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PubMed2001

Treatment of patients with thromboangiitis obliterans with cyclophosphamide.

This report describes a small, nonrandomized trial of cyclophosphamide in the treatment of patients with advanced thromboangiitis obliterans (TAO) with modest results. The rationale of the treatment was based on the immunopathogenesis of the disease, ie, autoimmune vasculitis of peripheral arteries. Twelve male patient volunteers with TAO were included for the trial. Diagnosis was based on the history of chronic smoking or tobacco chewing, clinical features of ischemia of peripheral vessels, radioarteriography showing arterial block, and characteristic histopathologic changes of affected arteries. Cyclophosphamide (400 mg) was given intravenously daily to the patients for 7 days followed by daily oral administration of 100 mg cyclophosphamide for another 7 weeks. Clinical conditions of the patients started to improve during the third week of the treatment and maximum benefit was noticed at the end of the treatment. There was significant decrease of intermittent claudication and twentyfold increase of claudication distance as well as relief of rest pain. Before starting treatment 6 patients had developed ulcers on their affected limbs; these healed completely in 2, partially healed in another 2, and showed no improvement in the remaining 2, who never stopped smoking. However, immunosuppressive therapy failed to show any improvement of arterial block, as evidenced by radioarteriography and any significant increase of skin temperature over the affected limbs. Nevertheless, histopathologic studies of biopsies taken from the diseased arteries after completion of therapy showed decreased influx of lymphocytes and plasma cells in the thrombi as well as in the arterial walls in comparison to the biopsies taken before the start of treatment. During the treatment the degree of immunosuppression was monitored by blood leukocyte and lymphocyte counts, which were kept between 4,000/mm3 and above 3,000/mm3 and not less than 500/mm3, respectively, indicating modest immunosuppression and no serious complications. All patients were followed up for 1 year. Only 2 patients, who resumed smoking, had relapse.

Administration, Oral↗
PubMedDate not supplied

Acute myeloid leukemia following chronic low-dose cyclophosphamide for metastatic breast cancer.

Unconventional treatments are commonly considered by the scientific community to have unproven efficacy but at least no toxicity. Here we report on the case of a breast cancer patient with lung and liver metastases who developed acute myeloid leukemia after treatment with Di Bella multitherapy, leading rapidly to death due to cerebral hemorrhage. Although an increased susceptibility to malignancy could not be excluded, we considered the possible etiologic role of the treatment received. The drug most likely to be associated with the development of leukemia was the cyclophosphamide contained in the Di Bella multitherapy regimen at a dose of 50 mg daily. The clinical features of this leukemia were therefore compared with those expected for secondary leukemia related to alkylating agents. A preceding myelodysplastic phase and the development of the leukemia after the intake of a cumulative cyclophosphamide dose of 15 g were typical chacteristics of secondary leukemia, but the interval between the start of therapy and the onset of leukemia was only 10 months. We conclude that long-term low-dose cyclophosphamide may have leukemogenic potential and the latency period may be shorter than that commonly reported.

Antineoplastic Agents, Alkylating↗
PubMed1989

A preliminary clinical study of cyclophosphamide with reduced glutathione as uroprotector.

Reduced glutathione (GSH) has been reported to be an effective protector against cyclophosphamide-induced urotoxicity in experimental models, providing protection comparable to that of mesna. This paper describes our preliminary results of the clinical use of GSH in combination with cyclophosphamide. GSH was administered i.v. in two divided doses of 2.5 g, 15 min before and 30 min after escalating doses of cyclophosphamide ranging from 1.2 up to 1.6 g/m2 (1-h infusion). GSH was well tolerated and did not produce unexpected toxicity. The lack of bladder damage, including microscopic hematuria, supports the protective role of this thiol compound.

Adult↗
PubMed2000

Overwhelming septic cavernous sinus thrombosis in a woman after combination of high-dose steroid and intravenous cyclophosphamide therapy for lupus nephritis.

There are many treatment methods for lupus nephritis, including high-dose steroids, pulse methylprednisolone, and cyclophosphamide therapy. In cyclophosphamide therapy, there can be some side effects such as nausea, vomiting, and infection. We report on a case receiving a combination of high dose steroid and intravenous cyclophosphamide. Following this, she developed a fever and a protruding right eye, and septic cavernous sinus thrombosis was diagnosed. This complication had never been reported in a patient with systemic lupus erythematosus, and related literature is reviewed.

Adult↗
PubMed2004

Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide.

Long-term data on lung function after bone marrow transplantation (BMT) are inconclusive. Previously, a persistent reduction in gas transfer 1 yr after allogeneic BMT with busulphan and cyclophosphamide conditioning was reported by the current authors. In the present study this reduction was examined to see if it was permanent, transient or progressive. Prospectively, 43 consecutive adult patients with malignant blood disorders undertook lung function measurements prior to BMT, at 3 month intervals during the 1st yr after BMT and finally after 5 yrs. Mean baseline lung function values were >90% predicted. Within the 1st yr after BMT a transient decline in lung volumes and a persistent reduction in gas transfer were observed. After 5 yrs, baseline values were restored for all variables, except in four patients who developed obliterative bronchiolitis. Acute leukaemia and smoking were independently associated with gas transfer reductions at baseline and during the 1st yr after BMT. Allogeneic bone marrow transplantation with busulphan and cyclophosphamide conditioning was associated with a reduction in gas transfer 1 yr after bone marrow transplantation but baseline values were usually restored after 5 yrs. Since recovery may be gradual and slow, an observation period >1 yr is required before drawing conclusions concerning the development of a permanent reduction in lung function after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide.

Adolescent↗
PubMed1996

Effect of hemithorax irradiation alone or combined with doxorubicin and cyclophosphamide in 47 pleural mesotheliomas: a nonrandomized phase II study.

In order to assess the value of radiotherapy in the treatment of pleural mesotheliomas, we studied tumour response and survival after hemithorax irradiation alone (RT), or radiotherapy combined with doxorubicin and cyclophosphamide chemotherapy (RTCT). Forty seven patients with pleural mesotheliomas received irradiation of the diseased hemithorax at 8 MV (megavolt) photons to a total dose of 40 Gy, administered in 20 daily fractions of 2 Gy for 5 days a week. One month after RT, patients aged < or = 70 yrs with a good performance status were offered supplementary chemotherapy (CT) with doxorubicin 30 mg.m-2 body surface on Day 1 and Day 8, combined with cyclophosphamide 600 mg.m-2 on Day 1, in cycles of 21 days. Tumour response was evaluated by computed axial tomography (CAT) before and 1 month after RT and/or CT. Only 3 of the 47 (95% confidence interval (95% CI)-0.6-13%) irradiated tumours responded with a partial response (PR). In 31 patients treated with RT alone, one PR was observed; whereas, in the combined treatment group, 2 out of 16 responded with PR to RT. CT with doxorubicin and cyclophosphamide induced only 2 out of 16 PRs (95% CI -3.4-28.4%), and the combined treatment consisting of RT followed by CT induced 2 out of 16 PRs. The median survival following the initiation of RT was 7 months in all patients (n = 47), 6 months in the RT group (n = 31), and 13 months in the combined RTCT group (n = 16). Chest pain, performance status and body weight were not favourably affected by the radiotherapy. We conclude that hemithorax irradiation of pleural mesotheliomas with a moderately high dose is not useful, since it produces no improvement in chest pain, few objective tumour responses and no prolongation of survival.

Aged↗
PubMed2002

NF-kappa B DNA-binding activity in embryos responding to a teratogen, cyclophosphamide.

BACKGROUND: The Rel/NF-kappaB transcription factors have been shown to regulate apoptosis in different cell types, acting as inducers or blockers in a stimuli- and cell type-dependent fashion. One of the Rel/NF-kappaB subunits, RelA, has been shown to be crucial for normal embryonic development, in which it functions in the embryonic liver as a protector against TNFalpha-induced physiological apoptosis. This study assesses whether NF-kappaB may be involved in the embryo's response to teratogens. Fot this, we evaluated how NF-KappaB DNA binding activity in embryonic organs demonstrating differential sensitivity to a reference teratogen, cyclophosphamide, correlates with dysmorphic events induced by the teratogen at the cellular level (excessive apoptosis) and at the organ level (structural anomalies). RESULTS: The embryonic brain and liver were used as target organs. We observed that the Cyclophosphamide-induced excessive apoptosis in the brain, followed by the formation of severe craniofacial structural anomalies, was accompanied by suppression of NF-kappaB DNA-binding activity as well as by a significant and lasting increase in the activity of caspases 3 and 8. However, in the liver, in which cyclophosphamide induced transient apoptosis was not followed by dysmorphogenesis, no suppression of NF-kappaB DNA-binding activity was registered and the level of active caspases 3 and 8 was significantly lower than in the brain. It has also been observed that both the brain and liver became much more sensitive to the CP-induced teratogenic insult if the embryos were exposed to a combined treatment with the teratogen and sodium salicylate that suppressed NF-kappaB DNA-binding activity in these organs. CONCLUSION: The results of this study demonstrate that suppression of NF-kappaB DNA-binding activity in embryos responding to the teratogenic insult may be associated with their decreased resistance to this insult. They also suggest that teratogens may suppress NF-kappaB DNA-binding activity in the embryonic tissues in an organ type- and dose-dependent fashion.

Abnormalities, Multiple↗
PubMed1999

'Sustained remission' in a case of SLE following megadose cyclophosphamide.

Cytotoxic therapy, especially with cyclophosphamide in the dose 8-20 mg/kg used as intermittent pulses, has been shown to improve both patient and renal survival in systematic lupus erythematosus (SLE), but to date there is no cure for the disease. Owing to the paucity of recognisable clones, the rationale and goal of cytotoxic immunosuppressive therapy in the treatment of immune-mediated diseases as against malignancies is to suppress the aberrant inflammation and immune-mediated reactions responsible for tissue damage, without dangerously suppressing the normal host defence mechanism(s). We report the case of a patient suffering from SLE with nephritis who has remained in sustained remission over the past 8 years without any maintenance therapy following an accidental administration of a single dose of 5000 mg of intravenous cyclophosphamide (44.2 mg/kg body weight). The patient recovered fully from pancytopenia following the injection. Presently, she is asymptomatic and working gainfully. Her laboratory parameters including blood counts, urine analysis, FANA and anti-dsDNA have reverted to normal. Cyclophosphamide in the dose of 30-160 mg/kg has been safely and effectively used in various neoplastic conditions with the aim of destroying every possible tumour cell. The experience of the present case suggests that such an approach may be applicable to SLE.

Adult↗
PubMed2002

Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects.

Cyclophosphamide is an alkylating agent used to treat malignancies and immune-mediated inflammatory non-malignant processes such as lupus nephritis and immune-mediated neuropathies. It has been studied as a treatment for multiple sclerosis (MS) for the past 30 years and is used by physicians in selected cases of progressive or worsening MS. Review of published reports suggests that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the central nervous system (CNS). There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Side effects include nausea, alopecia, infertility, bladder toxicity and risk of malignancy. The most commonly used regimens involve every 4- to 8-week outpatient i.v. pulse therapy given with or without corticosteroids and are usually well-tolerated by patients. Cyclophosphamide is currently used in patients whose disease is not controlled by beta-interferon or glatiramer acetate and those with rapidly worsening MS.

Adult↗
PubMed2003

Immunolocalization of caspase-3 in pancreatic islets of NOD mice during cyclophosphamide-accelerated diabetes.

Apoptosis may be a major mechanism of beta cell loss during insulin-dependent diabetes mellitus. Caspase-3 is a key enzyme involved in the terminal steps of this death process. Here, the intra-islet expression of caspase-3 in the NOD mouse was examined immunohistochemically following acceleration of the disease with cyclophosphamide. Female NOD mice were treated at day 95 with cyclophosphamide, and caspase-3 expression in pancreatic sections was studied at days 0, 4, 7, 11, and 14 and compared with age-matched control tissue. In the treated group at day 0, caspase-3 labeling was seen in several peri-islet macrophages and only extremely rarely in beta cells. At day 4, only a few beta cells weakly expressed the enzyme. From day 7, caspase-3 expression began to increase in intra-islet macrophages and reached a peak at days 11 and 14, when a small number of CD4 and CD8 T cells also showed positive labeling. Beta cell expression of caspase-3 at days 11 and 14 was rare. At this stage, several intra-islet immune cells with positive labeling for the enzyme coexpressed either Fas or interleukin-1beta. Only a small proportion of intra-islet caspase-3 cells showed apoptotic nuclei judged by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). We conclude that, during cyclophosphamide-accelerated diabetes, the predominant caspase-3 immunolabeling in intra- and extra-islet macrophages suggests that apoptosis of macrophages may be an important mechanism for their elimination. The virtual absence of caspase-3 immunolabeling in most beta cells even during the height of beta cell loss supports the need for developing other markers of early beta cell apoptosis in the NOD mouse.

Animals↗
PubMed1985

Extensive-stage small-cell bronchogenic carcinoma: intensive induction chemotherapy with high-dose cyclophosphamide plus high-dose etoposide.

Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.

Adult↗
PubMed1985

High-dose cyclophosphamide in small-cell carcinoma of the lung.

Eighteen patients with untreated small-cell cancer of the lung have been treated with cyclophosphamide 200 mg/kg on two occasions at an interval of four weeks. An additional eight patients received etoposide in addition to cyclophosphamide. Measurements of tumor volume were made by thoracic computed tomographic (CT) scan before and after each cycle. When compared with our previous study in which only one cycle of cyclophosphamide was given, the double procedure did not increase response rate, decrease the incidence of local relapse, or prolong the relapse-free interval. Survival after relapse was shorter with two cycles of chemotherapy mainly due to greater difficulty in administering further chemotherapy. The CT scans showed a decrease in tumor volume from 99.2 cc to 21 cc after the first cycle, but a smaller decrease to 14.1 cc after the second. These results show that the rapid emergence of drug resistance imposes limitations on the use of very high-dose cytotoxic chemotherapy.

Adult↗
PubMed1987

A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group.

To assess the effect of dose escalation in the treatment of small-cell lung cancer (SCLC), 298 patients with extensive-stage disease were treated with either conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1 mg/m2), (CDCAV); or high-dose cyclophosphamide (1,200 mg/m2), doxorubicin (70 mg/m2), and vincristine (1 mg/m2) (HDCAV). No dose attenuation was allowed during the initial three cycles of therapy in either treatment arm. All patients received CDCAV in cycles 4 through 6, during which time dosages were adjusted according to granulocyte and platelet nadirs. No additional chemotherapy was administered until disease progression or relapse was documented. Complete responses were more frequent with HDCAV (22% v 12%; P = .045). However, overall response rate (63% v 53%) and median survival (29.3 v 34.7 weeks) were not significantly different (P greater than .05). HDCAV was substantially more toxic than CDCAV, causing more episodes of life-threatening leukopenia (ie, granulocytes less than 500/microL; 79% v 40%; P less than .05) and infections (15% v 4%; P less than .05). Dose intensification of cyclophosphamide and doxorubicin during induction chemotherapy did not produce any survival benefit compared with conventional dosages of these agents in SCLC patients with extensive-stage disease.

Adult↗
PubMed1987

A phase I-II study of bialkylator chemotherapy, high-dose thiotepa, and cyclophosphamide with autologous bone marrow reinfusion in patients with advanced cancer.

Twenty patients with disseminated cancer both untreated and previously treated received bialkylator chemotherapy, thiotepa, and cyclophosphamide and reinfusion of cryopreserved autologous bone marrow (ABMR). The cyclophosphamide dose was constant at 7.5 g/m2 over three days, while thiotepa was started at 1.8 mg/kg for three days in escalating dose by a modified Fibonacci schema to 7 mg/kg. The median time to recovery of more than 500 granulocytes and more than 50,000 platelets/microL was 18 and 27 days, respectively. Four patients died as a consequence of severe, overwhelming infections or progressive disease during their period of aplasia. Of the 18 evaluable patients, a complete response (CR) was achieved in three patients and a partial response (PR) in ten patients for an overall response rate of 72%. The median duration of response was 14 weeks. Other nonhematologic toxicities included nausea/vomiting, diarrhea, stomatitis, skin rash, and cardiomyopathy. The maximum tolerated dose (MTD) of thiotepa was 700 mg/m2 or 6 mg/kg for three doses. Although there are substantial toxicities associated with this regimen, high-dose thiotepa and cyclophosphamide produce high response rates in patients with disseminated cancer.

Adult↗
PubMed1987

Combination chemotherapy using adriamycin, DTIC, cyclophosphamide, and actinomycin D for advanced soft tissue sarcomas: a randomized comparative trial. A phase III, Southwest Oncology Group Study (7613).

The term soft tissue sarcoma refers to a large variety of malignant tumors arising in extraskeletal connective tissues that connect, support, and surround discrete anatomic structures. All visceral organs also contain a connective stroma that can undergo malignant transformation. Because of the histological similarities of this group of tumors and their relative rarity, treatment prescriptions for patients that have disseminated disease are most often uniform. In this study, we asked the question whether adding a third drug (cyclophosphamide or actinomycin D) to Adriamycin (Adr [Adria Laboratories, Columbus, OH])-(3,3-dimethyl-1-triazeno)- imidazole-4-carboxamide (DTIC) would improve the response rate and/or survival. A unique feature of this cooperative group clinical trial was the mandatory pathology review of the histological material. All patients of the Southwest Oncology Group between June 1, 1976, and November 17, 1979, who had a biopsy-confirmed diagnosis of a soft tissue sarcoma with convincing clinical or biopsy-documented evidence of metastatic disease were eligible for the study. Patients were randomized to receive (1) Adr, 60 mg/m2 intravenously, day 1, and DTIC, 250 mg/m2 every 3 weeks (104 patients); (2) Adr and DTIC as in (1) and cyclophosphamide, 500 mg/m2, day 1 (112 patients); or (3) Adr and DTIC as in (1) and actinomycin D, 1.2 mg/m2, day 1, (119 patients). There was no statistically significant difference in response rates (33%, 34%, and 24%) (P = .25). Median durations of response were 31 weeks in the Adr-DTIC arm, 26 weeks in the cyclophosphamide-DTIC-Adr arm, and 23 weeks in the Adr-DTIC-Actinomycin D arm (P = .78). Median durations of survival were 37, 42, and 50 weeks, respectively. Again, no statistically significant differences were observed (P = .59). Toxicities from each of these treatment arms were formidable and were equivalent. Prognostic factor analysis showed a prognosis based on bone marrow reserve, sex, and pathology subtype favorable to patients.

Adolescent↗
PubMed1990

Cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose-finding study.

Cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) is a widely used conditioning regimen in autologous bone marrow transplantation (ABMT) of patients with refractory and relapsed lymphoma. However, the maximum-tolerated dose (MTD) of these agents when used in combination has not been systematically explored. We treated 58 patients (28 with non-Hodgkin's lymphoma [NHL], 30 with Hodgkin's disease [HD]) at seven dose levels of CBV. Doses were cyclophosphamide 4,500 to 7,200 mg/m2, BCNU 450 to 600 g/m2, and VP-16 1,200 to 2,000 mg/m2. The MTD was cyclophosphamide 7,200 mg/m2, BCNU 450 mg/m2, and VP-16 2,000 mg/m2. Six hundred milligrams per square meter of BCNU was associated with five of 18 cases of interstitial pneumonitis versus two of 40 at 450 mg/m2 (P = .02). Treatment-related mortality was 5% at dose levels less than or equal to the MTD and 22% at the highest dose. In this heavily pretreated patient population, most of whom had high volume residual disease, complete responses (CRs) to CBV and ABMT occurred in 25% of assessable patients with NHL and 43% of patients with HD. Thirteen of 28 patients with NHL and 14 of 30 with HD remain free from disease progression with median follow-up of 212 and 215 days, respectively. CBV can be administered with acceptable toxicity over a wide range of doses to patients with refractory and relapsed lymphoma.

Adolescent↗
PubMed1991

Evaluation of three oral dosages of ondansetron in the prevention of nausea and emesis associated with cyclophosphamide-doxorubicin chemotherapy.

We assessed the antiemetic efficacy and safety of three different oral doses of ondansetron (GR 38032F), a novel serotonin type-3 receptor antagonist, in three consecutive series of 20 breast cancer patients receiving cyclophosphamide-doxorubicin-based chemotherapy for the first time. Patients received oral doses of 8 mg, 4 mg, or 1 mg of ondansetron three times daily for 2 days, with the first dose given 30 minutes before the cyclophosphamide infusion. We then evaluated the efficacy of a conventional antiemetic regimen of intravenous lorazepam, metoclopramide, and diphenhydramine given before chemotherapy and 10 mg prochlorperazine given orally twice on study day 1 and three times on study day 2 in a fourth series of 20 patients with comparable characteristics. The number of emetic episodes, assessment of nausea and appetite, and adverse events were recorded throughout the 2-day study period. Pretreatment and posttreatment clinical laboratory data were also collected. No emesis was observed during the 2-day study period in 17 (85%), 13 (65%), and 11 (55%) patients treated with 8-mg, 4-mg, and 1-mg ondansetron doses, respectively, and in seven (35%) patients who received conventional therapy. The incidence and intensity of nausea were lower with increasing doses of ondansetron and were lower than in the conventional group. Ondansetron-related side effects were generally mild and reversible and did not appear to increase in a dose-dependent manner. These effects included headache, stomach cramps, diarrhea, fatigue, and elevated serum transaminase concentrations. One patient who received three 1 mg doses of ondansetron experienced tremors and muscle twitching. Oral ondansetron is an effective and safe antiemetic for patients receiving noncisplatin cyclophosphamide-doxorubicin-based chemotherapy, and its antiemetic activity appears to be dose-related.

Administration, Oral↗
PubMed1992

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.

Adult↗