome (2 patients), syncopal episodes (1 patient), pure red cell aplasia (1 patient). In conclusion the results of IFN-α and low-dose ara-C combined with ATRA in patients with early CML-chronic phase were disappointing, due to excessive toxicity. Whether different ATRA dose schedules may result in fewer side-effects and improve hematologic and cytogenetic response remains to be determined.

Etoposide-containing regimens with autologous bone marrow transplantation in children with malignant brain tumors.

Despite improvements in neurosurgical and neuroradiotherapeutic techniques, children with malignant brain tumors have a dismal prognosis. In an attempt to improve the efficacy of cytotoxic therapy, dose intensification of effective chemotherapeutic agents followed by autologous bone marrow transplantation (BMT) has been tried. Between May 1991 and August 1996, high-dose chemotherapy and autologous BMT were administered to 11 children with malignant brain tumors: 10 had recurrent (n = 8) or progressive (n = 2) disease, and 1 was treated before progression. The histological diagnoses were medulloblastoma (3), glioblastoma multiforme (2), supratentorial PNET (2), ependymoma (2), anaplastic astrocytoma (1), and anaplastic oligodendroglioma (1). In 6 of the 11 patients measurable disease was present at the time of BMT. The preparative regimen included BCNU 600 mg/m2 and VP16 1500 mg/m2 in 5 cases, and thiotepa 900 mg/m2 and VP16 1500 mg/m2 in 6 cases. The median times to achieve a neutrophil count over 0.5 x 10(9)/l and a platelet count over 50 x 10(9)/l were 14 and 28 days, respectively. The overall incidence of severe toxicity (grade III-IV) was 18% and consisted of oropharyngeal mucositis and diarrhea. Among the 6 patients with measurable disease at the time of BMT there were 2 with stable disease, whereas 4 patients had tumor progression: all these patients died of tumor recurrence 2-10 months after BMT. Five patients in whom there was no evidence of disease at the time of BMT are alive and free of progression with a median follow-up of 20 months (range 3-67). These preliminary results show that high-dose chemotherapy and BMT may be effective in children with malignant brain tumors. Etoposide-containing regimens seem to have significant activity in this setting, and the toxicity was manageable. The most important variable prognostic for progression-free survival is the disease status at the time of transplantation.

A prospective randomized trial to evaluate different oral dose regimens of medroxyprogesterone acetate in women with advanced breast cancer

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; x2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; x2= 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments.

The toxicity of daily inhaled amphotericin B.

Inhaled amphotericin was administered to 29 patients with prolonged neutropenia and toxicity was analyzed. Treatment consisted of 30 mg of amphotericin B administered by nebulizer once daily via either a hand-held nebulizer or face mask. The mean duration of treatment was 16 days. Toxicity was minimal and patient had significant toxic reaction to the inhaled medication. This study documents that nebulized amphotericin B has less than 10% incidence of severe toxicity with 95% confidence level. Guidelines for future trials and use are suggested.