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Originally published as JCO Early Release 10.1200/JCO.2005.01.6089 on October 2 2006 © 2006 American Society of Clinical Oncology. Impact on Survival of Time From Definitive Surgery to Initiation of Adjuvant Chemotherapy for Early-Stage Breast Cancer
From the Breast Cancer Outcomes Unit; Systemic Therapy Radiation Therapy Program; Population and Preventive Oncology Program, British Columbia Cancer Agency, Vancouver and Victoria; and the Faculty of Medicine, University of British Columbia Address reprint requests to Caroline Lohrisch, MD, FRCPC, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, British Columbia V5Z 4E6; e-mail: clohrisch{at}bccancer.bc.ca
PURPOSE: To determine if time to start of adjuvant chemotherapy after curative surgery influences survival in early-stage breast cancer.
PATIENTS AND METHODS: A retrospective review was conducted of 2,594 patients receiving adjuvant chemotherapy for stage I and II breast cancer between 1989 and 1998 at the British Columbia Cancer Agency. Relapse-free survival (RFS) and overall survival (OS) were compared among patients grouped by time from definitive curative surgery to start of adjuvant chemotherapy ( RESULTS: RFS and OS were similar for women starting chemotherapy up to 12 weeks after surgery. OS hazard ratio (univariate) for initiation of chemotherapy more than 12 weeks compared with 12 weeks or less after surgery was 1.5 (95% CI, 1.07 to 2.10; P = .017). Five-year OS rates were 84%, 85%, 89%, and 78%, (log-rank P = .013); RFS rates were 74%, 79%, 82%, and 69% (log-rank P = .004) for patients starting chemotherapy 4 weeks or fewer, more than 4 to 8 weeks, more than 8 to 12 weeks, and more than 12 to 24 weeks after surgery, respectively. In multivariate analysis, independent prognostic factors were grade, size, nodal status, estrogen receptor, age, and lymphatic and/or vascular invasion. Initiation of adjuvant chemotherapy more than 12 weeks from surgery remained significantly associated with inferior survival, with a hazard ratio of 1.6 (95% CI, 1.2 to 2.3; P = .005). CONCLUSION: This retrospective analysis suggests that adjuvant chemotherapy is equally effective up to 12 weeks after definitive surgery but that RFS and OS appear to be compromised by delays of more than 12 weeks after definitive surgery.
Numerous randomized trials have demonstrated the survival benefits of adjuvant chemotherapy in early-stage breast cancer.1 The widespread adoption of adjuvant chemotherapy for an increasing proportion of women with early-stage breast cancer has put pressure on treatment facilities to cope with a rising volume of patients in a timely manner. It is unclear how soon after definitive surgery chemotherapy should be initiated for maximal benefit. Most adjuvant chemotherapy trials defined a particular time from surgery to the start of chemotherapy beyond which patients were no longer eligible to participate. Strictly speaking, the benefits of a treatment described by a clinical trial are only applicable to patients treated within the same time frame as in the trial. Whether equivalent benefit can be ascribed when chemotherapy is started beyond the time window specified is not known. Clinical trials have addressed numerous aspects of treatment in an attempt to optimize adjuvant chemotherapy, but only one has addressed the timing of chemotherapy delivery.2,3 In this trial, radiation followed by chemotherapy (median time to first chemotherapy was 17 weeks) was not associated with inferior overall survival compared with chemotherapy first followed by radiation (median time to chemotherapy, 7.4 weeks). Retrospective analyses have not shown inferior outcome for chemotherapy started up to 13 weeks from surgery.4,5 Trials examining adjuvant versus neoadjuvant chemotherapy have shown equivalent survival for preoperative chemotherapy; however, these trials addressed patient populations at high risk of recurrence and therefore the results may not be widely generalizable.6,7 All of these studies have limitations, and the overall available literature on this subject is sparse. Clinical practice guidelines do not recommend a specific safe maximum interval between surgery and chemotherapy.8,9 This article describes a population-based analysis of the impact of time to initiation of adjuvant chemotherapy on relapse and mortality risks, using multivariate analysis to account for the effects of known prognostic factors.
Women 90 years of age and younger referred to the British Columbia Cancer Agency (BCCA) between 1989 and 1998 with stage I or II breast cancer with known pathologic nodal status, and who had received postoperative adjuvant chemotherapy were identified from the Breast Cancer Outcomes Unit database of the BCCA. The Breast Cancer Outcomes Unit database contains prospectively recorded demographic, pathologic, staging, initial treatment, and outcome information (first local, regional, and distant relapse, and if applicable, date and cause of death) for patients diagnosed with breast cancer in British Columbia since January 1, 1989, and who were referred to the BCCA. Initial treatment and disease data are abstracted at least 3 months after initial consultation at the BCCA. If the oncologist documents uncertainty about using tamoxifen, the chart is reviewed at a later date to determine whether it was initiated. Vital status of patients in the database is updated using the provincial death registry and recurrence status is sought on a proactive basis every 12 months from the primary physician. The BCCA operates four regional cancer clinics throughout the province of British Columbia, delivers all radiation, administers the budget for all antineoplastic drugs within the province, and sets provincial management guidelines for all cancers. The BCCA pharmacy database was used to abstract the type of chemotherapy given and the date of first administration. Patients were excluded if they had locally advanced or metastatic disease, could not be linked to the pharmacy database, started chemotherapy longer than 24 weeks from surgery, received neoadjuvant chemotherapy, had a prior or synchronous (within 3 months) breast cancer diagnosis, did not receive a standard chemotherapy for the time period under study (doxorubicin and cyclophosphamide [AC],10 cyclophosphamide, epirubicin, and fluorouracil [CEF],11 fluorouracil, doxorubicin, and cyclophosphamide [FAC, CAF],12,13 cyclophosphamide, methotrexate, and fluorouracil [CMF]14), relapsed within 12 weeks of surgery, or had a delay between initial diagnosis and definitive surgery of more than 17 weeks. Definitive surgery was defined as the most recent surgery (breast and/or axilla) for the diagnosed breast cancer performed before the start of adjuvant chemotherapy. In some cases this would be re-excision for positive margins or an axillary dissection alone, the gross tumor having been removed in a previous surgery. Data abstracted included: age at diagnosis; tumor size (maximum histologic or gross pathology size in millimeters, or the clinical size from a preoperative mammogram or notes of the referring surgeon); lymphatic or vascular invasion (LVI) in the tumor (absent, present, unknown); pathologic axillary nodal status (pN0, pN1, unknown); number of positive nodes; estrogen receptor (ER) status (positive, negative, unknown), and tumor grade (nuclear grade or histologic grade using the modified Scarff-Bloom-Richardson system15); date of diagnosis; type and date of surgery (breast conserving surgery, mastectomy, or other); use of radiation; type and date of first adjuvant chemotherapy; and use of adjuvant tamoxifen. The policy at the BCCA during the time period of the study was to start tamoxifen after the completion of chemotherapy. Tumors were designated ER unknown if there was no mention of ER–positive or –negative status in pathology documents. Tamoxifen was coded as not given if there was no record in the pharmacy database of it being prescribed and no mention of it by the consulting oncologist. Data was initially obtained on patients who started adjuvant chemotherapy up to 12 weeks after surgery, grouped into three time cohorts: 4 weeks or fewer, longer than 4 to 8 weeks, and longer than 8 to 12 weeks between definitive surgery and initiation of adjuvant chemotherapy. After initial analyses did not show any differences in outcomes between these three cohorts, we decided to include a fourth cohort of patients who began chemotherapy between 12 and 24 weeks after surgery. The outcomes of interest were (1) breast cancer event-free survival; defined as the time between diagnosis and first event, including relapse (local, regional, and/or distant), contralateral invasive breast cancer (CLBC), or breast cancer death in the absence of relapse or CLBC (with censoring of patients 6 months before date of data analysis or date of nonbreast cancer death in the absence of an event); (2) relapse-free survival; defined as time from diagnosis to first relapse (local, regional, and/or distant), or breast cancer death without relapse (with censoring at time of diagnosis of CLBC, nonbreast cancer death, or 6 months before date of data analysis in the absence of an event); and (3) overall survival; defined as time from diagnosis to death from any cause (with censoring of patients 6 months before date of data analysis for alive patients). The censoring date of 6 months before analysis was chosen to maximize the reliability of vital status and recurrence data within the database. Patients who died of unknown causes without a documented breast cancer relapse were not considered to have had a breast cancer event. The number of nonbreast cancer deaths was small in each cohort, and thus we chose to report overall survival rather than breast cancer specific survival. Institutional research ethics board approval was obtained for this retrospective analysis of anonymized electronic records. Analyses were conducted within the four cohorts defined by interval between definitive surgery and initiation of adjuvant chemotherapy. Relapse-free survival and overall survival curves were constructed using the Kaplan-Meier method.16 The statistical significance of the difference between survival distributions for each time cohort was determined by means of the log-rank test17,17A and multivariate tests of the relationship between prognostic factors, interval to chemotherapy, and outcome were performed with Cox proportional hazards analysis.18 In the first stage of the Cox analysis, known prognostic variables were entered, including age at diagnosis, axillary node status, T size, pathologic T-stage, LVI, anthracycline use, tumor grade (grade 1 or 2 and grade 3 or unknown), and ER status. Using forward selection, the best fitting prognostic model for each index of outcome was constructed. In the second stage of the Cox analysis, chemotherapy timing was entered into each prognostic model to assess its relationship with outcome independent of the prognostic factors selected in stage 1. As no difference was seen in the Kaplan-Meier curves between the first three time cohorts, they were collapsed into a single group for two-level factor analysis: chemotherapy start 12 weeks or fewer and longer than 12 to 24 weeks from surgery. It was decided a priori that timing would be considered to be independently related to outcome if there was a statistically significant (P < .05) improvement in the model fit resulting from the entry of timing. All statistical tests were two tailed and were performed using SPSS statistical software, version 10.0 (SPSS Inc, Chicago, IL).
Between 1989 and 1998, 3,588 patients were referred with stage I and II breast cancer after definitive surgery and who subsequently received adjuvant chemotherapy. Nine hundred ninety-four patients were excluded for reasons listed in Table 1. The remaining 2,594 patients were divided into four cohorts: time from definitive surgery to adjuvant chemotherapy 4 weeks or fewer (group 1, n = 993), longer than 4 to 8 weeks (group 2, n = 1,272), longer than 8 to 12 weeks (group 3, n = 217), and longer than 12 to 24 weeks (group 4, n = 112). Table 2 displays their prognostic and patient characteristics. The median time from diagnosis to definitive surgery was 2 weeks, similar for all four cohorts, and median follow-up was 6.2 years.
ER status, LVI, grade, and age at diagnosis were equally distributed between the four subgroups (P = not significant). Fifty-six percent of patients had ER–positive disease, lower than expected for the general breast cancer population. This can be explained by the selection criteria for the study, which required adjuvant chemotherapy to be given, thus enriching the study population with ER–negative cancers, for which hormone interventions are not beneficial. Group 1 had the highest proportion of positive nodes (68%, 56%, 49%, and 55% for groups 1 to 4; P < .001). Fewer patients in groups 3 and 4 received adjuvant tamoxifen compared with groups 2 and 1 (groups 1 to 4: 37%, 40%, 31%, 33%; P = .05) We found no detectable difference in overall survival between patients with ER–positive cancers who did or did not receive tamoxifen (P = .35), thus tamoxifen was not controlled for in multivariate analysis. The proportion of patients receiving anthracycline-based chemotherapy declined among groups with longer intervals from surgery to chemotherapy start (83%, 80%, 75% and 62%, respectively, for groups 1 to 4). From 1989 to 1998 there was a trend towards a reduction in the proportion of patients annually whose chemotherapy start was more than 12 weeks (group 4) and an increase in the proportion who started chemotherapy between 4 and 8 weeks from surgery. Five year Kaplan-Meier overall survival rates were 84%, 85%, 89%, and 78%, (log-rank P = .013); relapse-free survival rates were 74%, 79%, 82%, and 69% (log-rank P = .004) for groups 1 through 4, respectively (Table 3). In univariate analysis, the overall survival was significantly worse for group 4 compared with the other groups, with a hazard ratio of 1.5 (95% CI, 1.07 to 2.10; P = .017). Kaplan-Meier curves for breast cancer event-free survival, relapse-free survival, and overall survival are shown in Figures 1, 2, and 3 respectively. In multivariate analysis, independent prognostic factors were size, nodal status, age, and LVI (Table 4). Initiation of adjuvant chemotherapy longer than 12 to 24 weeks from surgery remained significantly associated with inferior overall survival (P = .005) after accounting for the distribution and import of other prognostic variables. In exploratory analyses we found no overall survival impact for chemotherapy initiation longer than 12 to 24 weeks from surgery for ER–negative and unknown patients (grouped together) but a significantly worse overall survival for the ER–positive patients.
Strictly speaking, the benefits of various chemotherapy regimens are only attributable when treatment is initiated within the time frame used by the clinical trial that established their benefit. Large cooperative trials usually define the time period between surgery and adjuvant chemotherapy allowable for enrollment. However, across trials there is a wide variation in the allowed time between surgery and chemotherapy. The National Surgical Adjuvant Breast and Bowel Project trials and the landmark CMF trial14 required chemotherapy to start between 2 and 5 weeks after surgery. Cancer and Leukemia Group B19 and National Cancer Institute of Canada11 trials have allowed enrollment of patients who are able to initiate chemotherapy within 12 weeks of surgery. Still other cooperative group trials define allowable time frames for chemotherapy initiation which range from within 3 weeks20 to within 6 weeks21-24 of surgery. The only randomized prospective trial to address the impact of delaying chemotherapy by first giving radiation did not show an inferior survival for the radiation first group; however, this trial deserves further inspection.2 In the radiation first group, the median time from surgery to chemotherapy start was 17 weeks while in the chemotherapy first group, it was 7.4 weeks. However, it was powered to show a large difference in median disease-free survival (from 4.8 to 8 years), and therefore required only a small sample size (N = 244). This likely explains why the 8% observed difference in survival favoring chemotherapy first (73% v 81%; P = .11) was not statistically significant. Of note, the hazard ratios for time to first distant recurrence (1.62; 95% CI, 1.01 to 2.62) favored the chemotherapy first group. In our study, women who received adjuvant chemotherapy between 12 and 24 weeks (n = 112) after definitive surgery for early-stage breast cancer had significantly inferior survival compared with women who began chemotherapy earlier (n = 2,482), even allowing for the distribution and impact of known prognostic factors. A smaller proportion of women in the 12 to 24 week group received anthracycline-based chemotherapy, but this group also had the lowest proportion of node-positive disease. Anthracycline-based chemotherapy was not routinely recommended for women with node-negative disease during the early part of the study period. It should also be noted that although only 38% of the study population received tamoxifen, while 56% had ER–positive tumors, 68% of the study population was 50 years old or younger, and adjuvant tamoxifen was not recommended for premenopausal women in the early years of the study. Our study is limited by its retrospective nature. There are certain imbalances in known and unknown prognostic factors which may influence the observed results. Missing data, such as the 7% for which ER status was unknown, and the suboptimal method of capturing tamoxifen use, must be borne in mind when interpreting the results. In addition, there may be factors that were not controlled for which influence both a delay to treatment start and an inferior outcome. Her2/neu status was not captured prospectively during much of the time spanned by our study. The database records which chemotherapy was started, but not how many cycles were given or the delivered dose intensity, so we cannot be certain that this was similar across all groups. Our observations are nevertheless consistent with other published retrospective series. One reported no diminished benefit for chemotherapy initiated either within or longer than 21 days from surgery (few patients started > 8 weeks after surgery).4 A further retrospective study of the Danish Breast Cancer Cooperative Group found no difference in outcome for 7,500 patients starting chemotherapy up to 13 weeks after surgery.5 However, neither study addressed the impact of more than 3 months delay to starting chemotherapy, which is unique to our report. Our study did not have a no chemotherapy comparison group. It is therefore impossible to speculate whether the benefit of chemotherapy is lost entirely or merely attenuated by a delay of more than 12 weeks after surgery. However, it does suggest the importance of timely administration of chemotherapy within 3 months of surgery whenever possible. Tamoxifen in premenopausal women and anthracyclines were used with increasing frequency over time. Anthracycline use was controlled for in the analysis, while tamoxifen was not as its use in ER–positive disease did not appear significant in univariate testing. Surgery and radiation principles did not change over the study period. The time interval between surgery and chemotherapy initiation is dictated by multiple factors, including the time required for pathologic assessment of the tumor, referral wait time to see an oncologist, postoperative healing time, and patient factors. Many centers may find it difficult or impossible to consistently meet some of the shorter time windows used in randomized trials. Reassuringly, initiation of chemotherapy up to 12 weeks from surgery appeared to confer similar benefit in this study. The diagnosis of breast cancer can be devastating and life altering for many women. Issues regarding sexuality, body image, wholeness, and health are dramatically challenged.25,26 Perceptions of the severity of chemotherapy adverse effects can be inflated in the lay person’s mind, leading to fear and anxiety about accepting chemotherapy. For many women, the time interval between initial diagnosis, sometimes disfiguring surgery, and embarking on a 4- to 6-month chemotherapy program is overwhelmingly short. They have insufficient time to digest one aspect of their illness and treatment before being confronted with another. It is unlikely that there will be additional prospective trials comparing outcomes for starting chemotherapy before or after a specified time from surgery. Therefore we must rely on retrospective data such as was reviewed in this study, with all limitations inherent in such observations. The finding that initiation of chemotherapy up to 12 weeks after surgery provides equivalent protection from recurrence allows women sufficient time to gather information, consider their options, and be actively involved in treatment decision making, the latter of which has been shown to reduce anxiety and depression associated with breast cancer.27 It also allows for adjustment time between the different components of breast cancer treatment for those who need it. Based on currently available data, including the findings in this study, patients should be encouraged to start chemotherapy before more than 3 months have elapsed from surgery, to maximize the anticipated benefit. The issue of timing between surgery and chemotherapy warrants further study, particularly in specific subgroups.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on October 2, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomized trials. Lancet 352:930-942, 1998[CrossRef][Medline] 2. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996 3. Bellon JR, Come SE, Gelman RS, et al: Sequencing of chemotherapy and radiation therapy for patients with early stage breast cancer: Updated results of a prospective randomized trial. Int J Rad Oncol Bio Physics 51:2, 2001 (suppl 1; abstr 4) 4. Shannon C, Ashley S, Smith IE: Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol 21:3792-3797, 2003 5. Cold S, Düring M, Ewertz M, et al: Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer 93:627-632, 2005[CrossRef][Medline] 6. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998[Abstract] 7. Mauriac L, Durand M, Avril A, et al: Effect of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3cm. Ann Oncol 2:347-354, 1991 8. The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer: Clinical Practice Guidelines for the Care and Treatment of Breast Cancer: A Canadian consensus document. Can Med Assoc J 158:S1-S83, 1998 (suppl 3)[Medline] 9. Anonymous: Proceedings of the 8th International Conference on Primary Therapy of Early Breast Cancer: St Gallen, Switzerland, March 12-15, 2003. Breast 12:349-582, 2003[CrossRef][Medline] 10. 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 node-positive breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990[Abstract] 11. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol 16:2651-2658, 1998[Abstract] 12. Albain K, Green S, Ravdin P, et al: Overall survival after cyclophosphamide, adriamycin, 5-FU, and tamoxifen (CAFT) is superior to T alone in postmenopausal, receptor (+), node (+) cancer: New findings from phase III Southwest Oncology Group Trial S8814 (INT-0100). Proc Am Soc Clin Oncol 20:24a, 2002 (abstr 94) 13. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994 14. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 332:901-926, 1995 15. Elston CW, Willis IO: Pathological prognostic factors in breast cancer: The value of histological grade in breast cancer: Experience from a large study with long-term follow-up. Histopathology 19:403-410, 1991[Medline] 16. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 17. Peto R, Pike MC, Armitage PB, et al: Design and analysis of randomised controlled trials requiring prolonged observation of each patient, Part I. Br J Cancer 34:585-612, 1976[Medline] 17. Peto R, Pike MC, Armitage PB, et al: Design and analysis of randomised controlled trials requiring prolonged observation of each patient, Part II. Br J Cancer 35:1-39, 1977[Medline] 18. Cox DR: Regression models and life-tables. J R Stat Soc Ser B 34:187-202, 1972 19. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 20. Kaufmann M, Jonat W, Abel U, et al: Adjuvant randomized trials of doxorubicin/cyclophosphamide versus doxorubicin/cyclophosphamide/tamoxifen and CMF chemotherapy versus tamoxifen in women with node-positive breast cancer. J Clin Oncol 11:454-460, 1993 21. Coombes RC, Bliss JM, Wils J, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: Results of a randomized trial. J Clin Oncol 14:35-45, 1996[Abstract] 22. French Adjuvant Study Group: Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19:602-611, 2001 23. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. J Natl Cancer Inst 90:1205-1211, 1998 24. International Breast Cancer Study Group: Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal beast cancer patients. J Clin Oncol 14:1885-1894, 1996 25. Shimozuma K, Ganz PA, Petersen L, et al: Quality of life in the first year after breast cancer surgery: Rehabilitation needs and patterns of recovery. Breast Cancer Res Treat 56:45-57, 1999[CrossRef][Medline] 26. Ganz PA, Schag CC, Polinsky ML, et al: Rehabilitation needs and breast cancer; the first month after primary therapy. Breast Cancer Res Treat 10:243-253, 1987[CrossRef][Medline] 27. Fallowfield LJ, Hall A, Maguire P, et al: Psychological effects of being offered choice of surgery for breast cancer. BMJ 309:448, 1994 Submitted February 18, 2005; accepted August 16, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
4 weeks, > 4 to 8 weeks, > 8 to 12 weeks, and >12 to 24 weeks). 
