Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study.

PURPOSE: The VICTOR-1 study demonstrated that the all-oral metronomic combination of vinorelbine and capecitabine is highly active and well tolerated in hormone receptor-positive/HER2-negative patients. The VICTOR-2 study was designed to confirm these results. METHODS: Patients received mVNR 40 mg three times a week and mCAPE 500 mg three times a day, continuously. The primary endpoint was the clinical benefit rate (CBR); secondary endpoints were toxicity, objective response rate (ORR), and progression-free survival (PFS). RESULTS: Eighty patients were evaluable for the primary efficacy analysis. Median age was 65.3 years; most patients had HR-positive tumors (65 %). The CBR was 45.7 % (95 % CI 28.8-63.4) and 51.1 % (95 % CI 35.8-66.3) in first- and ≥ second-line therapy, respectively. The ORR was 35.5 % in first-line (95 % CI 19.2-54.6) and 25.6 % in ≥second-line (95 % CI 13.5-41.2). The median duration of response was 11.3 and 6.4 months and PFS rates at 1 year were 24.3 and 22.2 %, respectively. In triple-negative breast cancer patients (N = 28, 35 %) a lower, but clinically relevant CBR (35.7, 95 % CI 18.6-55.9) was observed. The main toxicities per cycle were non-febrile neutropenia (1.1 %), hand-foot syndrome (1.0 %), nausea and vomiting (1.0 %), leucopenia (0.8 %), fatigue (0.7 %), and diarrhea (0.4 %). CONCLUSION: The VICTOR-2 study confirms the clinical activity of mVNR and mCAPE in HER2-negative breast cancer patients, suggesting that the easy schedule of administration, which requires monthly blood tests and limits patients' dependence on hospitals, and the low cost of the drugs are valuable elements, even for countries with limited access to innovative or expensive drugs.

Prospective dosimetry with 99mTc-MDP in metabolic radiotherapy of bone metastases with 153Sm-EDTMP.

PURPOSE: On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, (153)Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of (153)Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals. METHODS: Seven to 14 days before treatment with (153)Sm-EDTMP, 44 patients underwent (99m)Tc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc(%)) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc(%) was then compared to Sm(%) similarly derived from 10-min and 24-h whole-body scans. Tc(%) and Sm(%) were compared both with and without Brenner's method for soft tissue uptake. RESULTS: The correlation between Tc(%) and Sm(%) was R (2) = 0.81 and R (2) = 0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm(%) = 64.3 +/- 15.2, Tc(%) = 56.2 +/- 16.0; p = 0.017) with soft tissue correction, while was not statistically significant (Sm(%) = 68.2 +/- 15.5, Tc(%) = 66.9 +/- 14.0; p = 0.670) without soft tissue correction. CONCLUSIONS: The rate of retention of (99m)Tc-MDP in bone provides a reliable estimate of the (153)Sm-EDTMP rate of retention. The proposed method can be usefully adopted for prospective dosimetry seeing its extreme simplicity, and it requires no special investment in terms of human or instrumental resources. This allows an optimization of administered (153)Sm-EDTMP activity.

Metronomic Chemotherapy in Triple-Negative Metastatic Breast Cancer: The Future Is Now?

Triple-negative breast cancer (TNBC) shows a very bad prognosis, even in early stages of disease. Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. In the present article, we review preclinical and clinical data of metronomic administration of chemotherapy agents with or without biological agents in TNBC cell lines and patients, contextually reporting data from the VICTOR-2 study in the subgroup of patients with TNBC, in order to stimulate new ideas for the design of clinical trials in this subset of patients.

Combined therapy for primary central nervous system lymphoma in immunocompetent patients.

A retrospective series of 13 immunocompetent patients with histological diagnosis of primary central nervous system lymphoma (PCNSL) is presented. The series was divided into Group A, 6 patients treated with radiotherapy alone, and Group B, 7 patients treated with chemotherapy and radiotherapy. Clinicopathological patterns were similar for the two groups. In Group A, 4 patients achieved complete remission after radiotherapy (45-59.4 Gy) but relapsed within 9 months and died within 21 months of diagnosis. 4 Group B patients received chemotherapy followed by radiotherapy, and three who received a methotrexate-containing regimen are alive and disease-free at 34, 42 and 45 months, while the fourth died after 11 months. The other 3 subjects in this group were treated with radiotherapy followed by chemotherapy, and died within 15 months of diagnosis. Although radiotherapy is the standard treatment, chemotherapy has potentially an important role in the management of PCNSL. The sequence of combined treatment could be crucial to improvement of outcome.

Cisplatin versus carboplatin in combination with mitomycin and vinblastine in advanced non small cell lung cancer. A multicenter, randomized phase III trial.

BACKGROUND: In advanced not selected NSCLC chemotherapy achieved an advantage of approximately 1-2 months on median survival versus best supportive care. Chemotherapy seems to improve symptoms control, even if randomised studies with quality of life as first endpoint are lacking and often chemotherapy toxicity compromises the frail cost/benefit ratio. The aim of the present study is to evaluate the impact on QoL, substituting cisplatin, a pivot drug in NSCLC therapy, with carboplatin, an analogue with an improved toxicity profile. The combination of cisplatin with Mitomycin and Vinblastine was one of the most frequently used in the palliative setting at the time of design of our study. METHODS: Patients were randomized to receive MVP regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1-8, Cisplatin 100 mg/m2 d1) or MVC regimen (Mitomycin-C 8 mg/m2 d1, Vinblastine 4 mg/m2 d 1-8, Carboplatin 300 mg/m2 d1) every 3 weeks. The QoL was evaluated by the Spitzer QL-Index and by the EORTC QLQ-C30+LC 13 questionnaires before chemotherapy, after one cycle, after three cycles, and then every 6 weeks in the first 6 months and every 3 months thenafter. RESULTS: From September 1994 to July 1997, 153 consecutive patients were randomized to MVP (75 patients) or MVC arm (78 patients). Despite difficulties in carrying out and analysing QoL items in such patients, the global QoL evaluated by the Spitzer's questionnaire suggested an advantage for MVC regimen (P=0.05) and a significant difference was observed in global health subdomain (P=0.04). The disease-related symptoms improved with time, and the benefits lasted for the entire treatment period. When evaluated with the EORTC questionnaire there was significantly less nausea and vomiting (P=0.0001), appetite loss (P=0.01), insomnia (P=0.03), constipation (P=0.01) and peripheral neuropathy (P=0.01) in favour of MVC, and a trend for less hair loss (P=0.05). The advantage lasted for all the duration of chemotherapy. No differences were observed in global quality of life subdomain (P=0.40) between the two regimen. QoL was the first endpoint and the statistical power was inadequate to assess other parameters. However, we reported a response rate of 43.1 and 38.6%, respectively, in MVP and MVC arm (P=0.59) and a median survival of 10.2 and 7.2 months, respectively, for cisplatin and carboplatin arm (P=0.39). CONCLUSIONS: The carboplatin containing regimen (MVC) has a significant better toxicity profile than the cisplatin containing (MVP) regimen as proven both by the EORTC questionnaires and by the WHO toxicity data reported by physicians. No significant differences in terms of response rate, time to progression and overall survival were observed between the two regimen. The two chemotherapy regimen showed a similar effectiveness in symptom palliation when evaluated with C30 addendum of EORTC QOL questionnaire. With the Spitzer's questionnaires a trend towards an improved quality of life index was observed during treatment with the carboplatin combination in comparison to the cisplatin combination. This difference, however, was not observed when the global quality of life was evaluated with the EORTC patients compiled questionnaires. A carboplatin containing regimen with better toxicity profile and a similar potentiality for symptoms control offers an option in comparison to similar cisplatin containing combinations in the palliative treatment of advanced NSCLC.

Surgery following neoadjuvant MPV chemotherapy (mitomycin, cisplatin, vinblastine) in locally advanced (IIIa and IIIb) non-small cell lung cancer.

From November 1990 to August 1993, 32 patients with non-small cell lung cancer (NSCLC) entered a multimodality treatment study with neoadjuvant Mitomycin, Cisplatin and Vinblastine (MPV), surgery and radiotherapy at the San Raffaele Hospital in Milan, Italy. Neoadjuvant chemotherapy was performed on an outpatient basis. To date 23 patients (11 stage IIIa and 12 stage IIIb) have completed the chemotherapy treatment and are available for evaluation of response, toxicity, surgical eligibility and resection rate. The overall major response to MPV chemotherapy was 87%. The overall resection rate after major response to treatment was 60% (90% in stage IIIa and 17% in stage IIIb). After a median follow-up of 21 months (8-31) 17 patients are still alive (74%). Ten patients (83%) who had a complete resection are alive after a median follow-up of 23 months (21-30) and eight of them (66%) are in complete pathological remission. No treatment-related mortality was observed. The authors conclude that MPV is a highly effective neoadjuvant regimen for NSCLC and is feasible on an outpatient basis. Favorable resection rates can be obtained in stage IIIa patients. Stage IIIb patients can be downstaged and undergo complete resection. A longer follow-up is needed to assess the impact of this multimodality approach on long-term survival and to evaluate the role of adjuvant radiotherapy.

Cyclophosphamide, adriamycin, and cis-platinum (CAP) in metastatic and locally advanced breast cancer.

A combination of cyclophosphamide, adriamycin, and cis-platinum (CAP) was tested in 20 previously untreated patients with locally advanced or metastatic breast cancer with the aim of assessing the ability of this platinum-containing regimen to induce a high complete remission rate. The drug regimen was given on a 3/week schedule at the following doses: cyclophosphamide 200 mg/m2 i.v. on days 1, 2, 3; adriamycin 40 mg/m2 i.v. or day 1 and cis-platinum 20 mg/m2 i.v. plus hydration on days 1, 2, 3. In the absence of progression, six cycles of CAP were planned and response was evaluated at that time. Thirteen of 20 patients achieved partial remission (65%) but only one obtained complete remission (5%). Overall median duration of response was 9 months (range 4-20 + months). Tumor response was mainly documented in soft tissues (primary tumor: 14 of 16; other sites: 19 of 20). Grade II leukopenia was documented in 60% of patients. All patients experienced moderate to severe gastrointestinal toxicity and alopecia was universal. No renal toxicity was observed. Although CAP regimen at the given dose schedule induced a high overall response rate (70%), the complete remission rate in this limited number of patients was lower than expected. These results do not appear superior to those achieved with conventional drug regimens.

Use of dose-volume histograms and biophysical models to compare 2D and 3D irradiation techniques for non-small cell lung cancer.

For non-small cell lung cancer (NSCLC), unsatisfactory local control (LC) still remains an important cause of failure. It has been suggested that improved LC can be achieved with both higher radiation dosage and adequate target coverage. Modern three-dimensional treatment planning systems (3D-TPSs) offer many tools for planning optimization. Biophysical models, which estimate the normal tissue complication probability (NTCP), are gaining in importance in comparing plans. This study compares conventional two-dimensional (2D) with 3D irradiation techniques using parameters related to volumetric dose distribution and two different biophysical models predicting normal tissue tolerance to radiotherapy (RT). Nine patients with inoperable locally advanced NSCLC were treated with a beam's eye view-based 3D technique. For the same patients, a conventional treatment was simulated; the irradiation geometry and beam contour were fully defined at the simulator and then transferred to the 3D-TPS to calculate the dose distribution. Both techniques gave the same prescribed dose at the reference point. Dose-volume histograms (DVHs) and dose statistics of organs at risk (OARs) (heart, lung(s), parenchyma lung, spinal cord and oesophagus) were analysed. The probability of side effects was estimated using two different biophysical models: the integrated normal ("empirical") model and the relative seriality model. Apart from contralateral lung, the 3D irradiation technique significantly reduced the average mean doses to all OARs. The current analysis suggests that in the treatment of locally advanced NSCLC, the use of 3D irradiation techniques allows a large sparing of OARs; this advantage is confirmed by both dose statistics analysis and NTCP values.

Antiemetic activity of metoclopramide versus alizapride during cancer chemotherapy.

A prospective randomized study was conducted to compare the antiemetic efficacy of metoclopramide (MCP) versus its recent derivative alizapride (ALZ) in patients undergoing cancer chemotherapy. Both drugs were given at a dose of 2 mg/kg i.v. push for 5 doses. A positive response was defined as absence of nausea or emesis, or moderate nausea with one or two emeses per day. Eighty-two patients were evaluable. Forty-two received MCP and 40 received ALZ. A positive response was observed in 54% MCP-treated and 41% ALZ-treated patients. Neurologic toxicity, mainly extrapyramidal disturbances, was the most remarkable adverse side effect; it occurred more frequently in the MCP-treated group (31%) than in the ALZ-treated group (17%). Both drugs were found to be more effective in previously untreated patients and when employed together with steroids. MCP was more effective (52% positive response) than ALZ (41% positive response) in cisplatin-treated patients. To better control drug-induced vomiting, we believe that future trials should evaluate slow i.v. infusion of antiemetic agents and their combination with dexamethasone.

Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: a multicenter phase II study of the Italian Group on Rare Tumors.

The Italian Group on Rare Tumors undertook a phase II study of a combination of epirubicin and interleukin-2 in 21 chemotherapy-naive patients with malignant mesothelioma. All patients had bidimensionally measurable disease at CT scan. Treatment included Intravenous administration of epirubicin at a dose of 110 mg/m2 i.v. on day 1, and interleukin-2 at a dose of 9 MU subcutaneously from day 8 to day 12 and from day 15 to day 19. Cycles were repeated every three weeks, up to six times in the absence of progressive disease. Treatment response was evaluated after two cycles of therapy. Only one patient achieved a partial response, resulting in an overall response rate of 5% (1/21) with a median progression-free and overall survival of 5 and 10 months, respectively. Toxicity was relevant and caused treatment discontinuation in many patients. These results do not support the use of such a combination in the management of malignant mesothelioma.

Increasing dose of continuous infusion ifosfamide and fixed dose of bolus epirubicin in soft tissue sarcomas. A study of the Italian group on rare tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) of ifosfamide when given as a continuous infusion and in combination with fixed doses of bolus 4'-epidoxorubicin in advanced previously untreated adult soft tissue sarcoma patients. METHODS: Treatment consisted of epidoxorubicin, 60 mg/m2 days one and two, and ifosfamide, 1.5 g/m2 every 12 hrs as a 72-hr infusion, at the first level. Further levels of ifosfamide were defined as increments of 12 hrs of the same infusion program. G-CSF 300 microg/die was administered from days +7 to +14. Dose-limiting toxicity (DLT) was defined as: G4 leukopenia or thrombocytopenia of > or =5 days; any G3 neuro or nephrotoxicity; G4 toxicity of any kind. Patients had to complete at least 2 consecutive cycles, and MTD was defined as the level in which 20% of patients developed a DLT; 10-15 patients were entered in each level. RESULTS: First level: overall, 13 patients entered, 3 were not assessable for MTD, and only one developed a DLT. Second level: 18 patients entered, 3 were not assessable for MTD. Hematologic DLT was observed in 3/15 assessable patients. Therefore, the MTD was found at the ifosfamide level of 10.5 g/m2 given in 84 hrs. Eight patients of 29 assessable for response achieved an objective response: 1 complete and 7 partial. The overall response rate was 28% (95% CI: 13-47%). CONCLUSIONS: If we accept 4-day G4 leukopenia as a reliable cutoff for safety, ifosfamide intensification cannot be substantially exploited over already available schedules with the combination of ifosfamide and anthracyclines.

Irradiation fields and doses in glioblastoma multiforme: are current standards adequate?

AIMS AND BACKGROUND: The optimum conventional radiotherapy in glioblastoma multiforme patients has not been clearly defined by prospective trials. To better characterize a standard radiotherapy in glioblastoma multiforme, the impact on survival of different fields and doses was analyzed in a retrospective single center series. METHODS: One hundred and forty-seven patients with glioblastoma multiforme, submitted to biopsy only (n = 15), subtotal (n = 48) or total resection (n = 82) and who completed the planned postsurgical radiotherapy, were considered. The median age was 57 years, the male/female ratio 1.5/1, and the performance status > or =70 in 76%. Whole brain irradiation, followed by a boost to partial brain, was used in 75 cases with a whole brain dose of 44-50 Gy (median, 46) and a partial brain dose of 56-70 Gy (median, 60 Gy). Partial brain irradiation alone was used in 72 patients with a dose of 56-70 Gy (median, 61 Gy). Ninety-eight patients received 56-60 Gy (median, 59 Gy) to partial brain whereas 49 patients received 61-70 Gy (median, 63 Gy). RESULTS: There was an almost significantly longer survival in patients irradiated to the partial brain alone with respect to those also receiving whole brain radiotherapy (P = 0.056). Doses >60 Gy significantly prolonged survival (P = 0.006). Multivariate analysis confirmed that the impact on survival of radiation dose was independent of age, performance status, extent of surgery, field of irradiation and the use of chemotherapy. The extent of irradiation field was not independently related to improved survival. CONCLUSIONS: Our retrospective findings suggest that we reflect on the adequacy of the current standard irradiation parameters. Well-designed prospective trials are necessary to standardize the radiotherapy control group in patients with glioblastoma multiforme to be compared in phase III trials with innovative therapeutic approaches.

Cytarabine and cisplatin in advanced malignant melanoma.

Twenty-seven consecutive patients with advanced malignant melanoma were treated with cytarabine (Ara-C) and cisplatin. Of 25 evaluable patients, four achieved partial response, for a median duration of 3 months. Three of four responders belonged to the group of seven patients given Ara-C at a dose of 3 g/m2. The predominant toxic effect was hematologic and related to the dose of Ara-C. The cost-benefit ratio of this combination is inferior to that of dacarbazine or carmustine alone.

Four-drug sequential regimen in advanced breast cancer.

The results of two empirically designed and potentially non-cross-resistant combinations administered sequentially in advanced breast cancer with the intent of achieving a high rate of durable complete remissions were analyzed. The two drug combinations consisted of cyclophosphamide plus Adriamycin and high-dose methotrexate plus cisplatin given for a total of three cycles; twenty evaluable patients, not previously treated with chemotherapy, were entered into the study. Ten patients were allocated to receive cyclophosphamide and Adriamycin first followed by high-dose methotrexate and cisplatin, while the remaining patients received the opposite sequence. The overall response rate for the entire group was 85% (17 of 20). However, only three of 20 (15%) patients achieved complete remission. One additional complete response was observed when treatment was prolonged for an additional complete cycle. The overall median duration of response was 13 months (range, 5-20+ months). Responses were similarly distributed among different sites of lesions. Myelosuppression and gastrointestinal toxicity were mild and transient. Reversible acute renal failure was observed after methotrexate administration in three cases. Present results indicate that overall this sequential treatment appears effective in patients with advanced breast cancer. However, the lack of an increased complete remission rate over conventional regimens coupled with a potential risk of renal toxicity prevents further studies with this multiple drug combination.

Treatment of carcinoid syndrome with recombinant interferon alpha-2a.

The prognosis and the quality of life of patients with carcinoid tumors is related either to symptoms from the substances secreted or to progressive tumor growth. Medical treatment with cytotoxic agents is of marginal value for increasing life expectancy and reducing clinical symptoms. Recent studies with interferon have shown interesting results. In the present investigation, 22 patients with carcinoid tumors and syndrome were treated with recombinant interferon alpha-2a (r-IFN alpha-2a) at the dose of 6 x 10(6) IU intramuscularly daily for 8 weeks and three times weekly thereafter. The primary tumor was localized in the foregut (n = 11), midgut (n = 7), hindgut (n = 1), and unknown site (n = 3). Most cases had liver metastasis. Seventeen patients had elevated 5-hydroxyindoloacetic acid (5-HIAA) excretion and 5 had flushing and/or diarrhea as the only clinical manifestation. Six cases presented a complete syndrome (flushing, diarrhea and 5-HIAA excretion). Control of symptoms was obtained in 80% and a 5-HIAA level reduction in 58% of the patients. The interferon treatment was more effective for control of the carcinoid syndrome than for control of tumor growth. The treatment was well tolerated and fever, myalgia, anorexia and fatigue were the most frequent side-effects.

Lack of Activity of Docetaxel in Soft Tissue Sarcomas: Results of a Phase II Study of the Italian Group on Rare Tumors.

Purpose. The prognosis of advanced soft tissue sarcoma is poor, only a few drugs showing some activity with response rates around 15- 25%. Consequently drug development seems mandatory to improve treatment outcome. Following previous favourable EORTC experience, the Italian Group on Rare Tumors started a phase II study with docetaxel to confirm the activity of this drug in soft tissue sarcoma.Patients and methods. Thirty-seven patients with soft tissue sarcoma resistant to at least one anthracyclinecontaining regimen were enrolled in a phase II multicenter study evaluating docetaxel 100 mg/m(2) in a 1-h i.v. infusion q(3) weeks.Results.Thirty-seven patients were enrolled onto this phase II study and 36 were evaluable for response. Only one partial remission was observed [2.8% with 95% confidence interval (CI) 0.1- 16.2%]. Median progression-free and overall survival were 42 and 350 days, respectively. Neutropenia and leukopenia as well as cutaneous manifestations were the most common toxicities.Discussion. The results of this phase II study do not confirm a previous EORTC repor t on the activity of docetaxel in soft tissue sarcoma, but are consistent with other more recent phase II studies. The accumulated evidence does not justify the use of this drug in the management of patients suffering from this disease, resistant to anthracyclinecontaining regimens.