Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. Development of a new intensive therapy for acute lymphoblastic leukemia in children at increased risk of early relapse. The Memorial Sloan-Kettering-New York-II protocol. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. Prospective randomized Phase II trial of pegylated doxorubicin in the management of symptomatic hormone-refractory prostate carcinoma. Daunorubicin-induced cell kill with 1-hour versus 24-hour infusions: a randomized comparison in children with newly diagnosed acute lymphoblastic leukemia. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors.
We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A --> C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).
                High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A C) doxorubicin 40.5 mg/m2 IV days 1 and 2 every 3 weeks for four cycles followed by cyclophosphamide 2.4 gm/m2 IV every 2 weeks for three cycles. Total dose and duration were identical, but the intensity of each drug was increased on A C. Both arms included granulocyte colony-stimulating factor support and prophylactic antibiotics. All but premenopausal women with receptor negative tumors received tamoxifen after chemotherapy.
                Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor-positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A --> C. Grade 4 hematologic toxicity was greater on A --> C, but nonhematological grade 4 was similar.
                The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use. Both total dose and dose intensity of adjuvant chemotherapy are postulated to be important variables in the outcome for patients with operable breast cancer. The Cancer and Leukemia Group B study 8541 examined the effects of adjuvant treatment using conventional-range dose and dose intensity in female patients with stage II (axillary lymph node-positive) breast cancer.
                Within 6 weeks of surgery (radical mastectomy, modified radical mastectomy, or lumpectomy), 1550 patients with unilateral breast cancer were randomly assigned to one of three treatment arms: high-, moderate-, or low-dose intensity. The patients received cyclophosphamide, doxorubicin, and 5-fluorouracil on day 1 of each chemotherapy cycle, with 5-fluorouracil administration repeated on day 8. The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had two thirds the dose intensity as the high-dose arm but the same total drug dose. Disease-free survival and overall survival were primary end points of the study.
                At a median follow-up of 9 years, disease-free survival and overall survival for patients on the moderate- and high-dose arms are superior to the corresponding survival measures for patients on the low-dose arm (two-sided P<.0001 and two-sided P = .004, respectively), with no difference in disease-free or overall survival between the moderate- and the high-dose arms. At 5 years, overall survival (average +/- standard error) is 79% +/- 2% for patients on the high-dose arm, 77% +/- 2% for the patients on the moderate-dose arm, and 72% +/- 2% for patients on the low-dose arm; disease-free survival is 66% +/- 2%, 61% +/- 2%, and 56% +/- 2%, respectively.
                Within the conventional dose range for this chemotherapy regimen, a higher dose is associated with better disease-free survival and overall survival. Improved survival of children with acute lymphoblastic leukemia (ALL) has made it more difficult to develop new protocols to further improve results. The authors report the pilot experience with the Memorial Sloan-Kettering-New York-II (MSK-NY-II) protocol, based on the New York regimen with changes made in an attempt to improve efficacy while reducing toxicity.
                Forty-four of 46 consecutive patients were randomized to one of four regimens varying only in the sequence and mode of administration of the drugs during the first 48 hours of therapy, while the kinetics of the disappearance of the leukemic cells from the bone marrow was monitored with bone marrow aspirates and biopsies on days 0, 2, 7, and 14.
                Thirty-two high-risk and 12 average-risk patients were randomized. The marrow contained less than 25% blasts in 74.4% and 92.9% by day 7 and 14, respectively. Ninety-three percent achieved remission. Regimens beginning with daunorubicin achieved a greater and more rapid reduction in leukemic cells than those starting with cyclophosphamide. Daunorubicin infusion produced a more rapid cytoreduction than daunorubicin bolus. Two of 41 patients who achieved remission relapsed, and there was one death in remission. With a median follow-up of 54+ months, the event-free survival (EFS) rate was 86% +/- 10%. Disease-free survival (DFS) rate at 48 months was 93%. The estimated 4-year EFS rate for the high-risk and average-risk patients were 83 +/- 14% and 93 +/- 10%, respectively. Four of 18 patients given daunorubicin bolus and 0 of 18 patients given daunorubicin infusion who were monitored with serial echocardiograms had significant decrease in cardiac function (P = 0.10). The major toxicity of the therapy was infections, with 35% of patients developing serious infections during induction and consolidation. Half the patients had an episode of bacteremia from the venous catheter during the 2 years of maintenance.
                Close monitoring of kinetics of cytoreduction can rapidly distinguish between similar therapies, and the surrogate end-point may reduce the need for the long follow-up periods that may still be required to demonstrate differences in EFS. Continuous infusion of daunorubicin had less cardiotoxicity with faster antileukemic activity than bolus infusion. The MSK-NY-II protocol with a 86% 4-year EFS rate and a 95% DFS rate was a promising new regimen for the treatment of average-risk and high-risk ALL. A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented.
                From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments.
                Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low.
                Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen. 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. 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.
                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.
                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.
                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. Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells. On the basis of doxorubicin's demonstrated clinical efficacy against hormone-refractory prostate carcinoma (HRPCA), the authors conducted a prospective, randomized Phase II clinical trial to evaluate the feasibility, toxicity, and therapeutic efficacy associated with the pegylated form of this agent.
                Forty-eight patients with symptomatic HRPCA were randomized to receive pegylated liposomal doxorubicin at either 25 mg/m2 every 2 weeks for 12 cycles (Group A) or 50 mg/m2 every 4 weeks for 6 cycles (Group B). Thirty-eight of these 48 patients (79%) presented with severe pain (corresponding to a pain score of 7.5 on a visual analog scale [VAS] ranging from 0 to 10) due to osseous metastases. Therapeutic efficacy was assessed by serial evaluation of serum prostate-specific antigen (PSA) concentrations and by serial measurement of pain levels (using a VAS ranging from 0 to 10). Toxicity data were obtained using the National Cancer Institute of Canada/Cancer and Leukemia Group B criteria and the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.
                The median patient age was 68.9 years (range, 58-79 years), and the mean follow-up duration was 42 months. The mean pretreatment PSA level was 660.4 ng/mL (mean, 8-6340 ng/mL); an objective decrease in PSA levels (i.e., a decrease of > 50%) was observed in 8 of 31 patients (25.8%) in Group B, whereas no other patient in either group experienced such a decrease. The mean time to disease progression was 6.5 months, and the mean survival duration was 13.4 months. Patients in Group B had a significantly higher rate of response with respect to pain (52.6% vs. 28.6%; P = 0.04), and the mean 1-year survival rate also was significantly higher in Group B (42% vs. 15%; P = 0.02). Severe side effects were observed, with 24 patients (50%) experiencing World Health Organization Grade 3/4 toxicity. Toxicity types differed significantly between Group A and Group B; palmar-plantar erythrodysesthesia developed in 60% of patients in the former group (P < 0.0005), whereas tachycardia was more common in the latter group (39% of patients; P < 0.0005). No dose-limiting cardiotoxicities or hematotoxicities were documented.
                Pegylated liposomal doxorubicin yielded a noteworthy objective palliative response rate and a mean survival of 13 months for patients with symptomatic HRPCA. The dosage tested in the current study should be used in future Phase II and Phase III trials of pegylated liposomal doxorubicin-containing combination regimens for patients with HRPCA.
                Copyright 2004 American Cancer Society. Daunorubicin (DNR) is one of the most important drugs in treatment of acute lymphoblastic leukemia (ALL). Prolonged infusions of anthracyclines are less cardiotoxic but it has not been investigated whether the in vivo leukemic cell kill is equivalent to short-term infusions.
                In the cooperative treatment study COALL-92 for childhood ALL 178 patients were randomized to receive in a therapeutic window a single dose of 36 mg/m (2) DNR either as a 1-h (85 patients) or 24-h infusion (93 patients). Daily measurements of white blood cell count (WBC) and peripheral blood smears for seven days could be evaluated centrally in 101 patients (1-h: 43 patients, 24-h: 58 patients).
                The proportional decline of blasts at day 7 after DNR infusion showed no statistically significant difference between the two treatment arms. At day 3 the median percentage of blasts was less than 10%, at day 7 less than 2% for either the 1-h or 24-h infusion. Twelve patients (1-h: 5 patients, 24-h: 7 patients) had an absolute number of more than 1000 blasts per mul peripheral blood (PB) at day 7 after DNR infusion (DNR poor responders). Kaplan-Meier analysis showed an equal probability of EFS for the short- and long-term infusion group (24-h: 83%+/-5; 1-h: 81+/-6) after a median observation time of 12.3 years.
                We conclude that in children with ALL a 24-h infusion of DNR has the same in vivo cytotoxicity for leukemic cells as a 1-h infusion. This offers the possibility to use prolonged infusions with hopefully less cardiotoxicity without loss of efficacy. 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. In order to evaluate the possible cardiosparing effect of a prolonged infusion of doxorubicin as compared with the standard mode of administration 62 consecutive patients with metastatic carcinoma of the breast or carcinoma of the ovary Stage III or IV were prospectively randomized to receive doxorubicin either as a rapid infusion over 15 to 20 minutes at 8 AM or as a continuous infusion over 6 hours, 8 AM to 2 PM. The remaining protocol was identical for the two groups. The cardiotoxic effect of doxorubicin was evaluated by history and physical examination and by the decline in resting ventricular ejection fraction (LVEF) as determined by gated pool radionuclide angiography with technetium 99m (99mTc) and by the decline in the height of the QRS complexes in the standard leads of the echocardiogram (ECG). Initially there were 31 patients in each group. The cumulative dose of doxorubicin, was 410 mg/m2 +/- 42 SD in the standard infusion group and 428 mg/m2 +/- 48 SD in the 6-hour infusion group. The mean decline in LVEF after a cumulative doxorubicin dose of 300 mg/m2 was 17% in the first group and only 4.1% in the second. After 400 mg/m2 the mean fall in LVEF was 21% in the first group and 6% in the second. The mean decline in QRS voltage after 300 mg/m2 was 29% and 1.5%, respectively. Four patients, all in the standard infusion group, developed congestive heart failure. These data suggest that slow infusion of doxorubicin is associated with reduced cardiotoxicity. A prospective randomized trial was conducted to compare the cardiotoxic and therapeutic effects of doxorubicin (60 mg/m2 every 3 to 4 weeks) administered by bolus or 72-hour continuous infusion as adjuvant chemotherapy in 82 eligible patients after resection of high-grade soft tissue sarcoma of the extremity or superficial trunk. Cardiac toxicity, defined as a 10% or greater decrease in left ventricular ejection fraction as assessed by radionuclide cineangiography, was evaluated in 69 patients. Cardiotoxicity was seen in 61% of patients in the bolus treatment arm with the median doxorubicin dose of 420 mg/m2. Among patients who received continuous infusion, 42% had cardiotoxicity with a median dose of 540 mg/m2. The rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm (P = 0.0017). Two patients in each group had clinical congestive heart failure, with one cardiac death occurring in each. There was a trend toward a lower rate of metastasis (P = 0.19) and a significantly lower rate of death of disease (P = 0.036) for patients treated with the bolus dose. Cox model analysis identified three unfavorable characteristics for the rate of developing a distant metastasis: blood transfusion within 24 hours of operation (P less than 0.00001), tumor deep to the fascia and 5 cm or more in size (P = 0.0043), and a histologic subtype other than liposarcoma (P = 0.0002). The unfavorable effect of continuous infusion was not selected in the model (P = 0.16). Adjuvant chemotherapy for patients with soft tissue sarcoma is investigational. Furthermore, the impact of perioperative blood transfusion merits further study.
An anthracycline infusion duration of six hours or longer reduces the risk of clinical heart failure and it seems to reduce the risk of subclinical cardiac damage. Since there is only a small amount of data for children and data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children.
No significant difference in the occurrence of clinical heart failure was identified in patients treated with a doxorubicin peak dose of less than 60 mg/m2 or 60 mg/m2 or more. For the other identified peak doses only one RCT was available, so no definitive conclusions can be made about the occurrence of cardiotoxicity. More high quality research is needed, both in children and adults and in leukaemias and solid tumours.