The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m2) + cyclophosphamide (3000 mg/m2) every 21 days (group 1), doxorubicin (75 mg/m2) + cyclophosphamide (3000 mg/m2) every 15 days (group 2), and doxorubicin (75 mg/m2) + cyclophosphamide (6000 mg/m2) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC.
The efficacy of adjuvant chemotherapy for patients with node positive breast cancer is now clearly demonstrated and widely used in standard clinical practice. In this situation, anthracyclines and cyclophosphamide are validated as effective and are part of the most active regimens without taxanes. Since the 1990s, following the work of the National Surgical Adjuvant Breast and Bowel Project (NSABBP), four cycles of doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), every 21 days, are considered as the minimum requirement for effective adjuvant chemotherapy in breast cancer (AC regimen).1 With these two drugs, the importance of dose intensity has been clearly established in experimental models.2 Furthermore, clinical data have suggested and frequently demonstrated the relevance of dose and dose intensity in the breast cancer setting.3,4 Relatively modest dose variations of these drugs have been tested without the use of hematopoietic growth factors, resulting in benefits in dose escalation of anthracyclines but not clearly for cyclophosphamide.
We and others5,6,7,8,9 were able to develop much larger dose escalation of anthracyclines and cyclophosphamide in breast cancer when hematopoietic growth factors and/or peripheral blood stem cells (PBSC) were added to cycles of chemotherapy. In a previous report,10 we demonstrated that, when compared to the standard dose intensity of the AC regimen of the NSABBP, we could safely increase the relative dose intensity (RDI) of doxorubicin (×1.25) and cyclophosphamide (×5) (group 1) in intensive outpatient chemotherapy designed for poor risk patients.
We designed the present study to further increase relative dose intensity of doxorubicin and cyclophosphamide using the same support of hematopoietic growth factors and peripheral blood stem cell infusions.
The aim of the study was to evaluate the safety of two further approaches to escalating dose intensity, which would however remain compatible with mostly outpatient therapy:
in one group of patients (group 2), doxorubicin and cyclophosphamide were given every 15 days (resulting in an increase of RDI of doxorubicin ×1.88 and of cyclophosphamide ×7.5 when compared to the NSABBP standard regimen).
in another group of patients (group 3), doxorubicin and cyclophosphamide were given every 21 days with the same dose of doxorubicin but doubling the dose of cyclophosphamide (6000 mg/m2) (the increase of RDI of doxorubicin was ×1.25 and of cyclophosphamide ×10 when compared to the standard AC regimen).
We report here an analysis of the safety of such regimens in 81 patients treated in three consecutive cohorts of patients with poor risk breast cancer all receiving G-CSF and two infusions of peripheral blood stem cells.
Patients and methods
Between July 1993 and November 1998 at the Institute Paoli-Calmettes (Marseilles, France), 81 consecutive women received four cycles of intensive regimens with doxorubicin and cyclophosphamide and were analyzed for the present study.
Patients had a histologically proven breast cancer with more than four involved axillary homolateral lymph nodes. All of them had a good Karnofsky index and normal hematologic, renal, hepatic and cardiac functions. They had not to have been previously treated for breast cancer. The pretreatment characteristics of the patients are shown in Table 1.
Chemotherapy and Hematopoietic Growth Factor
Three successive cohorts of patients received four cycles of sequential intensive chemotherapy with doxorubicin (75 mg/m2) and cyclophosphamide (3000 or 6000 mg/m2) in a conventional hospital setting.
The first cohort (group 1 = 27 patients) was treated with four cycles of 3000 mg/m2 of cyclophosphamide and 75 mg/m2 of doxorubicin per cycle, every 21 days. The second cohort (group 2 = 24 patients) received the same chemotherapy but cycles were spaced at 15 days. In the third cohort (group 3 = 30 patients), cycles were given every 21 days at a dosage of 6000 mg/m2 of cyclophosphamide and 75 mg/m2 of doxorubicin per cycle.
The uroprotective agent, Mesna (Uromitexan), was systematically added to prevent hemorrhagic cystitis and was administered as an intravenous bolus at a dose of 1500 mg/m2 before each dose of cyclophosphamide, 4 and 8 hours after. No antibiotic prophylaxis was given. All patients received antiemetic therapy consisting of ondansetron and dexamethasone. No dose reduction was scheduled for hematological or extra-hematological toxic effects. At day 15 (group 2) or 21 (groups 1 and 3), absolute neutrophil count (ANC) had to have reached 1.5 × 109/l and platelet count 100 × 109/l to allow a new cycle to be administrated.
Each cycle of chemotherapy was followed by a daily subcutaneous administration of 5 μg/kg (maximum 300 μg) Filgrastim (Amgen, Thousand Oaks, CA, USA). For procedure mobilization (cycle 1 and/or 2), Filgrastim was started on day 3 or 5 after chemotherapy until the day before the last collection of PBSC. For cycles with PBSC infusion (cycles 3 and 4), Filgrastim began on day 3 after chemotherapy, immediately after stem cell infusion and was given until ANC >0.5 × 109/l for 3 consecutive days.
Stem cell collection and infusion
For each group of patients, PBSC were collected after cycle 1 on day 13 and/or 14, and if necessary after cycle 2, to reach the minimum target number of CD34 cells of 6 × 106/kg. As previously described,10 cells were divided into three bags and frozen. The thawed PBSC were infused after cycles 3 and 4, on day 3 post chemotherapy. Usually, one bag was infused after cycle 3 and the two other bags after cycle 4. Infusions were usually administered in the outpatient clinic.
Dose intensity, relative dose intensity and average relative dose intensity (Table 2)
According to the method developed by Hryniuk11,12,13 in both adjuvant and metastatic settings, dose intensity (DI) was defined as the amount of drug administered per unit time and was expressed as mg/m2/week and the relative dose intensity (RDI) as the amount of drug delivered per unit time compared to the standard single-dose regimen expressed as a decimal fraction. The calculation of the average relative dose intensity was as follows: sum of relative dose intensities in test regimen/number of drugs in standard regimen. Each experimental group of chemotherapy (groups 1, 2, 3) was compared with the standard AC regimen of NSABBP.1
The three cohorts of patients received the same total dose of doxorubicin, ie 300 mg/m2 for a total dose of 240 mg/m2 for the standard AC. The projected RDI of doxorubicin was up to 1.25 times higher than the standard regimen for groups 1 and 3, and up to ×1.88 higher for group 2.
The total dose of cyclophosphamide was 2400 mg/m2 for the standard AC, 12 000 mg/m2 for groups 1 and 2, 24 000 mg/m2 for group 3. The projected RDI of cyclophosphamide was up to five times higher than the standard for group 1, up to 0.5 times higher for group 2 and up to 10 times higher for group 3.
The projected average RDI consisted of an increase of ×3.12 for group 1, ×4.69 for group 2 and ×5.62 for group 3.
Criteria for evaluation of toxicity and statistical analysis
We evaluated the extra-hematological toxicities according to the World Health Organization (WHO) criteria and added frequency and duration of hospitalizations as pertinent criteria. Hematological toxicity was evaluated using both WHO criteria and red blood cell and platelet transfusion requirements.
Homogeneity of patient characteristics was tested using the Pearson's chi-square test for the categorical variables and Kruskal–Wallis test for the quantitative variables. The same tests were used to compare the toxicity variables between the three groups of patients. All tests were two-sided and performed at the 5% level of significance. For all significant differences between the three groups, the groups were compared in two–two time. Chi-square test was used for qualitative variables and the Siegel and Castellan method14 for quantitative variables. The overall survival was defined as the time between the diagnosis and the date of death or last follow-up, and was estimated using the Kaplan–Meier method.
Patient characteristics (Table 1)
There was no significant difference between the three groups of patients in terms of age, hormonal status and number of involved axillary lymph nodes at diagnosis. There was less ductal carcinoma in group 2 than in the two other groups (P < 0.05, group 1 vs group 2).
Seventy-five patients (92.6%) received four cycles of chemotherapy, as planned, with a total of 310 cycles administered.
The received dose intensity of doxorubicin was, as expected, higher in the group with the reduced intervals between the cycles of chemotherapy (P < 0.05, group 2 vs groups 1 and 3) and the received dose intensity of cyclophosphamide was lower in group 1 than in the two other groups (P < 0.05) (Table 2). There was no significant difference between the three groups in terms of received dose intensity/projected dose intensity.
Six (7.4%) of the 81 patients discontinued protocol therapy: 1/27 for group 1 (3.7%), 2/24 for group 2 (8.3%) and 3/30 for group 3 (10%). These differences were not statistically significant. In the first group, one patient decided to stop treatment after two cycles. In the second group, one patient was withdrawn from the study after the first cycle and one after the second cycle for apheresis failure. In the third group, two patients decided to stop the study after the first cycle and one patient presented a persistent thrombocytopenia with retinal bleeding after three cycles of chemotherapy and was withdrawn from the study due to toxicity.
Only 14 (4.5%) of 310 cycles administered were delayed for more than 4 days and less than 8 days for hematologic or extra-hematologic reasons. Overall, the second cycle was delayed in 15.3% of cases (7.4% for group 1, 4.3% for group 2 and 3.6% for the last group), the third cycle in 27.5% of cases (respectively for each group of patients: 7.7%, 9.1% and 10.7%), and the last cycle in 12.2% of cases (7.7% and 4.5%, no delay for the third group). During the whole therapeutic sequence, only 13 patients (13/81: 16%) had, at some time, a cycle delayed: 5/27 in group 1 (18.5%), 4/23 in group 2 (17.4%) and 4/28 in group 3 (14.3%).
Overall, no statistical difference was observed in the diverse variables of treatment completion between the three groups.
Extra-hematological and hematological toxicities
The results of cumulative extra-hematological and hematological toxicity for the four cycles of treatment are detailed in Table 3.
The most frequent extra-hematological toxicities were nausea/vomiting, asthenia, and mucositis. The incidence of these toxicities was higher in group 3 and for mucositis, the difference was statistically significant between groups 1 and 3 (P = 0.005).
A high rate of admissions or extended hospitalizations for toxicity occurred in the three groups of patients but it was higher in group 3 than in the two other groups (P = 0.042 group 2 vs group 3 and P = 0.007 group 1 vs group 3) as well as the number and duration of hospitalizations per patient (P < 0.05, groups 1 and 2 vs group 3). The most frequent reason for readmission was febrile neutropenia in all three groups of patients.
As expected the hematological toxicity was severe in the three groups. The incidence and duration of grade 4 neutropenia and grade 3–4 thrombocytopenia were significantly affected by the treatment. Overall, decreasing duration of treatment intervals or increasing doses of drugs resulted in more severe hematological toxicities as illustrated by an increase in platelet and red blood cells transfusion requirements.
Neither toxic death nor acute cardiac toxicity occurred during the study. Two patients (one in group 1 and one in group 3) experienced a marked decrease in the cardiac left ejection fraction 58 and 3 months, respectively, after the fourth cycle of chemotherapy. Four patients developed a second cancer: colon adenocarcinoma (group 1), small cell lung cancer and breast cancer (group 2), AML type 1 in group 3. The time from adjuvant chemotherapy (day 1, cycle 1) to the development of AML was 2 years.
With a median follow-up of 43 months (range, 26 to 91 months), the median overall survival is not yet reached and the estimated overall survival at 5 years is 78%. Eleven patients have died. At 5 years, the estimated overall event-free and metastasis-free survivals are 66 and 73% (95% IC: 61.1–75.6% and 64.1–77.5%). Subanalysis of the three therapy groups does not show any statistically significant difference of outcome.
We evaluated the impact, in terms of treatment completion and toxicity, of three types of modulation of dose intensity of the standard AC regimen of chemotherapy described by the NSABBP1 in high risk breast cancer. Compared to the standard AC, we chose in three consecutive cohorts to increase first the dose of the two drugs, then to reduce the interval between the cycles and finally to increase the dose of cyclophosphamide.
Our results show excellent treatment completion in the three groups of patients. The systematic use of G-CSF and peripheral blood stem cell infusions ensured overall massive dose intensity escalation in 92.6% of the 81 patients in a total of 310 intensive cycles. As previously illustrated,10,15,16 such systematic administrations of G-CSF and PBSC are extremely useful in ensuring adequate treatment completion in intensive sequential chemotherapy even if the drugs are not given at sublethal doses for the hemato- poietic system.
Despite the relatively small number of patients and even considering the analysis of consecutive cohorts without randomization, significant differences in the three groups of patients could be observed in terms of toxicity. We previously described (group 1) that four cycles of doxorubicin 75 mg/m2 and cyclophosphamide 3000 mg/m2 every 21 days could be administered in an outpatient setting without major toxicities. When such doses of chemotherapy are accelerated with intervals of 15 days (group 2) toxicity was slightly increased but without statistically significant differences when compared to group 1. On the contrary, using the same dose of doxorubicin and the same 21 day interval between cycles, doubling the dose of cyclophosphamide (6000 mg/m2) (group 3) resulted in a significant increase in hematological and extra-hematological toxicities when compared to patients of group 1 and group 2.
Despite the use of prophylactic setron, severe nausea and vomiting was impressive in the three groups probably related to the high dose of cyclophosphamide and doxorubicin used. Therapy of patients in group 3 resulted overall in a readmission rate of 97% and an overall median requirement of 12 days of hospitalization for management of complications such as febrile neutropenia. Such overall toxicity is comparable to that observed after intensive combination of alkylating agents followed by PBSC transplantation and prohibits the reality of intensive therapy in a real outpatient setting. The need for hospitalization in group 3 patients obviously implicates significant increases in cost of the therapy which would not differ markedly from those of autologous PBSC transplantation17,18 even if these were not specifically compared in the study.
Apart from acute toxicities, it should be noted that out of 81 patients who had a median follow-up of 43 months, four developed a second neoplasm (Kaplan–Meier estimation of risk of second cancer is 5.64% at 5 years, 95% IC: 0.62–10.66%). The relative imputability of intercalating alkylating drugs, G-CSF and immunosuppression in such late events is difficult to assess. However, since such risk has been previously described with similar frequency, the long-term risks of such procedures are of serious concern.19,20,21,22,23
The main question that can not be answered by this study remains the evaluation of the benefits of massive dose intensification in the setting of poor risk breast cancers with extensive lymph node involvement. Contradictory results24,25 are reported in the literature and so far no definitive answer is available. It seems, however, that if a benefit exists, which is supported by several pilot and even randomized studies, such benefit does not offer more than 10–20% event-free survival in comparison with ‘adequate’ standard chemotherapy.
Further implications of this work in adjuvant chemotherapy of poor risk breast cancer could only be considered if the benefits of intensification and autologous hematopoietic transplantation were clearly demonstrated. If that is the case, the present work would suggest that intensification of doxorubicin and cyclophosphamide compared to the standard AC can be safely achieved with an increase of relative dose intensity of doxorubicin ranging from ×1.25 to ×1.88 and of cyclophosphamide between ×5 and ×7.5, respectively, for groups 1 and 2 in this study. The experimental regimen in group 3 is associated with toxicities comparable to autologous transplantation and is not applicable in an outpatient setting. Even if these groups are too small and not designed to demonstrate benefits in event-free survival, longer follow-up is required before abandoning further use of the regimen designed for group 3 which may still be beneficial for breast cancer survival.
Finally, our study shows that very high dose intensities of the main active drugs used in poor risk breast cancer can be achieved in an outpatient setting when associated with G-CSF and PBSC. In this setting, doxorubicin 75 mg/m2 and cyclophosphamide 3000 mg/m2 can be used either every 21 or 15 days for four cycles offering a major dose intensity to kill residual tumor cells.
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-non responsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15 J Clin Oncol 1990 8: 1483 1496
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 1986 4: 1827 1834
Piccart MJ, Biganzoli L, Di Leo A . The impact of chemotherapy dose density and dose intensity on breast cancer outcome: what have we learned? Eur J Cancer 2000 36: (Suppl. 1) S4 10
Norton L . Evolving concepts in the systemic drug therapy of breast cancer Semin Oncol 1997 24: S10-3 S10-10
Ardizzoni A, Venturini M, Sertoli MR et al. Granulocyte–macrophage colony-stimulating factor (GM-CSF) allows acceleration and dose intensity increase of CEF chemotherapy: a randomised study in patients with advanced breast cancer Br J Cancer 1994 69: 385 391
Del Mastro L, Garrone O, Sertoli MR et al. A pilot study of accelerated cyclophosphamide, epirubicin and 5-fluorouracil plus granulocyte colony stimulating factor as adjuvant therapy in early breast cancer Eur J Cancer 1994 30A: 606 610
Scinto AF, Ferraresi V, Campiioni N et al. Accelerated chemotherapy with high-dose epirubicin and cyclophosphamide plus r-met-HUG-CSF in locally advanced and metastatic breast cancer Ann Oncol 1995 6: 665 671
Budd GT, Atiba J, Silver RT et al. Phase I/II trial of human recombinant granulocyte-colony-stimulating factor (filgrastim) and escalating doses of cyclophosphamide, mitoxantrone, and 5-FU in the treatment of advanced breast cancer J Cancer Res Clin Oncol 1999 125: 500 504
Hohaus S, Martin S, Schneeweiss A et al. Adjuvant high-dose therapy with peripheral blood stem cell support for patients with high-risk breast cancer Cancer Chemother Pharmacol 1999 44: S13 17
Viens P, Gravis G, Genre D et al. High-dose sequential chemotherapy with stem cell support for non-metastatic breast cancer Bone Marrow Transplant 1997 20: 199 203
Hryniuk WM . The importance of dose intensity in the outcome of chemotherapy Important Adv Oncol 1988 121 141
Hryniuk W, Levine MN . Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer J Clin Oncol 1986 4: 1162 1170
Hryniuk WM . Average relative dose intensity and the impact on design of clinical trials Semin Oncol 1987 14: 65 74
Siegel S, Castellan N . Nonparametric statistics for the Behavioural Sciences McGraw Hill: New York 1988
Stoppa AM, Bouabdallah R, Chabannon C et al. Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkin's lymphoma J Clin Oncol 1997 15: 1722 1729
Bouabdallah R, Stoppa AM, Rossi JF et al. Intensive sequential chemotherapy (ISC 95) with growth factors and blood stem cell support in high-intermediate and high-risk (IPI 2 and IPI 3) aggressive non-Hodgkin's lymphoma: an oligocentric report of 42 patients Leukemia 1999 13: 950 956
Hartmann O, Le Corroller AG, Blaise D et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs. A randomized, controlled trial Ann Intern Med 1997 126: 600 607
Le Coroller AG, Faucher C, Auperin A et al. Autologous peripheral blood progenitor-cell transplantation versus autologous bone marrow transplantation for adults and children with non-leukaemic malignant disease. A randomised economic study Pharmacoeconomics 1997 11: 454 463
Oddou S, Vey N, Viens P et al. Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution Leuk Lymphoma 1998 31: 187 194
Curtis RE, Rowlings PA, Deeg HJ et al. Solid cancers after bone marrow transplantation New Engl J Med 1997 336: 897 904
Chaplain G, Milan C, Sgro C et al. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: a population-based study J Clin Oncol 2000 18: 2836 2842
Linassier C, Barin C, Calais G et al. Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy Ann Oncol 2000 11: 1289 1294
Diamandidou E, Buzdar AU, Smith TL et al. Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas MD Anderson Cancer Center experience J Clin Oncol 1996 14: 2722 2730
Gianni A, Bonadonna G . Five year results of randomized clinical trial comparing standard versus high-dose myeloblative chemotherapy in the adjuvant treatment of breast cancer with >3 positive nodes (LN+) In: ASCO's 37th Annual Meeting; 2001 May 12–15; San Francisco, CA Am Soc Clin Oncol 2001 21A: (Abstr. 634)
Roche H, Pouillart P, Meyer N et al. Adjuvant high dose chemotherapy (HDC) improves early outcome for high risk (N>7) breast cancer patients: the Pegase 01 trial In: ASCO's 37th Annual Meeting; 2001; San Francisco, CA Am Soc Clin Oncol 2001 18A: (Abstr. 316)
This work received special grants from the French Administration of Health (PHRC) and Amgen France.
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Cite this article
Genre, D., Viens, P., Bertucci, F. et al. Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens. Bone Marrow Transplant 29, 881–886 (2002). https://doi.org/10.1038/sj.bmt.1703556
- breast cancer
- dose intensity
- adjuvant chemotherapy