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Cyclophosphamide, Methotrexate, and Fluorouracil Versus Tamoxifen Plus Ovarian Suppression as Adjuvant Treatment of Estrogen Receptor–Positive Pre-/Perimenopausal Breast Cancer Patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 Randomized Trial

By F. Boccardo, A. Rubagotti, D. Amoroso, M. Mesiti, D. Romeo, P. Sismondi, M. Giai, F. Genta, P. Pacini, V. Distante, A. Bolognesi, D. Aldrighetti, A. Farris, for the Italian Breast Cancer Adjuvant Study Group

From the Professorial Unit of Medical Oncology and Biostatistics Unit, University and National Cancer Institute, Genoa; Institute of Oncology, University of Messina, Messina; Department of Gynecologic Oncology, University and Mauriziano Hospital, Torino; Department of Gynecology and Obstetrics, Sant’Anna Gynecologic Hospital, Turin; Department of Radiotherapy, Policlinico Careggi; Department of Surgery, University of Florence, Florence; Department of Oncology–Radiotherapy, San Raffaele Hospital, Milan; and Department of Clinical Oncology, University of Sassari, Sassari, Italy.
Deceased.

Address reprint requests to Francesco Boccardo, MD, Professorial Unit of Medical Oncology, University and National Cancer Institute, Largo R. Benzi 10, 16132 Genoa, Italy; email boccardo{at}hp380.ist.unige.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

 
PURPOSE: To compare the efficacy of chemotherapy versus that of tamoxifen plus ovarian suppression in pre-/perimenopausal estrogen receptor–positive patients with early breast cancer.

PATIENTS AND METHODS: Patients were randomly assigned to receive either six cycles of a standard regimen of cyclophosphamide 100 mg/m² orally days 1 to 14, methotrexate 40 mg/m² intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m² IV days 1 and 8 (CMF), with all drugs restarted on day 29, or 5 years of tamoxifen, 30 mg/d, plus ovarian suppression with surgical oophorectomy, ovarian irradiation, or monthly goserelin 3.6-mg injections. Disease-free survival was the main study end point. Overall survival and toxicity were additional end points.

RESULTS: Between 1989 and 1997, 120 patients were assigned to CMF and 124 to tamoxifen and ovarian suppression (oophorectomy, n = 6; ovarian irradiation, n = 31; and goserelin injections, n = 87). At the time of analysis (median follow-up time, 76 months; range, 9 to 121 months), 82 patients had relapsed and 39 had died. No difference between groups had emerged with respect to either disease-free or overall survival. Treatments were comparable even in respect to age, tumor size, and nodal status, although a nonsignificant trend favored patients with poorly differentiated tumors treated with CMF. Leukopenia, nausea, vomiting, stomatitis, and alopecia were significantly more common in patients treated with CMF. There were few patients who developed benign gynecologic changes in either group, and numbers were comparable.

CONCLUSION: The combination of tamoxifen with ovarian suppression seems to be safe and to yield comparable results relative to standard CMF.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

 
THE GREAT MAJORITY of patients who undergo operation for breast cancer are currently candidates for some form of adjuvant systemic treatment, independent of nodal status.¹ Although chemotherapy is commonly recommended in premenopausal women, the most recent Early Breast Cancer Trialists’ Collaborative Group overview suggests that ovarian ablation or tamoxifen can probably achieve comparable results, especially in patients with estrogen receptor (ER)–positive tumors.^2,3 However, a limited number of trials have directly compared chemotherapy with endocrine therapy in these women, and the results are inconclusive.^4-6

In 1987, we completed the enrollment phase of our first study that compared chemotherapy with tamoxifen or a combination of the two in a group of node-positive women who were selected on the basis of their hormone-receptor status. This trial admitted both pre- and postmenopausal women, and detailed results have been published previously.^7-9 In brief, tamoxifen was found to be significantly superior to chemotherapy, although the difference was greater and statistically significant only in postmenopausal women. The two treatments combined yielded the best results. However, the additional benefit with respect to tamoxifen alone was small and limited to certain subsets. The results of this trial and those of the second Early Breast Cancer Trialists’ Collaborative Group meta-analysis¹⁰ prompted us to design a new comparative trial to confirm the safety and clinical efficacy of endocrine therapy in premenopausal women.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

 
Study Design
This was a randomized, parallel-group, multicenter study that compared the efficacy and tolerability of chemotherapy or the combination of tamoxifen plus ovarian suppression (TMX+OS) as adjuvant treatment of ER-positive pre-/perimenopausal breast cancer patients. The primary objectives were to compare treatments in terms of disease-free survival and overall survival. Secondary objectives included evaluation of the impact of patient age, tumor size, nodal involvement, tumor grade, and method of ovarian suppression on disease-free survival. The trial was also designed to evaluate the effects of treatment on menstrual function and treatment-related side effects.

Patient Population
Women of at least 35 years of age who were still actively menstruating or lacking regular menses for no longer than 1 year were considered eligible for inclusion in the study (women who had previously undergone hysterectomy were eligible if they were younger than 55 years or if they had baseline follicle-stimulating hormone serum levels less than 50 IU/mL). All women without regular menses were arbitrarily considered to be perimenopausal.

To be included in the study, the patient’s primary tumor and axillary nodes had to have been removed, either through radical mastectomy or lumpectomy with axillary dissection. In these patients, it was mandatory to irradiate the residual breast through two opposite fields for a total dose of 50 Gy followed by a boost dose of 10 Gy on the tumor bed. A histologic examination that showed the involvement of one or more nodes or no nodal involvement but a poorly differentiated tumor according to the Bloom and Richardson score was required for inclusion.¹¹ Women with negative nodes and well- or moderately well–differentiated tumors were included if they had tumors with labeling index of 2.8% or greater according to the technique originally described by Silvestrini et al¹² or S-phase values of 8% or greater as detected by flow cytometry.¹³ Only women with ER-positive tumors, defined as tissue that contains 10 femtomoles of cytosolic ER protein (according to the dextran-coated charcoal technique¹⁴ or a positive immunostaining of 10% or greater of tumor cells with specific anti-ER monoclonal antibodies [ER-ICA technique, Abbott Laboratories, Abbott Park, IL]), were eligible for participation in the study. Women with evidence of distant spread as assessed by clinical examination, chest x-ray, bone scan, or liver ultrasonography were not considered suitable for inclusion. Patients had to have an adequate bone marrow reserve (as indicated by a WBC count 4,000 cells/mL and by a platelet count 120,000 cells/mL) and normal liver and renal test results.

Patients with concurrent or prior malignancies, with the exception of skin epitheliomas and/or cervical in situ carcinoma, and those with other comorbid diseases that could jeopardize their compliance with treatment and follow-up visits were excluded from trial entry. Pregnant women and women considering subsequent pregnancies were also excluded.

Treatment Program
Patients were randomized to receive chemotherapy or TMX+OS on a 1:1 basis. Chemotherapy consisted of six cycles of cyclophosphamide 100 mg/m² orally days 1 to 14, methotrexate 40 mg/m² intravenously (IV) days 1 and 8, and fluorouracil 600 mg/m² IV days 1 and 8 (CMF), with all drugs being restarted on day 29. Endocrine therapy consisted of tamoxifen 30 mg/d for a total of 5 years, combined with one of the following means of ovarian suppression: surgical oophorectomy, ovarian irradiation through a 15-cm x 15-cm pelvic port for a total dose of 15 Gy, or medical castration. In the last case, goserelin acetate 3.6-mg injections were administered subcutaneously monthly for 2 years. The choice of suppressive maneuver undertaken in an individual patient was determined by the local investigator or by patient preference. In all women, randomized treatment was usually started within 4 weeks of mastectomy and continued as specified above, unless the patient withdrew her consent or developed adverse reactions that required discontinuation of treatment. When indicated, irradiation of the residual breast was started within 12 weeks of randomization.

Method of Randomization
Treatment assignment was coordinated by a central office at the National Cancer Institute in Genoa and was based on random number tables. Treatment assignments were balanced in blocks of varying sizes, and specific lists of randomization were available for each participating center. It was not possible for clinicians to know which treatment would be assigned until after the patient identifiers had been recorded centrally, and no patient for whom a treatment was assigned was subsequently withdrawn.

Efficacy Assessments
The primary efficacy end points were disease-free survival and overall survival. Patients were considered disease-free until one of the following events occurred: local recurrence of disease, occurrence of regional and distant metastases, recurrent disease in the ipsilateral breast, contralateral breast cancer, a second malignancy, or death of whatever cause. Death was considered in the analysis of overall survival. Times of events were measured from the date of randomization.

Patients were examined clinically every 3 months for the first 3 years, then every 4 months until the fifth year. A clinical checkup every 6 months was planned thereafter for 5 more years. During the first 5 years, blood counts were repeated every 3 months, chest x-ray every 6 months, and a bone scan was performed yearly. Chest tomography scan, bone survey and/or tomography, liver scan and/or ultrasonography, and all other investigations were performed whenever deemed necessary by the patient’s physician. The status of any patient who failed to present for examination was checked by contacting the patient by telephone to confirm that she was still alive.

Tolerability Assessments
Any detrimental change in a patient’s condition after randomization and during any follow-up period, unless related to disease progression, was considered an adverse event. However, for the purpose of this trial, the term toxicity referred specifically to those side effects that were expected to occur after exposure to the trial drugs. The severity of the side effects was scored according to World Health Organization criteria.¹⁵ In addition to monitoring for adverse events, we performed routine laboratory tests at baseline, at selected times during therapy, and at withdrawal. The results of clinical laboratory tests were reviewed for clinically relevant changes. Physical examinations were also performed at baseline, at selected times during therapy, and at withdrawal.

Statistical Analyses
The results of a previous study in premenopausal women showed tamoxifen to be superior to chemotherapy by approximately 10% with respect to disease-free survival.⁷ However, this difference was not significant because of the small number of patients in each subgroup. It was estimated that 300 patients, recruited in 3 years, would be adequate to detect a 10% to 15% difference in the 5-year disease-free survival, in favor of patients assigned to endocrine therapy, assuming an alpha error equal to 0.05 and a power of 80%. This assumption was made considering that the reported 5-year disease-free survival for premenopausal women treated with six cycles of the standard CMF regimen (the same regimen we used in the present study) is approximately 55%¹⁶ and that even better results would be expected with the combination of TMX+OS in ER-positive patients.

Survival and disease-free survival were estimated by the Kaplan-Meier method.¹⁷ The log-rank procedure was used to assess the statistical significance of treatment differences in event distribution.^18,19 The survival of patients who missed regular menses for 3 or more months (who were defined as amenorrheic) was compared with that of patients still regularly menstruating at the end of chemotherapy by use of the method first described by Mantel and Byar.²⁰ According to this method, subjects are compared according to their status (amenorrheic: yes or no) at each time point during the follow-up. All P values were derived from a two-sided test for significance.

Ethical Approval
The trial protocol was approved by the Ethical Committee of the National Tumor Institute in Genoa (which served as the coordinating center) and by the local ethical committees of each participating center where these existed. All women gave their informed consent.

	RESULTS

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Between January 1989 and January 1997, 244 patients from 17 centers (only six centers contributed more than 10 patients) were entered onto the trial, of whom 120 were randomized to CMF and 124 to TMX+OS. Of the 120 patients initially assigned to CMF, one withdrew her consent after randomization and chose to be treated with tamoxifen and goserelin injections. Of the 124 women initially assigned to endocrine therapy, five retracted their consent and chose to be treated with chemotherapy. All of the women who chose a different treatment from that originally assigned were maintained on analysis on the basis of the intention-to-treat principle. The main characteristics of study patients are summarized in Table 1. The treatments groups were well balanced with respect to age, menstrual status at entry, tumor histology, grade, and size, nodal status, and treatment of primary tumor. The dextran-coated charcoal technique was used in the majority (200 of 244: CMF = 99; TMX+OS = 101) of patients to determine ER concentration, and median values were comparable in the two groups. In 44 patients (CMF = 21; TMX+OS = 23), ER status was determined through an immunocytochemical assay, and again, groups were comparable relative to the median percentages of immunostaining (Table 1).

No difference between treatment groups was observed with respect to either overall survival or disease-free survival (Fig 1). Subgroup analyses of disease-free survival also revealed no differences between treatment groups when considering patient age, tumor size, or nodal involvement, which seemed to be strictly correlated with outcome after univariate analysis (Fig 2A to C). Figure 2D shows treatment outcome according to tumor grade. For the purpose of the present analysis, women (designated Gx) with tumor histologies other than specified ductal carcinomas, which are not usually scored according to the Bloom and Richardson grading system, were arbitrarily grouped with those affected by well (G1)– or moderately well (G2)–differentiated ductal carcinomas. Women affected by poorly differentiated (G3) ductal carcinomas were arbitrarily grouped with those affected by ductal tumors for whom grade scoring was missing (GU). In both cases, grouping was suggested by comparable outcome of patients within each group (data not shown). Although there was no difference relative to assigned treatment in the disease-free survival of the group of patients with G1, G2, and Gx tumors, a trend close to significance (P = .08) favored the patients assigned to CMF among the group containing G3 and GU tumors. The results did not change when Gx and GU patients were excluded from the analysis (data not shown). Also, no differences in the treatment outcome were evident after grouping patients according to median ER assay values, either in patients with ER values less than or equal to median values (P = .85) or in patients with ER values superior to the median values (P = .52). All of the above trends in disease-free survival were also observed with respect to overall survival (data not shown).

View larger version (18K): [in this window] [in a new window]   Fig 1. Overall and disease-free survival curves.

View larger version (17K): [in this window] [in a new window]   Fig 2. Disease-free survival curves according to patient age (A), tumor size (B), nodal involvement (C), and tumor grade (D). Abbreviations: T, tumor size; N, nodal involvement; G, tumor grade.

Patient age, tumor size, tumor grade, and nodal status were independent predictors of disease relapse after multivariate analysis. All of these factors also seemed to be independent predictors of the hazard of death, although the predictive value of tumor grade was no longer statistically significant, probably because the number of deaths was small. Multivariate analysis confirmed the lack of any significant difference between treatments with respect to either the risk of recurrence or the risk of death (Table 2). As listed in Table 3, there was no difference between groups in the pattern of recurrence.

All of the women treated with ovarian irradiation became amenorrheic (one patient was already amenorrheic at baseline), usually within 4 weeks of the completion of treatment, and remained so up to the time of analysis. One hundred twelve women were still regularly menstruating at the time they were randomized to CMF. One of these women chose to be treated with tamoxifen and goserelin injections. Three were not able to complete the six scheduled courses of chemotherapy, and information regarding menstrual history at the end of treatment was missing for two patients. Of the remaining 106 women, 72 (68%) became amenorrheic during treatment (usually after the third cycle) and remained so even after chemotherapy discontinuation.

Although drug-induced amenorrhea did not seem to influence disease-free survival (data not shown), there was a significant difference in overall survival in favor of patients who had become amenorrheic during chemotherapy (P = .05) (Fig 3). Patients who became amenorrheic still had a lower risk of death after multivariate analysis was performed and adjusted by age (relative risk = 0.41; P = .08).

View larger version (10K): [in this window] [in a new window]   Fig 3. Overall survival curves of patients treated with CMF according to chemotherapy-induced amenorrhea.

View larger version (28K): [in this window] [in a new window]   Fig 4. Main differences in side effects.

View larger version (24K): [in this window] [in a new window]   Fig 5. Main differences in gynecologic effects. Abbreviation: pts, patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

The trial reported here delivered six cycles of the standard CMF regimen. The median relative dose-intensity (ie, the ratio of the median dose actually given to that initially scheduled) was sufficient for all three drugs in the CMF regimen (median dose-intensities for cyclophosphamide, methotrexate, and fluorouracil were 0.83, 0.85, and 0.84, respectively). Use of the standard CMF regimen in this trial may explain why we failed to confirm the trend in favor of endocrine therapy, which we showed in an earlier trial in 1990, in which we used six 3-week courses of IV CMF followed by four 3-week courses of IV doxorubicin monotherapy as the control arm.⁷

The comparability in efficacy of endocrine therapy to chemotherapy in premenopausal women with ER-positive tumors is also supported by the data recently presented by an Austrian Collaborative Group at the 1999 annual meeting of the American Society of Clinical Oncology. Their study tested the efficacy of tamoxifen in combination with goserelin compared with chemotherapy in a large patient population (n = 1,045).²² Although still preliminary, the results of that study also confirm that the combination of TMX+OS with goserelin acetate injections is at least comparable to six cycles of the standard CMF regimen and indicate a significant benefit of the endocrine therapy combination over chemotherapy.

In our trial, there was no difference between treatments with respect to the main prognostic variables. In particular, patients’ age did not seem to influence treatment efficacy, whatever the assigned treatment, which confirms that younger patients should not be omitted from endocrine therapy if their tumors express an adequate amount of steroidal receptors. However, there was a trend in favor of chemotherapy among less differentiated tumors. This finding suggests that endocrine therapy alone might not be adequate for those women.

The trial presented here was originally designed to recruit 300 patients in 3 years. This number was thought to be sufficient to demonstrate prospectively a disease-free survival trend between 10% and 15% in favor of the patients treated with endocrine therapy. Unfortunately, recruitment lasted 8 years, and for this reason, it was halted when only 244 patients had been enrolled. Therefore, this trial is still underpowered, particularly with respect to survival, despite a relatively long median follow-up time. However, we do not expect that the results will change in direction when more events and deaths have occurred. Although this trial is small and its results are premature and, as such, should be regarded with caution, it seems to provide some additional information in a field that is becoming more and more interesting to clinicians.

The trial was not designed to evaluate the individual contribution of ovarian suppression and tamoxifen treatment to the efficacy of the endocrine regimen used. However, the indirect comparison of present results with those previously obtained by our group with tamoxifen alone,⁷ used at the same daily dose for the same duration of time (data not shown), allows us to speculate that some additional benefit might be achieved by combining tamoxifen with some form of ovarian suppression. In addition, the gynecologic changes induced by endocrine therapy in the present trial were few and were comparable to those developed by patients treated with chemotherapy. On the contrary, the incidence of gynecologic changes in our previous trial⁸ was significantly higher in patients treated with tamoxifen alone.

The possible superiority of the combination of tamoxifen with an LH-RH analog over tamoxifen alone also seems to be suggested by a recent trial in patients with disseminated disease²³; this would not be a surprising finding, considering the mechanism of action of antiestrogens. This finding may soon be confirmed by a recently completed large randomized trial by four international trial groups that included more than 2,600 patients who had previously undergone surgery, some of whom then received adjuvant chemotherapy.²⁴ The patients were randomized to receive no further therapy, tamoxifen alone, goserelin injections alone, or the combination of tamoxifen plus goserelin for 2 years. The trial was a 2 x 2 factorial study, and the preliminary analysis was restricted to the main effect of goserelin.²⁴ This trial and an intergroup trial completed in the United States²⁵ may also help to confirm how much the addition of tamoxifen to medical castration can enhance the results achieved by castration alone.

The preliminary results of the intergroup trial, which compared treatment with either goserelin alone or goserelin in combination with tamoxifen in a group of premenopausal women previously treated with six cycles of cyclophosphamide, doxorubicin, and fluorouracil, seem to support the use of combination therapy, particularly in those women with low estradiol levels at the end of chemotherapy.²⁵ However, the benefit of goserelin injections in these women could well be blunted by the amenorrhea induced by chemotherapy. Nonetheless, the superiority of combined treatment over castration alone would probably be expected, as demonstrated by the meta-analysis of four trials that compared the combination of tamoxifen and an LH-RH analog with the same LH-RH analog alone in patients with metastatic disease.²⁶ The combination was shown to be superior in terms of response rate and progression-free and overall survival.²⁶

Therefore, although results are still inconclusive in this regard, it seems that the combination of tamoxifen with some form of ovarian ablation is probably the best option for premenopausal women who are candidates for adjuvant endocrine therapy. Indeed, this combination is expected to be more effective than either modality alone, without implying any additional toxicity. In addition, the suppression of ovarian function could help in avoiding the gynecologic changes that otherwise would be caused by the hyperstimulatory effects induced by tamoxifen monotherapy.²⁷ Conversely, the weak estrogenic effects of tamoxifen could help in overcoming the harmful effects on bone density and blood lipids that are commonly induced by the suppression of ovarian function.²⁸ Because a significant decrease in contralateral breast primaries has also been demonstrated in women treated with goserelin,²⁴ a synergistic effect with tamoxifen in this regard can be anticipated.

In the present trial, patients who became amenorrheic during chemotherapy seemed to live significantly longer than those who maintained a regular menstrual function, which thus supports the view that chemotherapy in younger women acts at least in part through the endocrine effects it induces.^29,30 However, there was no difference in the disease-free survival or pattern of failure of patients relative to their menstrual status at the end of chemotherapy (data not shown). According to the original trial design, more patients in the CMF arm than in the TMX+OS arm were treated with endocrine therapy at the time of disease recurrence (49% v 19%, respectively). This allows us to speculate that the longer survival demonstrated in patients with drug-induced amenorrhea might be related to the response to treatment on recurrence rather than to the clinical activity of adjuvant chemotherapy itself. Irrespective of the mechanism involved, our trial confirms that patients who achieve drug-induced amenorrhea during adjuvant chemotherapy tend to live longer. Whether the suppression of ovarian function could be of help to patients who are not castrated by chemotherapy is as yet unknown and should be addressed in a future trial. However, preliminary results of the American intergroup trial have shown that goserelin therapy is more effective in patients who maintain premenopausal estradiol levels at the end of chemotherapy.²⁵

The optimal duration of treatment with goserelin injections also remains unsolved by our trial. However, some indications in this respect do emerge from the analysis of the menstrual history of patients. The results showed that 2 years of treatment with goserelin were sufficient to induce a persistent amenorrhea in the majority of the patients and that only a minority required 1 or more additional years of treatment. This might have important implications on cost saving, although it is still questionable whether the achievement of a persistent amenorrhea is preferable to the temporary suppression of ovarian function, especially in younger women. Unfortunately, the number of patients who resumed menstruation at the end of treatment with goserelin and who were willing to maintain a regular function until the occurrence of natural menopause was too small to allow any analysis in this respect. Moreover, one cannot rule out that the percentage of patients who resumed menstruation at the end of treatment with goserelin could be higher in the absence of concurrent medication with tamoxifen. Again, although more information in this regard will emerge from other trials on ovarian ablation, there is no doubt that this issue should be investigated further.

With respect to assessing whether medical castration is comparable to other forms of ovarian suppression in the adjuvant setting, we found our trial to be inadequate, although so far no difference has emerged in the clinical outcome of our patients regarding the various types of ovarian suppression used. In principle, this should be expected on the basis of the results of comparative trials in metastatic disease.^31,32 However, this may not be the case, particularly in younger women who have a higher probability of resuming menstruation, even after treatment with LH-RH analogs for long periods of time. The cost of prolonged treatment with LH-RH analogs and the present availability of videolaparoscopic techniques hamper the importance of comparative trials in this respect.

Finally, this trial confirmed our previous findings that endocrine therapy induces significantly fewer acute side effects than chemotherapy. Unfortunately, it was not possible to investigate the perception of treatment-related effects by the patients and to evaluate the impact of side effects on patients’ quality of life, particularly on specific aspects such as sexual functioning or fertility, which might be relevant, especially to younger women.

In conclusion, our trial suggests that the combination of TMX+OS is an effective, well-tolerated treatment compared with standard treatment with CMF, although this study cannot rule out the existence of a small-to-moderate benefit for one treatment over the other. This combination endocrine regimen may therefore represent an acceptable alternative adjuvant therapy for premenopausal ER-positive patients with breast cancer. Whether and to what extent the use of both chemotherapy and endocrine manipulations might be of more benefit for such women, especially those at lower risk of recurrence, and in this case, which form of endocrine treatment should be preferred, still represent a matter for future trials.

	APPENDIX Participating Members of the Italian Breast Cancer Adjuvant Study Group

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

 
S. Iacobelli and L. Irtelli (Università degli Studi, Chieti); D. Donati and P. Malacarne (Arcispedale S. Anna, Ferrara); V. Distante, S. Marzano, and P. Pacini (Policlinico Careggi, Firenze); D. Amoroso and F. Boccardo (Università degli Studi e Istituto Nazionale per la Ricerca sul Cancro); C. Caroti and L. Gallo (E.O. Ospedali Galliera, Genova); S. Banducci (Ospedale Civile, Merate); M. Mesiti and D. Romeo (Policlinico Universitario G. Martino, Messina); D. Aldrighetti, A. Bolognesi, and E. Villa (Istituto Scientifico S. Raffaele, Milano); B. Agostara and M. Cusimano (Ospedale Oncologico M. Ascoli, Palermo); M. Sassi (Ospedale Spallanzani, Reggio Emilia); A. Beni and A. Scoppola (Ospedale S. Giacomo, Roma); C. Gatti and D. Guarneri (Ospedale Civile, Sanremo); G. Burani and D. Schieppati (Ospedale Generale Provinciale, Saronno); M.G. Alicicco and A. Farris (Università degli Studi, Sassari); L. Galletto (Ospedale Generale E. Agnelli, Pinerolo); M. Giai and P. Sismondi (Università di Torino, Ospedale Mauriziano); F. Genta (Ospedale S. Anna, Torino); and M. Mansutti, M. Muggia, and G. Mustacchi (Centro Oncologico M. Lovenati, Trieste, Italy).

	ACKNOWLEDGMENTS

 
Supported in part by grants no. 92.02298, 93.022275, 94.01242, 95.00473, and 96.00670 PF 39 from the Italian National Research Council, Clinical Application of Oncological Research Project.

We remember the late Paolo Pacini, who contributed so much to the conceptualization and realization of this study, and thank Alessia Fossati for secretarial assistance and Grazia De Stefano and Simona Barozzi for data management.

	NOTES

 
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16–19, 1998.

See Appendix for a complete list of study participants.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Participating Members... REFERENCES

 
1. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlight: International Consensus Panel on the treatment of primary breast cancer. J Natl Cancer Inst 90:1601-1608, 1998[Free Full Text]

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15. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline]

16. Bonadonna G, Valagussa P, Rossi A, et al: Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 5:92-115, 1985

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

18. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: I. Introduction and design. Br J Cancer 34:585-612, 1976[Medline]

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Submitted September 20, 1999; accepted March 10, 2000.

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