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Preoperative Chemotherapy in Primary Operable Breast Cancer: Results From the European Organization for Research and Treatment of Cancer Trial 10902

From the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium; Leiden University Medical Center, Department of Surgery, Leiden, the Netherlands; Centre Henri Becquerel, Department of Surgery, Rouen; and Centre René Huguenin, Department of Medical Oncology, St Cloud, France.

Address reprint requests to C.J.H. van de Velde, MD, PhD, Department of Surgery, D6-43, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; email: velde{at}lumc.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy.

PATIENTS AND METHODS: Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR).

RESULTS: At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P = .38), PFS (hazards ratio, 1.15; P = .27), and time to LRR (hazards ratio, 1.13; P = .61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy.

CONCLUSION: The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
TRIALS THAT STUDIED the role of adjuvant chemotherapy in the management of primary operable breast cancer conducted during the 1970s and 1980s showed significant improvements in progression-free and overall survival.¹ Conventionally, adjuvant systemic therapy is administered after local treatment in early breast cancer.² However, since the introduction of conservative treatment modalities, there has been considerable interest in the efficacy of preoperative chemotherapy to decrease tumor size. One of the potential benefits of preoperative chemotherapy is the more frequent usage of breast-conserving treatment modalities. Moreover, it has been hypothesized that preoperative chemotherapy has a more powerful effect on survival compared with postoperative chemotherapy. The rationale for these hypotheses comes from several biologic premises. Findings in various animal models^3-5 showed an increase of labeling index in residual tumor cells as well as an increase of circulating growth-stimulating factors after the removal of the primary tumor in murine models. In these models, adjuvant systemic therapy administered before the removal of the primary tumor impaired this increase in cell-kinetic mechanisms.^6,7

In addition, Goldie and Coldman⁸ developed a hypothesis, which implies that as a tumor cell population increases, an ever-expanding number of drug-resistant phenotypic variants arise as a result of spontaneous somatic mutations. Although the merits of preoperative chemotherapy in the treatment of locally advanced breast cancer are well established, the feasibility of preoperative chemotherapy in early breast cancer is still a matter of discussion.

The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group started a randomized trial in 1991 to investigate the value of preoperative chemotherapy in early breast cancer, EORTC trial 10902.

The primary objective of this trial was to test whether preoperative chemotherapy yields better results in terms of progression-free and overall survival than the same chemotherapeutic regimen administered postoperatively. Another objective was to study whether preoperative chemotherapy would permit more breast-conserving therapies by reducing primary tumor size. A third objective was to determine whether preoperative chemotherapy resulted in better locoregional control, especially after breast-conserving surgery. An additional objective of the study was to evaluate the response of the primary tumor to preoperative chemotherapy and to correlate this response to disease-free and overall survival. This report compares the outcome of 698 women with early breast cancer randomized to receive either preoperative chemotherapy or the same regimen administered postoperatively.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
Between April 1991 and May 1999, 698 women were enrolled onto the EORTC study 10902 in 17 institutions in 14 countries. Patients had primary operable breast cancer (T1c, T2, T3, T4b, N0 to 1, and M0). Breast cancer was preferably diagnosed by core needle biopsy (CNB) or by fine-needle aspiration cytology as part of triple diagnosis. For the diagnosis of T1c tumors, CNB was mandatory. CNB was also mandatory in case of doubt or suspicion of carcinoma-in-situ after fine-needle aspiration. Exclusion criteria consisted of age older than 70 years; bilateral breast cancer; previous treatment for breast cancer; presence of distant metastases; pregnancy or lactation at the time of diagnosis; previous or current other malignancies except adequately treated basal or squamous carcinoma of the skin or cervix uteri; World Health Organization performance status more than 2; active cardiac disease; and severe hematologic, renal, or hepatic abnormalities. All patients gave informed consent before entering onto the trial. Randomization was performed centrally by the EORTC Data Center. At randomization, patients were stratified for institution, age ( 50 years or > 50 years), clinical tumor size, clinical nodal status (N- or N+), and planned type of surgery (mastectomy or breast-conserving surgery).

Patients 50 years old or younger were considered to be premenopausal, and those older were deemed postmenopausal. Tumor estrogen receptor (ER) status was estimated by the ligand binding assay technique or by the immunohistochemistry technique. For the ligand-binding assay, a concentration 10 fmol ER/mg protein was considered positive, and a value lower than 10 fmol ER/mg protein was considered negative. If the ER status was measured by immunohistochemistry, positivity or negativity was determined according to the scoring systems used by the individual institutions. There was no standardization of the assay, so general cutoff points cannot be given for immunohistochemistry (EORTC Manual for Clinical Research in Breast Cancer).⁹

Treatment
Treatment consisted of surgery in combination with either preoperative or postoperative chemotherapy. Surgery consisted of either a modified radical mastectomy or breast-conserving surgery (wide local excision of the tumor or quadrantectomy plus axillary dissection and adjuvant radiotherapy). Before treatment, investigators had to report which type of surgery was indicated at the time of diagnosis. Subsequently, the planned type of surgery and performed type of surgery were compared to investigate whether preoperative chemotherapy induced a higher rate of breast-conserving surgery. Guidelines and selection criteria that concerned surgery were given in the study protocol, but patient selection for breast-conserving therapy was ultimately left up to the treating surgeon.

Chemotherapy consisted of four cycles of preoperative fluorouracil 600 mg/m², epirubicin 60 mg/m², and cyclophosphamide 600 mg/m² (FEC) administered intravenously, at intervals of every 3 weeks. In the preoperative chemotherapy group, surgical therapy followed within 4 weeks of the fourth course of chemotherapy. In the postoperative chemotherapy group, the first cycle was administered within 36 hours after surgery, as has been advocated before.^10,11 Administration of FEC was delayed for a maximum of 2 weeks as a result of either hematologic, hepatic and renal, or gastrointestinal toxicities on day 1 of any cycle. Dose modifications were assessed according to the guidelines stipulated by the EORTC Breast Cancer Cooperative Group.⁹ Adjuvant radiotherapy was administered after surgery in the preoperative chemotherapy group. In the postoperative chemotherapy group, it was decided to administer irradiation after the completion of chemotherapy. This way, radiotherapy did not interfere with the chemotherapeutic regimen, in which the first course was to be administered preoperatively. All patients who underwent breast-conserving therapy received irradiation of the whole breast. Other recommended guidelines for radiotherapy, as stipulated in the protocol, consisted of chest wall and parasternal irradiation in patients with an initial tumor of 5 cm or more in its largest dimension and irradiation of the infraclavicular and supraclavicular fossa in patients with a positive infraclavicular node after lymph node dissection. Radiotherapy was indicated in all cases where surgery was not considered to be radical. Specified dose at the target volume was 50 gray, administered in four or five weekly fractions in 5 weeks. For the parasternal/infrasupraclavicular fossa and chest wall, at least 45 Gy had to be administered in four or five weekly fractions in 4.5 to 5 weeks. However, some hospitals used their own radiation protocol. Patients 50 years of age also received tamoxifen 20 mg daily for at least 2 years, regardless of their ER and nodal status.

End Points
The primary end point of this study was overall survival. Survival time was defined as the time between randomization and death from any cause. Secondary end points were progression-free survival and locoregional recurrence. Progression-free survival was defined as the time between the date of randomization and the date of disease relapse (including distant metastases, locoregional recurrences, secondary primary tumors, and contralateral breast cancers) or death, whichever came first. Locoregional recurrence was defined as a recurrence in the ipsilateral breast or in the ipsilateral regional lymph nodes, including supraclavicular nodes. Time to locoregional recurrence was defined as the time between date of randomization and locoregional recurrence, regardless of whether the locoregional recurrence was the first event or not.

It is well known that the administration of adjuvant chemotherapy is a considerable burden to the patient in terms of quality of life. However, not many data are available that concern the effects of preoperative chemotherapy on quality of life compared with conventional postoperative chemotherapy. Therefore, a quality-of-life study program was set up that was, however, unsuccessful as a result of poor compliance.

Tumor Response
Clinical tumor size and nodal status were estimated before the start of chemotherapy as well as at the time of surgery by both palpation and mammography. The product of the two greatest perpendicular diameters was used to compare tumor size before and after chemotherapy, as defined by the International Union Against Cancer criteria.¹² A clinical complete response (cCR) was considered a complete disappearance of all clinically detectable malignant disease by palpation as well as mammography. Tumor specimens from patients who underwent preoperative chemotherapy were examined for the presence of microscopic residual tumor to correlate the clinical absence of tumor with pathologic evaluation. If no signs of residual malignant cells at the primary site and axillary lymph nodes were seen with histologic examination, this was scored as a pathologic complete response (pCR). Clinical tumor response to preoperative chemotherapy was assessed at the time of surgery. If the tumor had become undetectable before completion of the four cycles of preoperative chemotherapy, chemotherapy was continued as outlined in the protocol. Clinical partial response was defined as 50% decrease in total tumor size after four cycles of preoperative chemotherapy at the time of surgery. An increase of 25% in tumor size after a minimum of two courses of preoperative chemotherapy was considered to be progressive disease (PD). In patients with clinically negative nodes at randomization, the development of palpable nodes during the administration of preoperative chemotherapy was considered evidence of PD. After a diagnosis of PD, patients immediately underwent surgery before completing the preoperative chemotherapy schedule. If the PD was not primary operable, the patient was declared to have experienced treatment failure, and subsequent treatment was left to the discretion of the responsible clinician. If patients did not meet one of the above-mentioned criteria after four cycles of chemotherapy, they were classified as having stable disease.

Follow-Up
All patients were followed up until death. In the first 2 years after surgery, patients were seen at least every 6 months and, in the following 3 years, every 6 to 12 months. Minimal requirements for follow-up were physical examination, locoregional evaluation, and performance scale assessment, with mammography, chest x-ray, and alkaline phosphatase and lactate dehydrogenase measurements every year postoperatively. One institute used CA 15-3 measurements instead of lactate dehydrogenase.

Statistical Aspects
All analyses were based on the intent-to-treat principle. The two treatment arms were compared by the log-rank test for the time-to-event end points. The differences between the two treatment groups were graphically depicted by Kaplan and Meier curves. As it seemed from literature studies that both nodal and menopausal status could have a substantial impact on the treatment comparison, it was decided before the start of the analysis to perform subgroup analyses for these two variables. The nominal significance level for each subgroup analysis was adjusted by the Bonferroni method. Thus, in the cases of the four subgroup analyses for nodal and menopausal status, the nominal significance level for each of the subgroup analyses was set at .0125 (.05 divided by 4). The trial was designed to detect a 10% survival difference at 5 years (from 75% to 85%) with 80% power, for which 102 events were needed.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
Of the 698 patients, 350 patients were randomized to receive preoperative chemotherapy, and 348 patients were randomized to the postoperative chemotherapy group (first cycle of FEC administered within 36 hours after surgery). Tumor and patient characteristics were well distributed between the two treatment arms (Table1), except for breast-conserving surgery rates, which were, as expected, higher in the preoperative chemotherapy group. Twenty-one patients were considered ineligible because of inadequate staging (n = 17), a World Health Organization performance status more than 2 (n = 3), or age greater than 70 years (n = 1).

Unfortunately, for approximately 30% of the patients, information that concerned ER status was missing. This was partly a result of the fact that this information was not mandatory and that tamoxifen was given irrespective of ER status in patients 50 years of age.

Surgery
Four hundred sixty-five patients underwent modified radical mastectomy, and 199 patients underwent breast-conserving surgery. Nineteen patients who underwent lumpectomy did not receive adjuvant radiotherapy. Thirty-eight percent of the patients on the study arm who were treated with mastectomy received radiotherapy, and 43% of the patients on the control arm who were treated with mastectomy received radiotherapy.

In the preoperative chemotherapy group, 20 patients did not receive the surgical treatment stipulated by the study protocol, versus 14 patients in the postoperative group. At the time of axillary clearance, at least six nodes had to be obtained for pathologic examination, and in 77% of the patients entered onto the study, 10 or more axillary nodes were examined. Surgical complications consisted of 16 grade 1/2 wound infections in the preoperative chemotherapy group, versus 25 grade 1/2 wound infections and two grade 3/4 wound infections in the postoperative chemotherapy group that required antibiotic treatment. Anticoagulant prophylaxis was administered on the basis of experience from previous trials that studied the efficacy of perioperative chemotherapy.^13,14 No severe postsurgical thromboembolic complications were observed in the postoperative chemotherapy group.

Overall Survival, Progression-Free Survival, and Locoregional Recurrence
Of the 698 randomized patients, 232 experienced relapse, from which 124 patients died. Furthermore, 10 patients died without experiencing a relapse. No significant differences between the two treatment arms were observed for progression-free and overall survival. Overall survival after 4 years was 82% in the preoperative group and 84% in the postoperative group (hazards ratio [HR], 1.16; 95% confidence interval [CI], 0.83 to 1.63; P = .38) (Fig 1). Progression-free survival rates after 4 years for the preoperative and postoperative groups were 65% and 70%, respectively (HR, 1.15; 95% CI, 0.89 to 1.48; P = .27) (Fig 2). To date, 69 patients have experienced a locoregional recurrence, 36 in the preoperative chemotherapy group and 33 in the postoperative chemotherapy group. Time to locoregional recurrence was not significantly different between the two treatment arms (HR, 1.13; 95% CI, 0.70 to 1.81; P = .61) (Fig 3). Sixty-two of these patients experienced a locoregional recurrence as first event.

View larger version (9K): [in this window] [in a new window]   Fig 1. Overall survival.

View larger version (10K): [in this window] [in a new window]   Fig 2. Time to disease progression or death.

View larger version (9K): [in this window] [in a new window]   Fig 3. Locoregional recurrence rate.

Tumor Response
Table 3 shows the clinical tumor response after chemotherapy. An overall objective response was observed in 49% of the patients randomized to the preoperative chemotherapy group. Twenty-three patients (6.6%) experienced a cCR and progression of disease was seen in five patients (1.4%). Of the twenty-three patients who experienced a cCR, only six patients did not have any invasive tumor left. Apart from the six patients who experienced a pCR in accordance with the clinical assessment, seven other patients were microscopically free of tumor at the primary site and axilla after four cycles of preoperative chemotherapy but were not classified as having a cCR. The thirteen patients without evidence of residual malignancy do have a significant advantage in terms of overall survival (HR, 0.86; 95% CI, 0.77 to 0.96; P = .008) compared with patients who still had residual tumor cells left after preoperative chemotherapy. Next, we tested the prognostic significance of clinical objective tumor response in terms of survival in a multivariate model together with clinical tumor size, clinical nodal status, and ER status. Clinical objective response, however, was not a significant prognostic factor.

View larger version (9K): [in this window] [in a new window]   Fig 4. Survival in planned versus downstaged breast-conserving therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
In 1986, the Breast Cancer Cooperative Group started a trial to study the effectiveness of one course of fluorouracil, doxorubicin, and cyclophosphamide administered perioperatively within 36 hours after surgery in early breast cancer patients. This regimen resulted in significantly improved locoregional control and disease-free survival rates.¹⁰ Therefore, the logical next step was to start a trial that would study the qualities of preoperative chemotherapy.

EORTC trial 10902 was designed to address whether preoperative chemotherapy yields the same or better results in terms of overall and disease-free survival compared with the same type of chemotherapy administered postoperatively and whether preoperative chemotherapy allows more breast-conserving therapies. A third objective was to assess the value of tumor response to preoperative chemotherapy as a predictor of disease outcome.

Several randomized, clinical, phase III trials that compared postoperative adjuvant chemotherapy and preoperative chemotherapy were performed in the past two and a half decades. These trials have been listed in Tables 10 to 12. A comparison of the results of these trials is difficult because of the fact that the study protocols differ substantially in design and chemotherapeutic regimen. However, to date none of these trials, including EORTC trial 10902, has been able to show a positive effect of preoperative chemotherapy in terms of progression-free or overall survival. Two trials, conducted by Mauriac and Scholl^15-20 initially reported a significant positive effect of preoperative chemotherapy on progression-free and overall survival, but after a longer period of follow-up, the significant benefit of preoperative chemotherapy on survival had disappeared. In addition, in the Mauriac trial, locoregional control was worse in the preoperative arm compared with the standard arm.

In the B18 trial, a clinical overall response was seen in 79%, whereas 35% of the preoperative chemotherapy group experienced a cCR. A pCR, however, occurred in only 9% of these patients. Disease-free, relapse-free, distant disease-free, and overall survival were better in women whose tumors showed a pCR compared with those patients with residual disease. This is in accordance with the results from the EORTC 10902 study and the experience of other investigators.^19,26

In the EORTC trial, tumor response to preoperative chemotherapy was low in comparison with the response rates described in the literature.^15-22,26-36 Clinical overall tumor responses after four to six cycles of preoperative polychemotherapy range approximately between 65% and 90%. The cCR rates vary between 10% and 30%. However, the pCR rate usually is much lower, resulting in a poor correlation. Controversially, in the EORTC 10902, trial 49% of the patients who received preoperative chemotherapy experienced a clinical overall response as assessed by palpation and 7% of the study-population had a cCR. The remarkable discrepancy between our results and those of other authors is difficult to explain. The vast majority of patients received the chemotherapeutic dose stipulated by the protocol, ie, four courses of FEC containing epirubicin 60 mg/m², which means that the regimen was well tolerated. Now, one could argue that total cumulative doses of epirubicin lower than 300 mg/m² are suboptimal. However, higher doses of epirubicin in a combined chemotherapy schedule have so far not been demonstrated to be more effective in terms of overall or relapse-free survival in primary operable breast cancer.^37-40 Several studies^23-25 have addressed this discrepancy between cCR and pCR and compared clinical measurements with mammographic and ultrasonographic measurements. These studies generally demonstrate an overestimation of tumor response by palpation alone. In the majority of clinical trials that study the effects of preoperative chemotherapy, clinical measurements are commonly used to assess the amount of tumor response, as described by the guidelines of the International Union Against Cancer. In EORTC trial 10902, tumor response was measured by using the data of both palpation and mammographic tumor measurements. Unfortunately, we were not able to demonstrate this confounding error induced by using palpation measurements alone because of a poor registration of measurements. Conclusively, mammographic measurements should be implemented in the assessment of tumor response on a standard basis to give an objective idea of the degree of tumor response. Moreover, in the case of a cCR, it may be helpful to perform ultrasonography in selecting those patients who do not require surgery after preoperative chemotherapy and in localizing abnormalities in those who do.^41,42

In locally advanced and primary inoperable breast cancer, the purpose of preoperative treatment is to enable adequate local treatment, favorably leading to breast conservation. In patients with stage I or II breast cancer who are candidates for breast-conserving therapy irrespective of preoperative chemotherapy, the goal of preoperative chemotherapy is unclear. Some investigators argue that tumor response to preoperative chemotherapy is an independent predictor of treatment outcome. Therefore, it could be of benefit for breast cancer patients to adjust systemic adjuvant treatment at an early stage if tumor response to preoperative chemotherapy is inadequate.

Controversially, preoperative chemotherapy might lead to overtreatment of breast cancer patients. This can be explained by the fact that patients receive systemic treatment regardless of histologic staging of the tumor and axillary nodal status.

The breast-conserving therapy rate was higher in the preoperative chemotherapy group in comparison with the postoperative chemotherapy group. This finding, together with the equal locoregional control rate in both groups, advocates the advantageous role of primary chemotherapy in breast-conserving management. On the other hand, 14% of patients who initially were supposed to undergo breast-conserving surgery received a modified radical mastectomy. This suggests that a delay in surgical treatment as a result of the use of primary chemotherapy can result in a more aggressive type of surgical management of breast cancer in a considerable number of patients. In addition, a hypothesis-generating analysis that compared survival rates of patients who underwent breast-conserving surgery as a result of downstaging of the tumor with patients who underwent breast-conserving surgery as initially was planned showed a favorable trend for the latter group of patients. Therefore, it can be hypothesized that patient prognosis is determined by the initial tumor stage and not tumor stage after preoperative chemotherapy.

The idea that changes in surgical management after preoperative chemotherapy are solely because of either increase or decrease of tumor volume is arguable. Because preoperative chemotherapeutic regimens take approximately 3 months to complete, patient or doctor surgical preferences may be altered for subjective reasons during this period of time.

The use of preoperative or primary chemotherapy was introduced approximately three decades ago in locally advanced breast cancer. Since then, its role in the management of locally advanced breast cancer has been firmly established. However, the advantages are not clear in early breast cancer. Despite the fact that preoperative chemotherapy may permit more breast-conserving treatment modalities, there may be problems, for instance in achieving adequate locoregional control as a result of the difficulty of assessing tumor margins after the administration of preoperative chemotherapy.

Moreover, it has become clear that the supposed survival benefits of preoperative chemotherapy based on preclinical data are not exerted in primary operable breast cancer patients. Although benefits of preoperative chemotherapy in early breast cancer patients are less clear compared with the locally advanced breast cancer patients, the potential to enhance breast-conserving therapy makes it an attractive treatment modality. Postmenopausal early breast cancer patients especially might benefit from preoperative chemotherapy, although preoperative chemotherapy may be less beneficial for young breast cancer patients who are at a higher risk of recurrence of disease, especially after primary conservative therapy. Although this trial did not show such differences (data not shown), other investigators have found young age to be a strong independent prognostic factor for recurrence after breast-conserving therapy.^11,43,44

Moreover, the possibility of studying the effects of chemotherapy on well-established tumor characteristics as well as experimental tumor markers makes chemotherapy in the preoperative setting highly attractive for translational research purposes.⁴⁵ The comparison of core needle biopsies with the same tumor after systemic treatment is a worthwhile reason to continue preoperative chemotherapy trials in early breast cancer.

Unfortunately, not many data concerning quality-of-life issues in relation to preoperative chemotherapy are available in the literature. Quality-of-life studies, however, have been performed to investigate the effects of breast-conserving therapy versus mastectomy and fail to show a clear benefit for the conservative treatment modality, except for a slightly less impaired body image.^46-49 Considering the fact that preoperative as well as postoperative chemotherapy seems to yield similar results in terms of prognosis, this might be a conclusive factor on the decision of which chemotherapeutic strategy should be chosen. Therefore, the role of preoperative chemotherapy should be studied in future trials that focus on translational research, equivalence, quality of life, and local control, rather than trying to detect overall and progression-free survival differences.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Federal Republic of Yugoslavia, C.J.H. van de Velde, M.A. Nooy, Hopital Cantonal Universitaire de Country, Principal Investigator, Institution France, J.-P. Julien, Centre Henri Becquerel, Rouen M. Tubiana-Hulin, F. Bachelot, Centre René Huguenin, St Cloud, T. Delozier, Centre Regional François Baclesse, Caen Netherlands, C.J.H. van de Velde, M.A. Nooy, Leiden University Medical Center, Leiden Switzerland, H. Bonnefoi, Hopital Cantonal Universitaire de Geneve, Geneva Republic of South Africa, J.A. van Zyl, A.G. Muller, University of Stellenbosch, Tygerberg Hospital, Tygerberg Egypt, S. Omar, National Cancer Institute, Cairo Poland, J. Jassem, J. Jaskiewicz, Medical University of Gdansk, Gdansk Spain, J.J. Grau, Hospital Clinico y Provencial de Barcelona, Barcelona Federal Republic of Yugoslavia, D. Vukotic, Institute of Oncology and Radiology, Belgrade Slovenia, T. Cufer, M. Snoj, The Institute of Oncology, Ljubljana Russia, O. Ivanova, V.F. Semiglazov, Petrov Research Institute of Oncology, St Petersburg Greece, I. Varthalitis, Evangelismos Hospital, Athens Saudi Arabia, A. Ezzat, King Faisal Spec. Hospital and Research Center, Riyadh

	ACKNOWLEDGMENTS

 
Supported by an educational grant from Pharmacia & Upjohn, Peapack, NJ, and a personal grant from the Dutch Cancer Society NKB/KWF, Amsterdam, the Netherlands.

We thank Marc J. van de Vijver, MD, PhD, and Pieter C. Clahsen, MD, PhD, for thoroughly reading the manuscript and giving their valuable advice and criticism.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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Submitted September 26, 2000; accepted June 29, 2001.

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