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© 1999 American Society for Clinical Oncology 5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk Node-Positive Breast Cancer: A Phase II StudyFrom the Breast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine, and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Medicine, Cornell University Medical College, New York, NY; and North Shore University Hospital, Manhasset, NY. Address reprint requests to Clifford Hudis, MD, Box #206, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email hudisc{at}mskcc.org
PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.
ADJUVANT CHEMOTHERAPY reduces the risk of relapse and death in operable breast cancer.1 However, this benefit is modest, and the risk of relapse remains significant, especially in patients with involvement of four or more axillary lymph nodes.2,3 Relapse of disease may be viewed as the clinical consequence of drug resistance, which may be heterogeneous within a tumor cell population.4 To overcome this resistance, various strategies, such as the use of non–cross-resistant drug regimens and manipulations of doses and schedules, have been investigated. However, the ideal strategy for combining these approaches has not yet been defined. A kinetic model predicts that tumor cell kill will be maximized by the administration of non–cross-resistant drugs in sequence rather than in an alternating fashion.5-7 The sequential schedule optimizes dose-intensity during the time of exposure, which has been shown to correlate with clinical outcome both retrospectively and prospectively.8,9 The increased dose-intensity is actually a consequence of shortened intertreatment intervals for each drug or combination. Hence, the treatment can be said to be more "dose-dense."10 A randomized trial from the National Cancer Institute of Milan can be interpreted as support for the further exploration of the dose-dense hypothesis.11 In that study, adjuvant sequential chemotherapy with doxorubicin for four cycles, followed by cyclophosphamide, methotrexate, and fluorouracil (CMF), was compared with the same regimen delivered in an alternating fashion. The sequential (more dose-dense) plan was associated with significantly improved disease-free and overall survival. Because laboratory models predict a steep dose-response relationship for cyclophosphamide and because the feasibility of every-other-week high-dose cyclophosphamide supported by granulocyte colony-stimulating factor (G-CSF) was demonstrated in a pilot study12 from the Cancer and Leukemia Group B (CALGB), we were motivated to substitute this dose-dense application of high-dose cyclophosphamide in place of CMF in the sequential plan of the Milan investigators.11 Hence, we conducted a phase II pilot study using doxorubicin (A) followed sequentially by high-dose cyclophosphamide (C) in the adjuvant setting for women with breast cancer and four or more involved axillary lymph nodes. The aim of this trial was primarily to determine the safety and feasibility of this dose-dense cyclophosphamide treatment and secondly to evaluate disease-free and overall survival in a nonrandomized trial.
Eligibility Nonpregnant females at least 17 years of age with a Karnofsky performance status of 80% or higher, an absolute neutrophil count (ANC) of at least 1,500/µL, a platelet count of at least 100,000/µl, a hemoglobin level of at least 10 g/dL, and normal liver, renal, and cardiac functions were eligible if less than 6 weeks had elapsed after definitive local control surgery revealing at least four ipsilateral lymph nodes with metastatic adenocarcinoma of the breast. Adequate cardiac function, measured as a left ventricular ejection fraction (LVEF) on radionuclide scan or echocardiogram, a negative baseline bone scan, and a negative chest radiograph, were also required. No prior systemic therapy or radiation therapy for cancer was permitted. The protocol was approved by the institutional review board of Memorial Sloan-Kettering Cancer Center, and all patients provided written informed consent.
Treatment Plan Three weeks after the last dose of doxorubicin, if the ANC was higher than 1,500/µL, the platelet count was more than 50,000, and the LVEF had not decreased by more than 25% from the pre-doxorubicin value and was more than 40%, patients received three cycles of cyclophosphamide 3,000 mg/m2 intravenously every 14 days. All cycles of cyclophosphamide were supported by G-CSF (supplied by Amgen, Thousand Oaks, CA), administered subcutaneously at 5 µg/kg daily on days 3 through 10 of each cycle of cyclophosphamide. Patients were admitted to the hospital overnight for intravenous hydration and monitoring of electrolytes and urine output during cyclophosphamide treatment. No dose reductions were planned for cyclophosphamide. Delays were instituted for ANC lower than 1,000/µL or a platelet count of less than 50,000/µL on the day of scheduled treatment. Mesna was not required but could be administered at the discretion of the treating physician. One month after completing all chemotherapy, patients treated with breast conservation received standard radiation therapy, and postmenopausal patients with estrogen receptor- and/or progesterone receptor-positive tumors began a planned 5-year course of tamoxifen treatment at 20 mg orally daily.
Evaluation During Treatment Follow-up consisted of history and physical examination and blood studies (complete blood cell count, liver function test, carcinoembryonic antigen, CA 15-3) at 3- to 4-month intervals indefinitely. Additional follow-up testing was performed at the discretion of the treating physician.
Statistical Methods
Patient Characteristics Seventy-three women were enrolled onto the study. Two patients were not assessable for toxicity and survival, because one patient was lost to follow-up after the first dose of cyclophosphamide and one patient began treatment with undetected metastatic disease involving the marrow. For the 71 assessable patients, the median age was 46 years (range, 21 to 74 years). The median primary breast tumor size was 2.6 cm (range, 0 to 7 cm), and the median number of involved ipsilateral axillary lymph nodes was 10 (range, four to 49). More than half of the patients had estrogen receptor- and/or progesterone receptor-positive tumors, and most patients were premenopausal at diagnosis (Table 1).
Toxicity During high-dose cyclophosphamide treatment, grade 3 or 4 anemia was seen in 52% of patients, 35% of patients required packed RBC transfusions, and only 4% of patients required platelet transfusions. Hospitalizations. All patients were admitted for each dose of cyclophosphamide. In addition, 37 patients (52%) were hospitalized for toxicity. Fever in the setting of neutropenia was the most common reason for admission. This occurred at least once during cyclophosphamide treatment in 28 patients (39%): seven patients were admitted only once, 11 patients were admitted twice, and 10 patients were admitted three times, for a total of 59 admissions for neutropenic fever during 211 cycles. There were four positive blood cultures: two for Staphylococcus in the setting of cellulitis, one for Streptococcus, and one for Escherichia coli. There were only 11 admissions for neutropenic fever after doxorubicin across 284 cycles of therapy. Hepatic. Serum assays for AST, alkaline phosphatase, and total bilirubin were obtained weekly during cyclophosphamide therapy. There was no clinical toxicity, but abnormal liver function studies were noted. For AST, 45% of patients developed grade 1 toxicity, whereas five patients (7%) had grade 2 toxicity, and three patients (4%) had grade 3 toxicity. This condition resolved in all patients without medical intervention. For alkaline phosphatase, 39% of patients experienced grade 1 toxicity, and two patients (3%) had grade 2 toxicity. Only one patient developed grade 2 toxicity in total bilirubin, which resolved spontaneously. Cardiac. The median cardiac ejection fraction before any treatment was 66% (range, 53% to 80%) and after all planned treatment was 65% (range, 38% to 72%). Two patients developed cardiac toxicity during treatment. One had nonspecific electrocardiographic changes after receiving a total dose of 300 mg/m2 of doxorubicin, but because her LVEF was 58%, she was treated with cyclophosphamide. However, after the second dose of cyclophosphamide (cumulative dose of 6,000 mg/m2), she experienced congestive heart failure (CHF) with an LVEF of 38%. Her cardiac function later improved on medication, but 4 months after completion of chemotherapy, the patient relapsed and eventually died of metastatic disease. A second patient had normal cardiac ejection fractions throughout treatment, but 3 months after completion of all chemotherapy, she developed symptomatic CHF and was found to have an LVEF of 46%. Long-term follow-up on the cardiac condition of this patient is not available. Metabolic. All serum sodium levels in the 24 hours after cyclophosphamide therapy were above 120 mEq/L. Serum sodium levels were above 129 mEq/L in 36% of patients, whereas a posttreatment sodium level between 125 and 129 mEq/L occurred in 48% of patients, and levels of 120 to 124 mEq/L occurred in 16% of patients. Hyponatremia was successfully managed conservatively with fluid restriction and diuretics in all patients. No adverse effects such as seizures or mental status changes were seen during periods of hyponatremia. Urinary. Fifty percent of patients had no hematuria after cyclophosphamide treatment. Forty-five percent of patients developed grade 1 hematuria with at least one cycle of cyclophosphamide, and 5% of patients developed grade 2 hematuria. Only two patients were treated with mesna, and all patients were treated successfully with aggressive intravenous hydration. No patients were removed from the study for urinary toxicity. Amenorrhea. Among the 48 premenopausal patients, the incidence of amenorrhea was 81.2% (n = 39). Six patients who had early relapses were subsequently re-treated, and the information on their menstrual status is not available.
Dose-Intensity The median intertreatment interval for cyclophosphamide was 14 days as planned (range, 11 to 25 days). However, two patients received only two cycles of cyclophosphamide: one patient secondary to the development of a cardiomyopathy, as mentioned previously, and one patient owing to an allergic reaction to G-CSF manifested by a diffuse rash. The planned dose-intensity for cyclophosphamide was 1,500 mg/m2/wk while on therapy and 500 mg/m2/wk from the start of all treatment. The average delivered dose-intensity was 1,443 mg/m2/wk (96% of planned dose-intensity) while on therapy and 471 mg/m2/wk (94% of planned dose-intensity) from the start of treatment.
Survival Analysis
In the subset of patients with four to nine involved axillary lymph nodes, the disease-free and overall survivals at 5 years were 64.5% (95% CI, 48.3% to 80.6%) and 70.1% (95% CI, 54.5% to 85.6%), respectively. In patients with 10 or more involved axillary lymph nodes, the disease-free and overall survivals were 40.2% (95% CI, 24.3% to 56.1%) and 50.8% (95% CI, 34.5% to 67.1%), respectively (Figs 3 and 4). By the log-rank statistic, a significant difference in overall survival (P = .0408) and a marginally significant difference in disease-free survival (P = .0556) were detected in the two groups (four to nine v
The elimination of viable undetectable micrometastatic disease remains one of the most important and elusive challenges in medical oncology. In breast cancer, the great majority of patients present with disease that seems confined to the breast. Despite this, a significant proportion eventually succumb to metastatic disease. Adjuvant chemotherapy with CMF-like regimens effectively reduces the odds of recurrence by approximately 16% to 39% each year independently of the absolute odds of recurrence without treatment. Hence, the majority of anticipated recurrences cannot be prevented.1 In particular, for breast cancer patients with more than three axillary lymph nodes involved at diagnosis, the benefit of adjuvant CMF is limited, with only approximately 35% of women remaining disease-free at 5 years.3 One promising approach to this problem is the use of increased dose and dose-intensity. This approach is aimed at one explanation for relapse after systemic adjuvant treatment: the presence and/or emergence of resistant cell clones. Resistance can be intrinsic to the cell (ie, overexpression of multidrug resistance phenotype) or extrinsic (ie, secondary to inadequate exposure to a drug that would be effective at higher dose). In the first case, the chemotherapy may be effective only against sensitive subclone(s), and the use of non–cross-resistant agents in a polychemotherapy schedule has been specifically designed to try to overcome this problem. Because chemotherapy has been demonstrated in animal models to kill cells by first-order kinetics—a constant percentage of cells, not a constant number, is killed with each cycle—and because this percentage is directly proportional to the rate of growth immediately before treatment, it is possible that clinically feasible dose levels are inadequate to completely eliminate even sensitive cells.15 This may explain the second type of resistance mentioned above: inadequate exposure. Failure to achieve a greater benefit in clinical outcome despite manipulations of schedules and combinations of drugs may be due to inadequate drug administration as required to limit toxicity.16,17 To circumvent this problem, dose-escalation is being investigated broadly. Support for this comes from laboratory models indicating that some forms of resistance to cytotoxic drugs could be eliminated by an increase in drug dose18-20 and also that the class of cytotoxic agents most consistently shown to have a steep dose-response relationship is the alkylating agents, including cyclophosphamide.21 Hryniuk et al,22 by correlating the dose-intensity of adjuvant chemotherapy with relapse-free survival in early-stage breast cancer patients, also support the use of escalated doses. In 1994, Wood et al9 reported the results of the CALGB 8541 study, in which 1,572 women with node-positive, operable breast cancer were randomized to adjuvant treatment with three different doses of cyclophosphamide, doxorubicin, and fluorouracil: 600/60/600 mg for four cycles (high) versus 400/40/400 mg for six cycles (moderate) versus 300/30/300 mg for four cycles (low). At a median 3.4 years of follow-up, the women treated with high or moderate dose-intensity had significantly longer disease-free and overall survival compared with the low–dose-intensity group; however, the difference between the two groups treated with moderate or high dose-intensity was not statistically significant. The authors concluded that a reduction in chemotherapy doses below the "moderate" level compromises outcome. However, their data provide no evidence of an additional benefit for even higher doses.9 In addition to dose, a second important variable in the dose-intensity calculation is the time of treatment. The Norton-Simon extension5 of the Skipper-Schabel model15 addresses this variable. According to this model, each cycle of chemotherapy kills a percentage of cells, but the time between treatments is sufficient to allow tumor regrowth, so that the overall impact of conventional repeated treatments is diminished. The delivery of multiple cycles of chemotherapy using the shortest possible intervals is therefore hypothesized to minimize tumor regrowth between one cycle and the next. This is called "dose-dense" chemotherapy, wherein an increase in dose-intensity is obtained by shortening the intervals between treatments and not, as has been done previously, by simply increasing dose levels. It should be noted that the biologic impact of more frequent application of maximally effective therapy may not be adequately reflected in the mathematical transformation used to define dose-intensity. This would be true if, for example, there were a plateau in the dose-response relationship so that dose "A" of chemotherapy is as effective as a dose twice its size ("2A"). If 2A is given every 2 weeks for four cycles, the calculated dose-intensity is the same as if A is given weekly for eight cycles. But the latter is predicted in this example to be more effective. One of the simplest and most elegant investigations of this approach is the randomized trial of doxorubicin and CMF conducted at the National Cancer Institute of Milan. In that study,11 359 women with stage II breast cancer involving four or more ipsilateral axillary nodes were randomized to adjuvant treatment with either doxorubicin 75 mg/m2 for four cycles followed by eight courses of CMF, or the same regimen given in an alternating fashion, ie, two courses of CMF alternated with one course of doxorubicin, repeated four times; this latter schedule based on the prediction of the Goldie-Coldman model.23 At a median follow-up of 9 years, both disease-free and overall survival were significantly superior for patients who had received the sequential regimen compared with those given the alternating one.11 The authors remarked that, whereas in the alternating plan four cycles of doxorubicin were spread over 27 weeks, in the sequential plan they were administered within 9 weeks, and therefore, the increased dose-intensity of doxorubicin could account for the superiority of the latter plan. Functionally, dose-intensity was increased by shortening the intervals without increasing dose levels of doxorubicin, thus providing clinical support for exploration of the hypothesis that more dose-dense chemotherapy can improve the outcome.
Based on this and on laboratory data demonstrating a steep dose-response relationship for alkylating agents, in particular for cyclophosphamide, and also because the feasibility of every-other-week high-dose cyclophosphamide had been demonstrated in a pilot study from the CALGB,12 we decided to substitute cyclophosphamide at high dose in place of CMF in the sequential plan from the Milan study. Our pilot study demonstrates that A At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. These results, although promising, must be viewed cautiously, because this was a nonrandomized phase II trial. Clearly, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose/schedule of doxorubicin and cyclophosphamide, and therefore, it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials are now becoming assessable. In May 1997, the results of 5 years of follow-up of the National Surgical Adjuvant Breast and Bowel Project B22 trial were published.24 In that study, 2,035 patients with operable breast cancer and one or more histologically positive lymph nodes and no evidence of metastatic disease were randomized to receive adjuvant chemotherapy with either four courses of standard doxorubicin and cyclophosphamide (AC) regimen, or with an intensified cyclophosphamide AC regimen, or with an intensified and increased cyclophosphamide dose AC regimen, the dose and intensity of doxorubicin remaining the same in all groups. Simultaneous comparison of the three treatment groups through 5 years of follow-up indicated no significant difference in disease-free and overall survival. Specifically, no significant benefit was noted when cyclophosphamide was either dose-intensified only or both dose-intensified and dose-escalated. In particular, in patients with four to nine positive nodes, the 5-year disease-free survival was 55%, 53%, and 55%, respectively, in the three treatment groups, and in patients with 10 or more positive nodes, it was 36%, 33%, and 41%, respectively. The authors concluded that "intensifying and increasing the total dose of cyclophosphamide is not appropriate in the treatment of women with primary breast cancer."24,p.1867 A subsequent study, B-25, has not yet been formally published, but according to preliminary reports, no advantage for a further increase in dose or dose-intensity has been seen. If simple dose-escalation is ultimately proven ineffective, dose-dense treatment, perhaps with the addition of other active drugs, offers a promising alternative. At the same time, the demonstration that escalated dose levels are not beneficial could allow us, instead, to define an "ideal" (ie, maximally effective) dose level to use in trials of dose-dense therapy. For example, the current CALGB-led node-positive trial, (CALGB 9741) randomizes patients toreceive cyclophosphamide (as well as doxorubicin and paclitaxel) at a dose of 600 mg/m2, using a less (every-3-weeks treatment) or more (every-2-weeks treatment) dose-dense plan. In this trial, dose-intensification via increased dose-density is specifically being tested without dose-escalation.
Based on the demonstrated feasibility and promising efficacy of dose-dense A
Ultimately, for clinical relevance, dose-dense therapy must be tested and proven in well-designed, prospective randomized trials. The first, based on our pilot study, is Southwest Oncology Group trial 9313, an intergroup trial that compared concurrent AC versus sequential A
Supported in part by National Cancer Institute contracts no. CM-07311 and NCI P50-CA68425. (Specialized Programs of Research Excellence)
C. Hudis and J. Crown are recipients of American Cancer Society Career Development Awards. A. Seidman is recipient of an American Society of Clinical Oncology Career Development Award.
1. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women—Early Breast Cancer Trialists' Collaborative Group. Lancet 339:1-15, 71-85, 1992 2. Fisher B, Slack N, Katrych D, et al: Ten year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet 140:528-534, 1975[Medline] 3. Bonadonna G, Valagussa P, Rossi A, et al: Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 5:95-115, 1985[Medline] 4. DeVita VT: Principles of cancer management: Chemotherapy, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 5). Philadelphia, PA, Lippincott, 1997, pp 333-347 5. Norton L, Simon R: The Norton-Simon hypothesis revisited. Cancer Treat Rep 70:163-169, 1986[Medline] 6. Goldie JH: Scientific basis for adjuvant and primary (neoadjuvant) chemotherapy. Semin Oncol 14:1-7, 1987
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Goldie JH, Coldman AJ: The genetic origin of drug-resistance in neoplasms: Implication for systemic therapy. Cancer Res 44:3643-3653, 1984 8. Hryniuk WM, Figueredo A, Goodyear M: Applications of dose intensity to problems in chemotherapy of breast and colorectal cancer. Semin Oncol 14:3-11, 1987 (suppl 4) [Medline]
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Wood WC, Budman D, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast cancer. N Engl J Med 330:1253-1259, 1994 10. Gilewski T, Norton L: Cytokinetics and breast cancer chemotherapy, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the Breasts. Philadelphia, PA, Lippincott-Raven, 1996, pp 751-768 11. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. JAMA 273:542-547, 1995[Abstract]
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Lichtman S, Ratain M, Van Echo D, et al: Phase I trial of granulocyte-macrophage colony stimulating factor (GM-CSF) plus high dose biweekly cyclophosphamide: A CALGB study. J Natl Cancer Inst 85:1319-1326, 1993 13. Ajani J, Welch S, Raber M, et al: Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 8:147-159, 1991 14. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 15. Skipper HE: Kinetics of mammary tumor cell growth and implications for therapy. Cancer 28:1479-1499, 1971[Medline]
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DeVita VT: Dose-response is alive and well. J Clin Oncol 4:1157-1159, 1986 17. Bonadonna G, Valagussa P: Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10-15, 1981[Abstract] 18. Von Hoff DD, Clark GM, Weiss GR, et al: Use of in vitro dose-response effects to select antineoplastics for high-dose or regional administration regimens. J Clin Oncol 4:1827-1834, 1986[Abstract] 19. Frei E III, Canellos GP: Dose, a critical factor in cancer chemotherapy. Am J Med 69:585-594, 1980[Medline] 20. Frei E III, Antman K, Teicher B, et al: Bone marrow autotransplantation for solid tumors: Prospects. J Clin Oncol 7:515-526, 1989[Abstract]
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Henderson IC, Hayes DF, Gelman R: Dose-response in the treatment of breast cancer: A critical review. J Clin Oncol 6:1501-1515, 1988 22. Hryniuk W, Levine MN, Levin L: Analysis of dose-intensity for chemotherapy in early (stage II) and advanced breast cancer. Natl Cancer Inst Monogr 1:87-94, 1986 23. Goldie JH, Coldman AJ: A mathematical model for relating drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979[Medline] 24. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from NSABP B-22. J Clin Oncol 15:1857-1869, 1997 25. Riccio L, Hudis C, Seidman A, et al: Long-term distant disease-free survival (DFS) from 2 pilot studies of dose-dense (DD) sequential adjuvant chemotherapy (CRX) in women (PTS) with resected breast cancer (BC) and > 3 positive lymph nodes (+ LN). Proc Am Soc Clin Oncol 16:145a, 1997 (abstr) Submitted July 31, 1998; accepted November 24, 1998. This article has been cited by other articles:
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 positive lymph nodes). 
C is feasible without excessive toxicity. As expected, the most common toxicity was hematologic, with 88% of assessable cycles of cyclophosphamide associated with grade 3 or 4 leukopenia and 52% of patients hospitalized during treatment. Fever in the setting of neutropenia was the most common reason for admission. Despite this level of toxicity, all but two patients were able to finish the planned chemotherapy program, and there was no treatment-related mortality. No cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. 
