Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study

Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy, the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy, the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy, 10.6 months; infusional therapy, 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events, P = .04; clinical events, P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy, 12 received surgery, and of those 12, eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.     

Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol.

PURPOSE: Acute doxorubicin-induced cardiotoxicity can be prevented in adults by continuous infusion of the drug, but mechanisms of cardiotoxicity are different in children. We compared cardiac outcomes in children receiving bolus or continuous infusion of doxorubicin. PATIENTS AND METHODS: In a randomized study, children with high-risk acute lymphoblastic leukemia received doxorubicin 360 mg/m(2) in 30-mg/m(2) doses every 3 weeks either by bolus (within 1 hour, n = 57) or by continuous infusion (over 48 hours, n = 64). Echocardiograms obtained before doxorubicin and at longest follow-up times were centrally remeasured, and z scores of cardiac measurements were calculated based on a healthy population. RESULTS: The groups were similar in age, sex distribution, doxorubicin dose, and duration of follow-up. Before treatment, measures of left ventricular (LV) structure and function did not reveal dilated cardiomyopathy and were not statistically different between bolus and continuous-infusion groups. The follow-up echocardiograms demonstrated no significant difference between the two groups for any cardiac characteristic, but both groups showed significant abnormalities of LV structure and function compared with normal and with baseline. For example, the mean LV fractional shortening fell by approximately two SD in both groups between the two echocardiograms. LV contractility was depressed in both groups (for bolus patients, median z score = -0.70 SD, P =.006; for continuous-infusion patients, median z score = -0.765, P =.005). Dilated cardiomyopathy and inadequate LV hypertrophy were noted in both groups. Clinical cardiac manifestations and event-free survival did not differ. CONCLUSION: Continuous doxorubicin infusion over 48 hours for childhood leukemia did not offer a cardioprotective advantage over bolus infusion. Both regimens were associated with progressive subclinical cardiotoxicity. Other cardioprotective strategies should be explored.     

Doxorubicin followed by sequential paclitaxel and cyclophosphamide versus concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial of adjuvant dose-dense chemotherapy for women with node-positive breast carcinoma.

PURPOSE: We conducted a randomized Phase II trial to directly compare toxicity, feasibility, and delivered dose intensities of two adjuvant dose-intensive regimens containing doxorubicin, paclitaxel, and cyclophosphamide for patients with node-positive breast carcinoma. EXPERIMENTAL DESIGN: Forty-two patients with resected breast carcinoma involving one or more ipsilateral axillary lymph nodes, were randomized to receive two different schedules of adjuvant chemotherapy using 14-day dosing intervals: either (a) three cycles of doxorubicin 80 mg/m(2) as i.v. bolus followed sequentially by three cycles of paclitaxel 200 mg/m(2) as a 24-h infusion and then by three cycles of cyclophosphamide 3.0 g/m(2) as a 1-h infusion (arm A); or (b) the same schedule of doxorubicin followed by three cycles of concurrent cyclophosphamide and paclitaxel at the same doses (arm B). All cycles were supported by granulocyte colony-stimulating factor administration. RESULTS: Forty-one patients were assessable for toxicity and feasibility; 37 (90%) completed all planned chemotherapy. There was no treatment-related mortality; however, increased toxicity was observed on arm B compared with arm A, manifested by an increase in hospitalization for toxicity, mainly neutropenic fever, and an increased incidence of transfusion of packed RBCs transfusions for anemia. The mean delivered dose intensities for paclitaxel and cyclophosphamide were significantly greater for arm A compared with arm B (P =.01 and P =.05, respectively). There is no long-term, treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSIONS: Dose-dense sequential single-agent chemotherapy is more feasible than doxorubicin with subsequent concurrent paclitaxel and cyclophosphamide.     

A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer

Seventy-seven patients with progressive metastatic breast cancer refractory to prior therapy participated in a prospective randomized trial designed to compare the efficacy and toxicity of doxorubicin and epirubicin administered as single agents. In arm 1, 60 mg/m2 of doxorubicin and, in arm 2, 90 mg/m2 of epirubicin were administered by 48-h continuous i.v. infusion every 3 weeks. In arm 3, 90 mg/m2 of epirubicin was administered by bolus every 3 weeks. Patients in the three groups had similar characteristics, except that in arm 3 more patients were premenopausal, had more extensive disease, and fewer patients had been exposed to doxorubicin. Objective remission rates were 29, 26, and 13%, respectively for the three arms. Median response durations ranged from 4-6 months. No significant differences occurred in response rate, remission duration, or survival among patients in the three arms. The incidence of gastrointestinal toxicity and alopecia was evenly distributed. Hematologic toxicity was more severe in arms 2 and 3, and there was a higher incidence of infectious complications in arms 2 and 3 compared to arm 1 (p = 0.05). Two episodes of congestive heart failure occurred in arm 1, one in arm 2, and three in arm 3. Although the total cumulative anthracycline dosage was highest in the arm 2 group, they had the lowest incidence of cardiac toxicity. Epirubicin by bolus and doxorubicin administered by continuous infusion have similar potential for cardiac toxicity. Epirubicin administered by continuous infusion appears less cardiotoxic than doxorubicin by either method of administration or epirubicin given by bolus. Epirubicin appears equally active and less cardiotoxic than the parent compound doxorubicin in patients with metastatic breast cancer.     

Combination chemotherapy with doxorubicin, dacarbazine, and ifosfamide in advanced adult soft tissue sarcoma. Canadian Sarcoma Group--National Cancer Institute of Canada Clinical Trials Group

Forty-three adult patients with locally advanced or metastatic soft tissue sarcoma entered a pilot study of combination chemotherapy comprising 50 mg of doxorubicin/m2 by intravenous bolus, 850 mg of dacarbazine/m2 by 1-hour infusion, and 5 g of ifosfamide/m2 by 24-hour infusion with mesna uroprotection. The overall response rate in 40 assessable patients was 25% with two complete remissions. Twenty-four episodes of infection occurred in 148 courses (16%). These infections were usually associated with neutropenia (granulocyte count less than 0.5 X 10(9)/L), which occurred in 70% of the courses. These results do not differ from those elicited by each agent alone, and may reflect inadequacies of dose intensity or scheduling, or evaluation in a study population with adverse prognostic factors.     

A randomised study of bolus vs continuous pump infusion of ifosfamide and doxorubicin with oral etoposide for small cell lung cancer.

One hundred and fifty-nine previously untreated patients with small cell lung cancer (SCLC), who were not eligible for intensive chemotherapy, were entered into a randomised study of intravenous (i.v.) doxorubicin and ifosfamide (with mesna) and oral etoposide. The i.v. drugs were given either by bolus therapy or by a continuous infusion (CI) pump over 7 days via a central venous line. Therapy was given for 6 weeks only. On weeks 1, 3 and 5 IV doxorubicin 35 mg m-2 was given with 5 days of oral etoposide 100 mg m-2 daily. On weeks 2, 4 and 6 IV ifosfamide 5 g m-2 was given with equidose mesna. The overall median survival was 25 weeks for patients in the bolus arm and 30 weeks for the CI therapy (P = 0.45). The overall response rate was 64% (18% complete response-CR) and 69% (30% CR) respectively (P = 0.13). The median WHO score for haematological toxicity was 4 for bolus therapy and 3 for CI therapy (P = 0.0007). Despite a trend for less supportive care for patients on CI therapy there were no significant differences in the use of i.v. antibodies and blood or platelet transfusions. There were fewer treatment delays due to myelotoxicity in the CI arm (P = 0.04). The median WHO score for non-haematological toxicity was 2 in both treatment groups. There was significantly less nausea (P = 0.037) but more mucositis (P = 0.01) in the CI arm. Weekly chemotherapy using CI treatment was as effective as bolus therapy. It was well accepted by patients. The assessment of quality of life in a subgroup of patients showed a statistically significant reduction in anxiety and depression for both groups of patients during therapy.     

Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma

Two hundred and seventy-four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48-hour (79 patients) or 96-hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinical cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48-hour or 96-hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P less than 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P less than 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a greater than 75% decrease in the frequency of clinical congestive heart failure at cumulative dosages greater than or equal to 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48-hour or 96-hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.     

Randomized phase II study of docetaxel versus doxorubicin in first- and second-line chemotherapy for locally advanced or metastatic soft tissue sarcomas in adults: a study of the european organization for research and treatment of cancer soft tissue and bone sarcoma group.

PURPOSE: To assess antitumor response and time to progression (TTP) with docetaxel compared with doxorubicin in first-line treatment of advanced and/or metastatic soft tissue sarcoma. PATIENTS AND METHODS: Patients with measurable soft tissue sarcoma lesions and adequate bone marrow, liver, and renal function were entered onto the study. They were randomized to either docetaxel 100 mg/m(2) given as a 1-hour intravenous infusion every 3 weeks or doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks. A maximum of seven cycles of treatment were scheduled. The study was designed as a randomized phase III study evaluating TTP by log-rank model. There was a clause for premature closure of the trial if fewer than five responses were observed among the first 25 assessable patients in the docetaxel treatment arm. RESULTS: Eighty-six patients were entered onto the study; 85 were assessable for toxicity and 83 for response. The rate of severe granulocytopenia was not significantly different between the two arms. Nausea (P =.001), vomiting (P <.001), and stomatitis (P =.005) were more common with doxorubicin therapy, whereas neurotoxicity was more frequent with docetaxel treatment. The response rate to doxorubicin therapy was 30% (95% confidence interval, 17% to 46%), whereas no responses to docetaxel therapy were seen (P <.001). In view of this, the trial was closed prematurely and the phase III study part was not conducted. CONCLUSION: Docetaxel is inactive in soft tissue sarcomas and cannot be recommended for further use in treatment of this disease.     

Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group.

PURPOSE: To estimate the toxicity and response rate of high-dose liposome-encapsulated doxorubicin (TLC D-99, Evacet, The Liposome Company Inc, Princeton, NJ) in patients with advanced breast cancer. PATIENTS AND METHODS: Fifty-two breast cancer patients with bidimensionally measurable metastatic disease and no prior chemotherapy for metastatic disease received a 135 mg/m2 intravenous (i.v.) bolus of TLC D-99 with 5 microg/kg of granulocyte colony-stimulating factor via subcutaneous injection every 21 days. RESULTS: The median number of treatment cycles of TLC D-99 was three (range, one to 10 cycles), and the median total cumulative dose of TLC D-99 was 405 mg/m2 (range, 135 to 1,065 mg/m2). Grade IV neutropenia, thrombocytopenia, and mucositis were experienced by 48 (92%), 46 (88%), and 10 (19%) patients, respectively. Twenty (38%) of patients experienced cardiac toxicity: four (8%) experienced a decrease of 20% or more in left ventricular ejection fraction (LVEF) to a final value > or = 50%, nine (17%) experienced a decrease of 10% or more in LVEF to a final value less than 50%, and seven (13%) developed symptomatic congestive heart failure (CHF), including one patient who died of cardiomyopathy after receiving a total dose of 1,035 mg/m2. In a stepwise logistic regression model, the significant risk factors for the development of CHF were the cumulative dose of prior adjuvant doxorubicin (P = .007) and the total cumulative dose of TLC D-99 (P = .032). The overall response rate was 46% (95% confidence interval [CI], 32% to 61%) on an intent-to-treat basis. The median duration of response was 7.4 months (95% CI, 6.1 to 19.6 months) and the median progression-free survival was 6.1 months (95% CI, 5.4 to 7.5 months). CONCLUSION: There was no added therapeutic benefit to the dose escalation of TLC D-99 in this study. A high rate of cardiotoxicity was also observed, especially among patients who had received prior adjuvant doxorubicin. This was probably attributable to the dose and schedule of TLC D-99 used in this trial, as well as the patient's lifetime cumulative doxorubicin dose. Administration of high-dose TLC D-99 at 135 mg/m2 every 3 weeks by i.v. bolus infusion does not warrant further investigation.     

Phase II study of vinorelbine administered by 96-hour infusion in patients with advanced breast carcinoma.

BACKGROUND: Vinorelbine given by weekly bolus injection is active and less toxic than bolus vinblastine in the treatment of patients with metastatic breast carcinoma. Vinblastine given by 5-day continuous infusion showed a steep dose-response curve. Pharmacokinetic studies of vinorelbine showed that it is possible to achieve a comparable antitumor effect with a smaller amount of the drug if it is given by continuous infusion. The purpose of this study was to determine the efficacy of vinorelbine given by 96-hour continuous infusion to patients with refractory metastatic breast carcinoma patients. METHODS: Between May 1996 and August 1997, 47 patients with metastatic breast carcinoma were registered into the study. All patients previously had received doxorubicin and 70% had undergone prior paclitaxel treatment. Approximately 56% of the patients had >/=2 metastatic sites. All patients received vinorelbine according to the following dose schedule: 8 mg bolus followed by 11 mg/m(2) by continuous infusion over 24 hours every 4 days every 3 weeks. RESULTS: Forty-four patients were evaluable for response. A total of 193 cycles were administered. The overall response rate was 16% (2 patients achieved a complete response and 5 patients achieved a partial response). The median duration of response was 4.3 months and the median overall survival was 8.6 months. Patients with visceral metastases and/or multiple sites of involvement had shorter durations of response than patients with only soft tissue disease or single-site metastasis (3.1 months vs. 4. 9 months) and shorter overall survival (8.1 months vs. 12 months). Dose reductions were necessary due to cumulative stomatitis and/or fatigue in 12 cycles and neutropenia and/or infection in 13 cycles. CONCLUSIONS: Due to toxicity, a revised maximum tolerated dose for continuous infusion vinorelbine is proposed by the authors: 8 mg intravenously over 10 minutes followed by 10 mg/m(2) by continuous infusion over 24 hours every 4 days. The current dose schedule did not offer an advantage either in response rates or survival over the weekly vinorelbine bolus injection in doxorubicin-resistant and paclitaxel-resistant patients.     

Safety and efficacy of the multidrug-resistance inhibitor biricodar (VX-710) with concurrent doxorubicin in patients with anthracycline-resistant advanced soft tissue sarcoma.

PURPOSE: Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma. EXPERIMENTAL DESIGN: In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks. RESULTS: Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months. CONCLUSION: Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.     

Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer.

PURPOSE: A prospective study in breast cancer patients was undertaken to determine whether escalating doses of doxorubicin and cyclophosphamide would result in a higher fraction of patients free of disease, and to evaluate the role of leukocyte alpha-interferon. PATIENTS AND METHODS: Between 1982 and 1986, 319 consecutive patients with stage II or III breast cancer with one or more positive nodes were assigned randomly to receive adjuvant chemotherapy that consisted of escalating doses of doxorubicin and cyclophosphamide in combination with vincristine and prednisone or the same chemotherapy regimen followed by 1 year of leukocyte alpha-interferon. Doxorubicin was administered by 72-hour continuous infusion through a central venous catheter (maximum total cumulative dose, 430 mg/m2). All patients with positive or unknown estrogen receptor status were also given tamoxifen for 1 year. RESULTS: The median follow-up was 71 months (range, 35 to 99 months). Correlation of disease-free survival (DFS) with dose-intensity of cyclophosphamide and doxorubicin showed no improvement in DFS for patients who were able to receive escalated drug doses compared with those who were not. Doxorubicin administered by continuous infusion was associated with a negligible risk of cardiotoxicity in this study despite the administration of higher accumulative doses than in our previous adjuvant therapy studies. The DFS rates of patients who did and those who did not receive leukocyte alpha-interferon were similar. CONCLUSIONS: In this study, there was no real evidence that higher drug dose intensity was associated with longer DFS. Leukocyte alpha-interferon as it was used in this study had no therapeutic value. Doxorubicin administered by infusion was associated with a reduced risk of cardiotoxicity.     

Doxorubicin-paclitaxel: a safe regimen in terms of cardiac toxicity in metastatic breast carcinoma patients. Results from a European Organization for Research and Treatment of Cancer multicenter trial

BACKGROUND: The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies. METHODS: In a large multicenter Phase III trial, 275 anthracycline naive metastatic breast carcinoma patients were randomized to receive either doxorubicin (60 mg/m(2)) followed 30 minutes later by paclitaxel (175 mg/m(2) 3-hour infusion; AT) or a standard doxorubicin-cyclophosphamide regimen (AC; 60/600 mg/m(2)). Both treatments were given once every 3 weeks for a maximum of six cycles. Close cardiac monitoring was implemented in the study design. RESULTS: Congestive heart failure (CHF) occurred in three patients in the AT arm and in one patient in the AC arm (P = 0.62). Decreases in left ventricular ejection fraction to below the limit of normal were documented in 33% AT and 19% AC patients and were not predictive of CHF development. CONCLUSIONS: AT is devoid of excessive cardiac risk among metastatic breast carcinoma patients, when the maximum planned cumulative dose of doxorubicin does not exceed 360 mg/m(2).     

Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial.

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) dose escalation was planned at cycle 2 if no grade >or= 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen     

Doxorubicin cardiotoxicity in children: reduced incidence of cardiac dysfunction associated with continuous-infusion schedules

We retrospectively reviewed the medical records of 97 children (59 boys and 38 girls) with a median age of 13 +/- 4 years who had been treated with continuous infusion of doxorubicin at a dosage of 60 mg/m2 over 24 h (61 patients) or at a dosage of 75 mg/m2 over 72 h (36 patients). The drug was administered every 3 weeks. The cardiac status of patients was evaluated as a baseline and every 6 months during, and following therapy (median, 30.5 months). The evaluations included M-mode and two-dimensional echocardiography. Congestive heart failure developed in only one patient in this series, an 8-year-old girl who ultimately died of her cardiac complication. This incidence of doxorubicin-induced cardiotoxicity was compared with that seen in a control group of pediatric patients previously treated with doxorubicin at similar dosages but with a rapid infusion. The result compared favorably to the 13% incidence of cardiotoxicity (p = 0.03) and 7% mortality (p < 0.01) in the control group. No changes in the levels of tumor response were noted in children treated by continuous infusion when compared with historical controls. Continuous-infusion schedules of doxorubicin thus result in fewer incidences of cardiotoxicity in children and should be considered for wider application in pediatric cancer patients receiving doxorubicin.     

5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group Study

In order to determine the clinical applicability of the in vitro observation of enhanced cytotoxicity of 5-fluorouracil (5-FU) in the presence of excess reduced folates, the Southwest Oncology Group (SWOG) performed a randomized trial evaluating two dose schedules of 5-FU and folinic acid (FA) in 128 patients with metastatic colorectal cancer. Of 125 eligible patients, 62 were randomized to receive bolus FA (200 mg/m2 days 1 through 4) in addition to 5-FU (1,000 mg/m2 days 1 through 4) by continuous four-day infusion (infusion arm), while 63 were randomized to receive bolus FA (200 mg/m2 days 1 through 5) in addition to 5-FU (325 mg/m2 days 1 through 5) by bolus injection (bolus arm). The toxicities of the two schedules differed, with stomatitis being more severe in the infusion arm and leukopenia being more severe in the bolus arm. The response rates and survival data for the two arms are nearly identical. The median survival of patients on the infusion arm is 11.0 months and of patients on the bolus arm, 10.3 months. The infusion arm produced one complete response (CR) and 12 partial responses (PRs), for a major response rate of 21% of eligible patients. The bolus arm produced three CRs and 11 PRs, for a major response rate of 22% of eligible patients. The response rate produced is minimally superior to recent cooperative group studies of colorectal cancer, but the response rate and survival experience are within the range of experience for treatment with 5-FU alone.     

Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or ''FULON'' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.     

Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients

Thirty adult patients with non-Hodgkin's lymphoma were studied to evaluate prospectively the significance of early decline in left ventricular ejection fraction after low cumulative doxorubicin dose (200 mg x m(-2)) in predicting the later impairment of left ventricular function. Cardiac function was monitored with radionuclide ventriculography at baseline and after cumulative doxorubicin doses of 200, 400 and 500 mg x m(-2). Cardiotoxicity was defined as a decrease in left ventricular ejection fraction of more than 10% units to a final left ventricular ejection fraction < or =50%. Twenty-eight patients received doxorubicin > or =400 mg x m(-2) and were evaluable for cardiotoxicity. Clinical heart failure developed in two patients (7%) after a cumulative doxorubicin dose of 500 mg m(-2). Left ventricular ejection fraction decreased more than 10% absolute ejection fraction units to a final left ventricular ejection fraction < or =50% in 10 patients (36%). Left ventricular ejection fraction decreased from 56+/-1.5% to 53.6+/-1.5% (P=0.016) in patients with no cardiotoxicity, and from 60.8+/-2.4% to 41.8+/-2.0% (P<0.001) in patients with cardiotoxicity. For patients who developed cardiotoxicity, the fall in left ventricular ejection fraction after a cumulative doxorubicin dose of only 200 mg x m(-2) was highly significant (left ventricular ejection fraction 49.7+/-1.8%, P=0.001 vs baseline). In receiver operator characteristic analysis, the area under the curve for the decrease in left ventricular ejection fraction at a cumulative doxorubicin dose of 200 mg x m(-2) for predicting cardiotoxicity in all patients was 0.858. The decrease in left ventricular ejection fraction of more than 4% units after a cumulative doxorubicin dose of 200 mg x m(-2) had a 90% sensitivity and 72% specificity for predicting later cardiotoxicity. Our results show that the significant impairment of left ventricular function during doxorubicin therapy can be predicted early, already at low cumulative doxorubicin doses. This finding may be of value in identifying patients at high or low risk for the development of anthracycline cardiotoxicity.     

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas.     

Mitoxantrone, Etoposide and bleomycin (meb) chemotherapy in non-hodgkins-lymphoma patients non-elegible for standard cyclophosphamide, Doxorubicin, vincristine and prednisone (chop) combination

The antitumor activity and toxicity profile of a new therapeutic combination was investigated for patients with non-Hodgkin's lymphoma (NHL). The regimen consisted of mitoxantrone (10 mg/m(2)/day by intravenous (i.v.) bolus injection on day 1), etoposide (100 mg by 24 hours continuous i.v. infusion on days 1, 2, 3) and bleomycin (4 mg by i.v. bolus injection on day 1 followed by 24 hours continuous i.v. infusion at 4 mg/m2/day dose on days 1, 2, 3) (MEB). MEB chemotherapy was administered to 22 patients affected by intermediate/high grade or clinically symptomatic low grade NHL who were considered non-elegible for standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. Major responses were achieved in 11/22 (50%) patients with 5 (23%) complete responses. Grade 3-4 neutropenia occurred in 59% of patients. The results of this study demonstrate that MEB chemotherapy possesses good antitumor activity and a manageable toxicity in a prognostically unfavourable subset of lymphoma patients.