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Sequential Dose-Dense Doxorubicin, Paclitaxel, and Cyclophosphamide for Resectable High-Risk Breast Cancer: Feasibility and Efficacy

From the Breast and Gynecologic Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Clifford Hudis, MD, MSKCC, 1275 York Ave, Box 206, New York, NY 10024; Email hudisc{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A T C) as adjuvant therapy.

METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m² x 3, then paclitaxel 250 mg/m²/24 hours x 3, and then cyclophosphamide 3.0 g/m² x 3; all doses were given with subcutaneous injections of 5 µg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy.

RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease.

CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A T C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
COMBINATION CHEMOTHERAPY WITH cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or similar regimens modestly reduces the risks of relapse and death for patients with operable primary breast cancer.¹ Although some are widely used, no other regimen, including anthracycline combinations, has been consistently found to be greatly superior to CMF.^2-5

In an attempt to improve upon these results, various manipulations of dose and the schedule of administration have been tested. Dose-intensification has generated great research interest over the last decade. The term dose-intensity was formulated and popularized as body size–adjusted dose (usually mg/m²) divided by time (usually per week).⁶ Part of the appeal of dose-intensity has been the experimental observation that cell killing can be increased for some agents and some tumor models by an increase in dose size.⁷ In these laboratory models, anticancer drugs kill a fraction of cells (called log-kill), and this is constant regardless of the number of cells present when the drugs are administered. Dose escalation is effective because this fraction increases as dose increases. Because each agent in a combination of agents should add its own log-kill effect, enough cycles of enough drugs at high enough individual dose levels should kill a very high percentage, if not all, of the cells, but clinical results do not match this prediction.

Resistance is the hypothesized reason that some (if not all) breast cancers are not cured by combination drug regimens.^7-10 To overcome resistance, combination chemotherapy using several drugs simultaneously at full dosages or, when this is impossible, in rapid alternation was predicted to be superior and studied clinically.¹¹

The lack of success with alternating therapy in breast cancer suggests that the underlying assumptions may be incorrect. For example, human solid tumors do not exhibit exponential growth but rather seem to grow in a Gompertzian pattern.¹² With the Gompertzian model, the doubling time is not constant but rather increases with increasing tumor size. When the Gompertzian model is in effect, preclinical cancers proliferate more rapidly than we would predict from observations of clinical cancers, and it takes less time for the preclinical cancer to reach clinical size than we would estimate for an exponential tumor. Similarly, tumor regrowth after subcurative therapy could be quite rapid after each cycle of treatment, so eradication of disease is difficult, even when all of the cells are "sensitive" to the drugs used.¹³

If we conceive of the whole breast cancer in an individual patient as a collection of different sublines with different proliferation rates and different sensitivities to treatment, it seems likely that eradicating some sublines by chemotherapy would leave others to grow, and these residual sublines would do so rapidly by virtue of their Gompertzian kinetics. Hence, very effective therapies, even those killing most of the cells present, could translate to only small increases in disease-free survival in the clinic.

An alternative model predicts that the best way to cure this heterogeneous mix of cells is to eradicate the more numerous, faster growing cells first. Next, therapy should be directed against the smaller population of slowly growing and therefore more resistant cells.¹³ This is termed sequential therapy, and this approach has been proven clinically superior to the alternating plan.¹⁴ Sequential use of single agents also facilitates dose escalation by avoiding overlapping toxicities, which increases the probability of eradicating the drug-sensitive subpopulations.^15,16 The most widely used method of increasing dose-intensity is dose escalation, which has been proven to be modestly successful for some drugs in some dose ranges.¹⁷ However, the total impact of a therapy, from the first moment of treatment to the very end of the drug administration period, could be related to the cell kill for each dose, the length of time drugs are given, and the rate of tumor growth between treatments. If so, then a fixed cell kill achieved repeatedly at shorter time intervals should increase the overall impact of therapy. This concept and approach is called dose density.

Dose-dense treatments increase dose-intensity not by increasing the numerator (dose), as with dose escalation, but by decreasing the denominator (time). Although dose-intensity may be increased by dose escalation or by increasing the dose density or by both, an advantage of dose density is that it should work even if the dose-response relationship for the agents being used is not rising steeply in the feasible dose range. Because sequential therapy is by definition more dose-dense than alternative plans and was superior in earlier studies, we chose this approach for further development, using three active agents in breast cancer: doxorubicin, paclitaxel, and cyclophosphamide. These three drugs were chosen on the basis of their high single-agent activity and previous demonstrations that high doses could be administered in a dose-dense fashion.^14,18-21 In this article, we report the results of this pilot trial of sequential, dose-dense doxorubicin, paclitaxel, and cyclophosphamide (Fig 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. Treatment plan for sequential dose-dense therapy.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Treatment Plan
Nine cycles of chemotherapy were planned using 14-day intertreatment intervals. The first three treatments consisted of doxorubicin 90 mg/m², given by intravenous push; the second three treatments consisted of paclitaxel 250 mg/m², given as a 24-hour infusion (Taxol; Bristol-Myers Squibb, Princeton, NJ, supplied by the National Cancer Institute, Bethesda, MD); and the third three treatments consisted of cyclophosphamide 3.0 g/m², given as a 1-hour infusion (see Fig 1). All nine cycles of chemotherapy were supported by granulocyte colony-stimulating factor (G-CSF) (Neupogen; Amgen, Thousand Oaks, CA) at a dose of 5 µg/kg SC on days 3 through 10 inclusive. With cyclophosphamide, the use of mesna was permitted but not required. Treatment was started within 8 weeks of the date of the final local control procedure.

Actual body weight was used for body surface area (m²) calculations, but patients who were more than 40% above their ideal weight were dosed using the corrected weight (actual weight plus the ideal weight divided by 2).

A complete blood count with leukocyte differential was performed before each cycle of chemotherapy and three times a week after each cycle. Weekly determinations of total bilirubin, SGOT, and alkaline phosphatase were obtained. After the completion of the doxorubicin, paclitaxel, and cyclophosphamide portions of therapy, cardiac safety was assessed by chest radiographs and cardiac ejection fraction determinations, using either nuclear scanning or echocardiography. A daily calendar was provided on which patients recorded all doses of G-CSF along with any symptoms. Nonhematologic toxicity was graded by a nurse clinician and a physician during review of the calendar at each pretreatment visit.

Dose Modifications
Doxorubicin. Treatment was delayed if on the scheduled day of administration, the granulocyte count was less than 1,500 or the platelet count was less than 100,000. Treatment was resumed when these minimal levels were achieved. Dose reductions of 25% were required for patients who developed neutropenic fever (absolute granulocyte count below 1,000/mL³ at the time of a documented temperature of 38^oC or higher) or a documented bacteremia. Doxorubicin was withheld for grade 2 or 3 mucositis, dysphagia, and diarrhea, but it was resumed at full dose when these toxicities resolved.

Paclitaxel. Treatment was delayed if the granulocyte count was less than 1,500 or the platelet count was less than 100,000 on the scheduled day of administration. Paclitaxel was resumed when these levels were achieved. Dose reductions of 20% (to 200 mg/m² and then to 160 mg/m²) were required for neutropenic fever and for any grade 3 nonhematologic toxicity attributable to a prior dose of paclitaxel.

Cyclophosphamide. No dose reductions were planned for cyclophosphamide. Instead, cyclophosphamide administration was delayed if the granulocyte count was less than 1,000 or the platelet count was less than 50,000 on the scheduled day of treatment. Treatment was resumed when these levels were achieved.

Granulocyte colony-stimulating factor. Administration of G-CSF was stopped when the absolute neutrophil count exceeded 75,000, but it was restarted when the count dropped to less than 10,000 if the drop occurred less than 10 days after the last dose of chemotherapy.

Radiotherapy
After mastectomy, patients with 10 or more involved axillary lymph nodes and patients whose tumor exceeded 5 cm in greatest diameter received chest wall radiotherapy. Patients treated with breast conservation also underwent radiation therapy. Standard dosing guidelines and techniques were used, and treatment was started approximately 4 weeks after the last dose of cyclophosphamide.

Tamoxifen
All patients who were amenorrheic at the end of chemotherapy and whose tumors expressed either (or both) the estrogen or progesterone receptor were placed on a 5-year course of tamoxifen 20 mg/day beginning approximately 4 weeks after the last dose of cyclophosphamide.

Follow-Up
To obtain the most accurate and conservative estimate of outcome and to monitor long-term toxicities, patients were followed closely after they completed chemotherapy. Histories and physical examinations were repeated at 3-month intervals, along with complete blood count, SGOT, alkaline phosphatase, carcinoembryonic antigen, and cancer antigen 15–3 tests. Chest radiographs, nuclear bone scans, and computed tomography scans of the chest and abdomen with contrast were obtained yearly. Any abnormal result prompted further investigation. Diagnosis of stage IV disease required tissue confirmation if possible.

Biostatistics
Dose-intensity. For each patient, the delivered dose-intensity for all three drugs was calculated by adding the total dose administered (per meter squared) and dividing by the number of weeks of treatment. For doxorubicin, the treatment duration was from the first day of doxorubicin until the first day of paclitaxel. For paclitaxel, the treatment duration was from the first day of paclitaxel until the first day of cyclophosphamide. For cyclophosphamide, the treatment duration was from the first day of cyclophosphamide until 14 days after the third (final) treatment.

Disease-free survival. Actuarial disease-free survival was calculated using the method of Kaplan and Meier,²² starting from the date of local control surgery. Any recurrence of disease at any site (including ipsilateral and contralateral breast cancer) constituted a recurrence.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Between March 1993 and June 1994, 42 patients were enrolled in the study (see Table 1). One patient was removed from the study when she developed a recurrence in her mastectomy scar on day 29 when she presented for her third dose of doxorubicin. She was not assessable for feasibility but was included in the disease-free survival analysis. Two additional patients refused the last dose of cyclophosphamide. Thus, all but three patients (7%) received all nine planned chemotherapy treatments, and 41 patients (98%) were assessable for feasibility.

Hematologic Toxicity
Hematologic toxicity was marked but varied distinctly among the three agents (see Table 2). The incidence of neutropenic fever was greatest during treatment with doxorubicin and cyclophosphamide, whereas the requirement for packed RBC transfusion rose with increased cycles of treatment and was greatest during cyclophosphamide treatment. Platelet transfusion was necessary in four patients (10%) but only during the final cycles of cyclophosphamide. Overall, the majority of patients (69%) developed neutropenic fever, with 39% experiencing more than one episode, and 67% required transfusions of packed RBCs. All patients had full recovery of their peripheral blood counts at the conclusion of treatment. Prolonged follow-up has not revealed evidence of prolonged cytopenia.

Nonhematologic Toxicity
Grade 2 alopecia was universal. Other nonhematologic toxicities were frequent but mild, as shown in Table 3. There were no grade 4 nonhematologic toxicities, but specific grade 3 toxicities, including fatigue, bone pain, and stomatitis, were seen in up to 24% of patients. There was no clinically significant cardiac toxicity. All premenopausal patients became amenorrheic after completion of chemotherapy.

Dose-Intensity
The planned dose-intensity was 45 mg/m²/week for doxorubicin, 125 mg/m²/week for paclitaxel, and 1,500 mg/m²/week for cyclophosphamide. As shown in Table 4, the median delivered dose-intensity for all three agents exceeded 92% of planned. For paclitaxel and cyclophosphamide, it exceeded 98%. For these calculations, the patient who experienced disease progression during the second cycle of doxorubicin was excluded, but the two patients who did not receive the third cycle of cyclophosphamide were included with an assumption that their third treatment would have required an additional 14 days. Thus, the delivered dose-intensity of cyclophosphamide was decreased by one third in these two patients.

Disease-Free Survival
At the time of analysis, the median duration of follow-up from the date of definitive local control surgery was 48 months (range, 3 to 57 months). In addition to the patient with early recurrence, eight other patients (21%) relapsed. Three relapses (7%) occurred in the central nervous system on days 254, 259, and 537, and four relapses (7%) occurred in soft tissues and/or viscera on days 551, 602, 768, and 1378. There was one bone-only relapse on day 819 (27 months). The median disease-free survival has not been reached. At the median follow-up of 48 months, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%) (see Fig 2). The follow-up period for the 33 patients who showed no evidence of relapse ranged from 44 to 57 months. Four patients (10%) have died of disease progression.

View larger version (10K): [in this window] [in a new window]   Fig 2. Disease-free survival using the method of Kaplan and Meier (with 95% confidence limits).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Adjuvant systemic chemotherapy prevents less than half of the expected relapses in early-stage breast cancer.¹ Increased dose-intensity and the addition of non–cross-resistant agents are two maneuvers predicted to improve the effectiveness of treatment, and this pilot study addresses both: Dose-intensification was achieved by combining dose escalation with increased dose density, and a newer, non–cross-resistant agent, paclitaxel, was incorporated.

The feasibility of the sequential application of dose-dense therapy is demonstrated by this pilot study, as we reported previously.²³ Presently, with a median follow-up exceeding 4 years on this nonrandomized trial, the disease-free survival rate of 78% is extremely promising and merits continued study of the principle of dose density, even as we continue to explore and learn more about the value of dose escalation.

It is important to emphasize that comparisons with other randomized and nonrandomized data sets are difficult and could easily be misleading. However, to justify continued study, the results of this pilot study should, at minimum, approach or exceed historic outcomes. In this regard, one basis for comparison is the sequential versus alternating chemotherapy trial from Milan.¹⁴ In the Milan study, women with resected breast cancer metastatic to four or more nodes were randomly assigned treatment consisting of alternating CMF and doxorubicin (represented as CCACCACCACCA) or sequential (ie, more dose-dense) therapy, with all four cycles of doxorubicin preceding all eight cycles of CMF (represented as AAAACCCCCCCC). The sequential therapy arm was superior, and at 5 years (comparable to our follow-up time), the disease-free survival rate was 61% for 179 patients with an average of nine involved lymph nodes.²⁴ Another comparative data set could be any of the nonrandomized trials of high-dose, autologous stem cell-supported consolidation, including one from Duke University reporting 81% disease-free survival for women with four to nine positive nodes at 2-year follow-up.²⁵ Finally, in the Cancer and Leukemia Group B trial (CALGB 8541), patients with four or more positive nodes treated with higher-dose cyclophosphamide, doxorubicin, and fluorouracil had an approximately 67% disease-free survival rate at 3.4 years.¹⁷ Taken together, these data suggest that our result is at least similar to others and certainly could be superior.

The pilot trial we present here used higher doses than are considered standard by many clinicians, and it is not clear that these more toxic dose levels are beneficial. In fact, if this regimen is ultimately proven superior, it could be because of the inclusion of paclitaxel and/or the use of more frequent dosing. Nonetheless, for doxorubicin, our planned dose-intensity was 45 mg/m²/week. By comparison, the dose-intensity for doxorubicin as part of the doxorubicin/cyclophosphamide (AC) regimen is 20 mg/m²/week.²⁶ The highest-dose arm of the now-completed CALGB-led Intergroup trial (93–44) planned for only 30 mg/m²/week (90 mg/m² every 21 days). At 18-month follow-up, the available randomized data did not suggest an advantage for doses of more than 60 mg/m², making the value of our level of doxorubicin questionable.²⁷

For cyclophosphamide, our planned dose-intensity of 1,500 mg/m²/week also exceeds that of other standard regimens. In comparison, the planned dose-intensity for this agent is 200 mg/m²/week when intravenous CMF is given at 21-day intervals, and it was 800 mg/m²/week on the highest-dose arm of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-25.²⁸ Comparisons of dose-intensity with high-dose, stem cell-supported regimens are more difficult, because in some regimens either the drugs are given only once (although typically in divided doses over one or several days) or the dose-intensity is diluted by including the standard-dose combination therapy preceding the transplant in the calculation. Again, recent data from NSABP B-22 and B-25, which tested doses of cyclophosphamide from 600 mg/m² every 21 days x 4 up to 2,400 mg/m², do not yet suggest clear advantage for the latter.^28,29

Until recently, the dose-intensification for paclitaxel was less studied than that for doxorubicin and cyclophosphamide and was complicated by the duration of infusion. Now, however, for advanced disease, there seems to be an advantage for 175 mg/m² compared with 135 mg/m² when it is administered over 3 hours, and even higher doses may offer a small additional benefit.^30,31 An advantage for longer infusion durations is also possible, although not completely resolved.^32-34 With no confirmation that lower doses and 3-hour infusions were equivalent to higher doses and longer infusions, and on the basis of the earlier clinical trials of paclitaxel, we chose to use the latter in this pilot trial. However, if 3-hour infusions are ultimately proven equivalent to 24-hour infusions, then the less toxic, shorter infusion schedule could be substituted.

On the basis of our demonstration of feasibility for dose-dense chemotherapy and our promising disease-free survival rates, several studies have been designed to build on our results. The American Intergroup is currently accruing to a Southwest Oncology Group-coordinated trial (96–23) comparing a regimen similar to the one we report here with conventional chemotherapy (AC) followed by a single cycle of high-dose chemotherapy rescued by autologous hematopoietic stem cell reinfusion in patients with four to nine involved nodes. Because of our experience with toxicity and a separate subsequent randomized trial we conducted, the doxorubicin and paclitaxel doses on the sequential dose-dense arm of this trial were reduced slightly to 80 mg/m² and 200 mg/m², respectively.

The recently closed Intergroup study coordinated by the CALGB (93–44) asked not only whether escalated dose levels of doxorubicin improve disease-free or overall survival of patients with node-positive primary breast cancer, but also whether sequential chemotherapy with paclitaxel after AC conveys therapeutic benefit. On the basis of the safety of AC followed by paclitaxel, the recently reported lack of benefit with escalated doses of doxorubicin, and the superiority of adding paclitaxel, the CALGB is coordinating the next node-positive Intergroup trial (CALGB 97–41), in which all patients will receive doxorubicin, paclitaxel, and cyclophosphamide at standard doses. On the basis of CALGB 93–44 as well as the NSABP B-22 and B-25 trials discussed above, the doses of doxorubicin, paclitaxel, and cyclophosphamide are fixed at 60, 175 (over 3 hours), and 600 mg/m², respectively, for all patients.^27,29,35 The design is factorial 2 x 2: one avenue of questioning will compare the use of AC followed by paclitaxel with the sequential use of doxorubicin, paclitaxel, and cyclophosphamide; the other line of questioning will compare the administration of drugs every 2 weeks (as allowed by the use of G-CSF) with the conventional 3-week schedule (in the latter case, G-CSF is permitted only when febrile neutropenia complicates therapy). Importantly, this new 2 x 2 Intergroup trial has been designed to address principles rather than specific regimens, and the answers to the questions being asked should be valid and informative even if we later learn that different dose levels or infusion durations (in the case of paclitaxel) are superior to the dose levels that we used in the trial described in this article.

Dose-dense therapy using sequential doxorubicin, paclitaxel, and cyclophosphamide at escalated doses is feasible and associated with a promising disease-free survival result. Wider use of this specific regimen requires appropriate randomized study, as is now ongoing. As we better define the optimal dose levels for routine use, the concepts underlying this pilot study could have even broader application, as will be determined from the randomized trials we have described.

	ACKNOWLEDGMENTS

 
Supported in part by NCI Contract No. CM-07311 and NCI P50-CA68425 (Specialized Programs of Research Excellence). The authors are recipients of the following grants and awards: American Cancer Society Career Development Award (C.H. and J.P.A.C.), American Society of Clinical Oncology Career Development Award (A. Seidman and J.B.), and Physician Scientist Award (D.L.).

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
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, Redmond C, Wickerham DL, et al: Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 7:572-582, 1989[Abstract]

3. Misset J, Palma M, Delgado M, et al: Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: Final report after a 16-year median follow-up duration. J Clin Oncol 14:1136-1145, 1996[Abstract/Free Full Text]

4. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial. J Clin Oncol 14:35-45, 1996[Abstract]

5. Carpenter JT, Velez-Garcia E, Aron BS, et al: Five-year results of a randomized comparison of cyclophosphamide, doxorubicin (adriamycin), and fluorouracil (CAF) vs. cyclophosphamide, methotrexate and fluorouracil (CMF) for node positive breast cancer: A Southeastern Cancer Study Group study. Proc Am Soc Clin Oncol 13:66, 1994 (abstr 68)

6. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986[Abstract/Free Full Text]

7. Skipper H, Schabel FJ, Wilcox W: Experimental evaluation of potential anticancer agents XIII: On the criteria and kinetics associated with "curability" of experimental leukemia. Cancer Chemother Rep 35:1, 1964 (abstr) [Medline]

8. Law L: Origin of resistance of leukaemic cells to folic acid antagonists. Nature 169:628, 1952 (abstr) [Medline]

9. Goldie J, Coldman A: Application of theoretical models to chemotherapy protocol design. Cancer Treat Rep 70:127-131, 1986[Medline]

10. Luria S, Delbruck M: Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491, 1943 (abstr) [Free Full Text]

11. Goldie JH, Coldman AJ, Gudauskas GA: Rationale for the use of alternating non-cross-resistant chemotherapy. Cancer Treat Rep 66:439-449, 1982[Medline]

12. Norton L: A Gompertzian model of human breast cancer growth. Cancer Res 48:7067-7071, 1988[Abstract/Free Full Text]

13. Surbone A, Gilewski T, Norton L: Cytokinetics, in: Holland JF, Bast RC Jr, Morton DL, et al (eds): Cancer Medicine, Vol 1 (ed 4). Baltimore, MD, Williams & Wilkins, 1996, pp 769-798

14. Bonadonna G, Zambette 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/Free Full Text]

15. Peters WP, Ross M, Vredenburgh JJ, et al: High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11:1132-1143, 1993[Abstract/Free Full Text]

16. Crown J, Kritz A, Vahdat L, et al: Rapid administration of multiple cycles of high-dose myelosuppressive chemotherapy in patients with metastatic breast cancer. J Clin Oncol 11:1144-1149, 1993[Abstract/Free Full Text]

17. Wood W, Budman D, Korzun A, et al: Dose and dose intensity trial of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994[Abstract/Free Full Text]

18. Bronchud MH, Howell A, Crowther D, et al: The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer 60:121-125, 1989[Medline]

19. Seidman A, Reichman B, Crown J, et al: Taxol plus recombinant human granulocyte colony stimulating factor as initial and as salvage chemotherapy for metastatic breast cancer: A preliminary report. J Natl Cancer Inst Monogr 15:171-175, 1993

20. Lichtman S, Ratain M, Van Echo D, et al: Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: A Cancer and Leukemia Group B study. J Natl Cancer Inst 85:1319-1326, 1993[Abstract/Free Full Text]

21. Hudis C, Lebwohl D, Crown J, et al: Dose-intensive sequential crossover adjuvant chemotherapy for women with high risk node-positive primary breast cancer, in: Salmon SE (ed): Adjuvant Therapy of Cancer IV. Philadelphia, PA, JB Lippincott, 1993, pp 214-219

22. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

23. Hudis C, Seidman A, Baselga J, et al: Sequential adjuvant therapy with doxorubicin/paclitaxel/cyclophosphamide for resectable breast cancer involving four or more axillary nodes. Semin Oncol 22:18-23, 1995 (suppl 15)

24. Buzzoni R, Bonadonna G, Valagussa P, et al: Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three axillary lymph nodes. J Clin Oncol 9:2134-2140, 1991[Abstract]

25. Hussein A, Plumer M, Vredenburgh J, et al: High-dose chemotherapy (HDC) with cyclophosphamide (C) cisplatin (P), and BCNU (B) (CPB) and autologous bone marrow (ABM) and peripheral blood progenitor cells (PBPCs) for stage II/III breast cancer involving 4–9 axillary lymph nodes. Proc Am Soc Clin Oncol 15:A1026, 1996

26. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990[Abstract]

27. Henderson I, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (Pts) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390a)

28. DeCillis A, Anderson S, Bryant J, et al: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) on NSABP B-25: An update. Proc Am Soc Clin Oncol 16:130a, 1997 (abstr)

29. Fisher B, Anderson S, Wickerham D, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings fromNational Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15:1858-1869, 1997[Abstract/Free Full Text]

30. Nabholtz J-M, Gelman K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996[Abstract/Free Full Text]

31. Winer E, Berry D, Duggan D, et al: Failure of higher dose paclitaxel to improve outcome in patients with metastatic breast cancer: Results from CALGB 9342. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 388)

32. Seidman A, Hochhauser D, Gollub M, et al: Ninety-six- hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14:1877-1884, 1996[Abstract/Free Full Text]

33. Holmes F, Valero V, Walter R, et al: Phase III trial of paclitaxel administered over 3- or 96-hours for metastatic breast cancer. Proc Am Soc Clin Oncol 15:106, 1996 (abstr 91)

34. Mamounas E, Brown A, Smith R, et al: Effect of taxol duration of infusion in advanced breast cancer (ABC): Results from NSABP B-26 trial comparing 3- to 24-hr infusion of high-dose taxol. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 389)

35. Wolmark N, Fisher B, Anderson S The effect of increasing dose intensity and cumulative dose of adjuvant cyclophosphamide in node positive breast cancer: Results of NSABP B-25. Breast Cancer Res Treat 46:26, 1997 (abstr)

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