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Annals of Surgical Oncology 10:369-375 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Randomized Multicentric Study of Perioperative Chemotherapy With Mitoxantrone in Early Breast Cancer

Thierry Petit, MD, PhD, Christian Borel, MD, Serge Theobald, MD, Daniel Serin, MD, Jean-François Rodier, MD, FACS, Gilles Prevot, MD, Jean-Philippe Brettes, MD and Théo Klein, MD

From the Departments of Medical Oncology (TP, CB, TK), Epidemiology and Biostatistics (ST), and Surgical Oncology (J-FR), Centre Paul Strauss, Strasbourg, France; Clinique Sainte Catherine (DS), Avignon, France; Gynecology Department, Hospices Civils (J-PB), Strasbourg, France; and Radiotherapy Department (GP), Centre Hospitalier, Mulhouse, France.

Correspondence: Address correspondence and reprint requests to: Thierry Petit, MD, PhD, Department of Medical Oncology, Centre de Lutte Contre le Cancer Paul Strauss, 3 Rue de la Porte de l’Hôpital, BP42, 67065 Strasbourg Cedex, France; Fax: 33-3-88-25-24-48; E-mail: tpetit{at}strasbourg.fnclcc.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: To confirm the hypothesis that reducing the interval between surgery and adjuvant chemotherapy could improve prognosis, a randomized multicentric study of adjuvant perioperative chemotherapy (POC) in breast cancer was initiated.

Methods: A total of 552 patients were randomized to evaluate whether the addition of POC to standard adjuvant treatment significantly improved outcome. Patients were stratified according to menopausal status, with 362 patients in the postmenopausal group and 192 patients in the premenopausal group. Premenopausal women with positive axillary nodes, negative hormonal receptors, or grade 3 tumors received adjuvant mitoxantrone-based chemotherapy. Node-negative premenopausal patients with grade 1 or 2 tumors expressing hormonal receptors received no standard adjuvant treatment. All postmenopausal women received hormonal therapy (tamoxifen 20 mg/day for 3 years). The perioperative regimen was a 14 mg/m2 mitoxantrone infusion at the end of tumor excision.

Results: With a median follow-up of 6.1 years, this study showed no significant advantage of POC on overall survival, disease-free survival, or metastasis-free survival for the total cohort or for the premenopausal and postmenopausal groups.

Conclusions: POC was a safe procedure in this study. However, the addition of POC to standard adjuvant treatment offered no benefit in breast cancer adjuvant treatment.

Key Words: Breast cancer • Perioperative chemotherapy • Randomized study • Mitoxantrone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Adjuvant systemic therapy after primary surgery of breast cancer has significantly increased disease-free survival (DFS) and overall survival (OS) of patients with a high risk of recurrence.1 Different modalities were studied to increase the benefit given by adjuvant treatment. Prolongation of the adjuvant treatment did not seem to make it more efficient. Prolongation beyond 6 months did not provide additional benefit.2 A 4-month course of doxorubicin and cyclophosphamide was as effective as a 6-month course of cyclophosphamide, methotrexate, and 5-fluorouracil.3 Increasing the dose-intensity of these treatments with stem cell support has given disappointing results up to now.4,5 The introduction into the adjuvant setting of new anticancer agents that have no cross-resistance to classic agents (such as taxanes) has given interesting preliminary results.6 Another strategy was to reduce the interval between surgery and subsequent chemotherapy to destroy micrometastases present at the time of diagnosis and stop the shedding of tumor emboli.

According to the Goldie and Coldman model, the number of resistant tumor cells increases with time and delay of treatment.7,8 In breast cancer, the demonstration of a labeling index increase in residual tumor cells after surgical excision of the primary tumor was an additional support for using early systemic treatment.9 Therefore, it seemed optimal to introduce systemic treatment as early as possible in the antitumor strategy. To confirm the hypothesis that reducing the interval between surgery and after adjuvant chemotherapy could improve prognosis, a randomized multicentric study of adjuvant perioperative chemotherapy (POC) in breast cancer was initiated in March 1988. This study was to compare the initiation of chemotherapy during breast tumor excision with standard delayed adjuvant chemotherapy.

Anthracycline- and anthracenedione-based regimens have demonstrated increased activity compared with a cyclophosphamide, methotrexate, and 5-fluorouracil regimen in an adjuvant setting.1 Mitoxantrone is a dihydroanthracenedione with a terminal half-life longer than 24 hours. This agent has two original characteristics compared with anthracyclines: a high concentration remaining for weeks in organs and the prevention of tumor growth in animal models when it is injected before tumor cell grafting.10,11 Thanks to these two properties, mitoxantrone seemed to be the appropriate drug for POC; thus, an adjuvant mitoxantrone-based regimen was chosen for this study. We report the results of this multicentric randomized study, comparing adjuvant treatment with and without POC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Five hundred seventy-eight patients from 16 institutions were randomized and randomly assigned to receive 1 cycle of POC or no POC from March 1988 to June 1991. Randomization was stratified according to participating institution and menopausal status. The randomization schedule was produced by using pseudorandom numbers. Inclusion criteria were histopathologically confirmed breast adenocarcinoma, stage I to IIIA; no prior treatment for breast cancer; no prior malignancies; age <=65 years; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Metastatic disease was excluded, and contralateral mammography, chest x-ray, liver sonography, and bone scan were mandatory before inclusion. Two hundred ninety-three patients were randomized in the POC arm and 285 in the control arm.

Patients were stratified according to menopausal status; postmenopausal status was defined either by the absence of menstrual periods for at least 5 years or by dosage of luteinizing hormone and follicle-stimulating hormone. Three hundred eighty-one patients were in the postmenopausal group, and 197 patients were in the premenopausal group. Patient characteristics in term of age, tumor size, surgery type, number of involved nodes, histoprognostic grade, and hormonal receptors were well balanced in the two arms (Table 1). Tumor hormonal receptor status was measured with a biochemical assay according to the best method available in every institution. A value of >=10 fmol of estrogen receptor or progesterone receptor per milligram of protein was considered positive.


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  		TABLE 1. Patient characteristics
 
Treatment
Surgery consisted of modified radical mastectomy or tumorectomy with axillary node dissection. Premenopausal women with positive axillary nodes, negative hormonal receptors, or grade 3 tumors received adjuvant mitoxantrone-based chemotherapy (fluorouracil 500 mg/m2, mitoxantrone 12 mg/m2, and cyclophosphamide 500 mg/m2 every 3 weeks for six cycles) starting within 30 days of surgery. Node-negative premenopausal patients with grade 1 or 2 tumors expressing hormonal receptors received no standard adjuvant treatment. Tamoxifen (20 mg/day for 3 years) was added to all postmenopausal women. Locoregional radiotherapy was planned for patients with conservative surgery and was delivered concomitantly with the adjuvant chemotherapy.

After randomization, POC was performed in 103 patients in the premenopausal group and in 190 patients in the postmenopausal group. The perioperative regimen was a 14 mg/m2 mitoxantrone infusion over 20 minutes just after the end of tumor excision and axillary dissection.

Criteria of Evaluation and Statistical Methods
The primary end point of the study was OS. Secondary end points were DFS, local failure–free survival (LFFS), and metastasis-free survival (MFS). DFS was defined as the interval between surgery and disease progression. Disease progression could have been local recurrence, metastatic evolution, contralateral breast cancer, or secondary primary cancer. Locoregional recurrence was defined as a recurrence in the homolateral breast or in the homolateral axillary lymph nodes. Only locoregional recurrences as a first event were taken into account. Supraclavicular lymph node involvement was defined as metastatic evolution. MFS was defined as the interval between surgery and metastatic progression.

OS, DFS, MFS, and LFFS were displayed by using the Kaplan-Meier method. Survival data of the two treatment arms were compared by using a log-rank test stratified by menopausal status. For each group, according to the menopausal status, the two treatment arms were also compared by using the log-rank test. The statistical analysis was performed with BMDP statistical software (Biomedical Computer Programs, Los Angeles, CA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Median follow-up was 74.1 months (range, 0–101 months). Twenty-six patients (4.5%) were excluded from the statistical analyses because of lack of follow-up.

Toxicity
Grade III/IV leucopenia was observed in 34% of perioperative chemotherapy cycles, without any septic complication. No increase in the frequency of local problems was seen in the POC-treated group. Two patients treated in the POC arm experienced acute myeloid leukemia (AML). The first patient was 66 years old when she received 21 mg of mitoxantrone in the POC arm. She was diagnosed with AML (type 2 according to the French-American-British classification) 9 years after this unique injection of mitoxantrone. The second patient was 64 years old when she had 20 mg of mitoxantrone in the POC arm. Metastatic evolution was discovered 2 years after the initial treatment. AML (type 3 according to the French-American-British classification) appeared 8 years after the mitoxantrone injection, at the end of an 11-month cyclophosphamide-based chemotherapy.

Overall Survival
No statistical difference was observed in OS between the two treatment arms for the total cohort or for the subgroups (premenopausal and postmenopausal patients) with a 74.1-month median follow-up (range, 0–101 months; Figs. 1 and 2). In the POC arm, 226 patients were still alive, compared with 216 patients in the control arm. The 7-year OS was 79% in the POC arm, compared with 75% in the control arm. The differences in survival did not reach the .05 level of statistical significance ({chi}2 = .5; P = .21). In the premenopausal group, the 7-year OS was 79% in the POC arm and 77% in the control arm (Table 2). In the postmenopausal group, the 7-year OS was 79% in the POC arm and 74% in the control arm (Table 3).



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  		FIG. 1. Premenopausal patients’ overall survival. POC, postoperative chemotherapy; OS, overall survival.

 

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  		TABLE 2. Treatment and survival of premenopausal patients
 

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  		TABLE 3. Treatment and survival of postmenopausal patients
 


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  		FIG. 2. Postmenopausal patients’ overall survival. POC, postoperative chemotherapy; OS, overall survival.

 
Disease-Free Survival
No statistical difference in DFS was observed between the two treatment arms for the total cohort and the subgroups (Table 3). In the POC arm, metastases or local recurrence occurred in 67 patients, compared with 77 patients in the control arm. The 7-year DFS was 73% in the POC arm, compared with 68% in the control arm. The differences in survival did not reach the .05 level of statistical significance ({chi}2 = 1.61; P = .20). In the premenopausal group, the 7-year DFS was 74% in the POC arm and 66% in the control arm. In the postmenopausal group, the 7-year DFS was 72% in the POC arm and 69% in the control arm.

Local Recurrence
Twenty-seven (10%) patients had local recurrence in the POC arm, compared with 20 (7%) in the control arm. No significant difference between the two treatment arms was observed for the total treated cohort and the subgroups ({chi}2 = .55; P = .5)

Metastasis Evolution
No significant difference in MFS between the two treatment arms was observed. Fifty-one patients had metastatic evolution in the POC arm, compared with 64 patients in the control arm. With a median follow-up of 7 years, MFS was 78% in the POC arm, compared with 73% in the control arm ({chi}2 = 2.67; P = .10). In the premenopausal group, the 7-year MFS was 80% in the POC arm, compared with 74% in the control arm. In the postmenopausal group, the 7-year MFS was 77% in the POC arm, compared with 73% in the control arm.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This randomized multicentric study evaluated whether POC could prolong, first, OS and, second, DFS, LFFS, and MFS. With 277 patients in each arm and taking into account OS as the primary end point, sufficient power was lacking because of a low number of patients included in this trial. With an alpha error of .05, the statistical power of this study was only 39%. To reach a statistical power of 80% with this absolute difference of 5%, 906 patients should have been included in each arm, but this trial was closed prematurely because of lack of inclusion. With a median follow-up of 6.1 years, this study showed no significant advantage of POC on OS and DFS. There was an absolute difference of 5% for the 7-year MFS between the two arms for the total cohort (78% in the POC arm and 73% in the control arm); this difference had no statistical significance.

The prognostic importance of shortening the interval between surgery and subsequent adjuvant chemotherapy has been widely studied. According to the Goldie and Coldman model, the number of resistant tumor cells increases with the delay in beginning chemotherapy after surgery.7,8 Initial clinical studies showed evidence that the interval between surgery and chemotherapy initiation could be of clinical importance. In a small randomized study, Brooks et al.12 demonstrated a beneficial effect of early adjuvant treatment (<=4 weeks) for patients with fewer than four involved axillary nodes. Pronzato et al.13 showed that an interval of <35 days between surgery and chemotherapy was an independent prognostic factor for node-positive patients. A relationship between early initiation of prolonged adjuvant chemotherapy and estrogen receptor expression was recently reported.14 Premenopausal patients with node-positive breast cancer and no estrogen receptor in their tumors had an improved outcome when chemotherapy was initiated within 21 days of surgery.

A meta-analysis of randomized POC trials was conducted with data from 5 clinical trials, 6093 patients, and a median follow-up of 5.3 years.15 No benefit of POC on OS was detectable. DFS and time to local recurrence were significantly prolonged in the POC arm. This effect of POC was the most beneficial in node-negative patients. Two randomized trials with POC were recently reported with a follow-up longer than 10 years. In the European Organization for Research and Treatment of Cancer trial 10854, POC was of benefit in patients who received no additional systemic therapy.16 Patients who received additional systemic therapy did not benefit from one course of POC. The recent analysis of the International Breast Cancer Study Group trial V focused on patients with node-negative disease.17 These patients were randomized to receive POC or no adjuvant treatment. The DFS did not significantly differ between the POC and the no-adjuvant-treatment groups in premenopausal patients. Among postmenopausal patients, improved DFS in the POC group was demonstrated only in patients with hormonal receptor–negative tumors.

In this study and in most reported trials on POC strategy, POC alone was compared with no further adjuvant treatment in low-risk patients, whereas POC effect was studied in addition to conventional adjuvant therapy in high-risk patients in the premenopausal group. In low-risk patients, any demonstrated benefit of POC could have been the result of any chemotherapy versus no chemotherapy, rather an effect of early chemotherapy. In high-risk patients, any benefit of POC is probably lost because of prolonged adjuvant treatment, as was demonstrated in the two last reported trials (European Organization for Research and Treatment of Cancer and International Breast Cancer Study Group trials).16,17 In our study, all postmenopausal patients were treated with tamoxifen. There was an improvement of the 7-year OS (79% vs. 74%), DFS (72% vs. 69%), and MFS (77% vs. 73%) for the POC arm in this postmenopausal group, but it did not reach a statistical difference.

On the basis of the same Goldie and Coldman mathematical model (the longer the delay in starting systemic treatment, the higher the number of resistant tumor cells),7 a preoperative chemotherapy strategy was studied. Four main randomized studies evaluated whether preoperative chemotherapy could prolong DFS and OS compared with the same regimen administered after surgery,18–21 and their results were reported later than the start date of this trial. In these studies, preoperative chemotherapy failed to improve survival benefit beyond that obtained with postoperative chemotherapy, but downstaging of large tumors with preoperative chemotherapy allowed more patients to be treated with lumpectomies.

In conclusion, POC was a safe procedure in this study, with no leukemia related to the mitoxantrone-based adjuvant chemotherapy.22 With a median follow-up of 6.1 years, this study did not demonstrate any benefit of POC, even in the postmenopausal group, in which all patients received the same adjuvant treatment.


   Acknowledgments
 
We thank the patients, physicians, and nurses who participated in this trial.

The acknowledgments are available online at www.annalssurgicaloncology.org.


   Footnotes
 
In this multicentric randomized study, one single injection of mitoxantrone was added to standard adjuvant treatment in the experimental arm at the end of breast tumor excision. With a median follow-up of 6.1 years, this strategy offered no survival benefit.

Received for publication July 16, 2002. Accepted for publication November 27, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Early Breast Cancer Trialists’ collaborative group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998; 352: 930–42.[CrossRef][Medline]
  2. Tancini G, Bonnadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983; 1: 2–10.[Abstract]
  3. 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 adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8: 1483–96.[Abstract]
  4. Rodenhuis S, Richel DJ, Van der Wall E, et al. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 1998; 352: 515–21.[CrossRef][Medline]
  5. Hortobagyi GN, Buzdar AU, Theriault RL, et al. Randomised trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 2000; 92: 225–33.[Abstract/Free Full Text]
  6. Henderson IC, Berry D, Demetri G, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer (abstract). Proc Am Soc Clin Oncol 1998; 17: 390A.
  7. Goldie JH, Coldman AJ. A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979; 63: 1727–33.[Medline]
  8. Goldie JH. Scientific basis for adjuvant and primary (neoadjuvant) chemotherapy. Semin Oncol 1987; 14: 1–7.
  9. Fisher B, Gunduz N, Saffer EA. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Cancer Res 1983; 43: 1488–92.[Abstract/Free Full Text]
  10. Alberts DS, Peng YM, Leigh S, Davis TP, Woodward DL. Disposition of mitoxantrone in cancer patients. Cancer Res 1985; 45: 1879–84.[Abstract/Free Full Text]
  11. Alberts DS, Peng YM, Bowden GT, Dalton WS, Mackel C. Pharmacology of mitoxantrone: mode of action and pharmacokinetics. Invest New Drugs 1985; 3: 101–7.[Medline]
  12. Brooks RJ, Jones SE, Salmon SE, et al. Improved outcome with early treatment in an adjuvant breast cancer program (abstract). Proc Am Soc Clin Oncol 1983; 2: 431.
  13. Pronzato P, Campora E, Amoroso D, et al. Impact of administration-related factors on outcome of adjuvant chemotherapy for primary breast cancer. Am J Clin Oncol 1989; 12: 481–5.[Medline]
  14. Colleoni M, Gelber S, Coates AS, et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol 2001; 19: 4141–9.[Abstract/Free Full Text]
  15. Clahsen PC, Van de Velde CJH, Goldhirsch A, et al. Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer. J Clin Oncol 1997; 15: 2526–35.[Abstract/Free Full Text]
  16. Van der Hage JA, Van de Velde CJH, Julien JP, et al. Improved survival after one course of perioperative chemotherapy in early breast cancer patients: long-term results from the European Organization for Research and Treatment of Cancer Trial 10854. Eur J Cancer 2001; 37: 2184–93.
  17. Colleoni M, Gelber S, Coates AS, et al. Influence of endocrine-related factors on response to perioperative chemotherapy for patients with node-negative breast cancer. J Clin Oncol 2001; 19: 4141–9.
  18. Scholl SM, Pierga JY, Asselain B, et al. Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer 1995; 31A: 1969–75.[CrossRef]
  19. Makris A, Powles TJ, Ashley SE, et al. A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol 1998; 9: 1179–84.[Abstract/Free Full Text]
  20. Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998; 18: 2672–85.
  21. Mauriac L, MacGrogan G, Avril A, et al. Neoadjuvant chemotherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol 1999; 10: 47–52.[Abstract/Free Full Text]
  22. Chaplain G, Milan C, Sgro C, Carli PM, Bonithon-Kopp C. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: a population-based study. J Clin Oncol 2000; 18: 2836–42.[Abstract/Free Full Text]



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