|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Local Failure Is Responsible for the Decrease in Survival for Patients With Breast Cancer Treated With Conservative Surgery and Postoperative RadiotherapyFrom the Department of Radiation Oncology, Hôtel-Dieu de Québec Hospital, Université Laval, Québec, Canada. Address reprint requests to Dr André Fortin, Radiation-Oncology, Hôtel-Dieu de Québec, Pavillon Carlton-Auger, 25 rue Charlevoix, Québec GIR 5C3, Canada.
PURPOSE: The aim of the present study was to evaluate the role of local failure (LF) in the survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis (DM) but also a cause. METHODS: Charts of patients treated with breast conservative surgery between 1969 and 1991 were reviewed retrospectively. There were 2,030 patients available for analysis. The median duration of follow-up was 6 years. A Cox regression multivariate analysis was performed using LF as a time-dependent covariate. RESULTS: Local control (LC) was 87% at 10 years. Local failure led to poorer survival at 10 years than local control (55% v 75%, P < .00). In a Cox model, local failure was a powerful predictor of mortality. The relative risk associated with LF was 3.6 for mortality and 5.1 for DM (P < .00). In patients with LF, the rate of DM peaked at 5 to 6 years, whereas it peaked at 2 years for patients with LC. The mean time between surgery and DM was 1,050 days for patients without LF and 1,650 days for patients with LF (P < .00). CONCLUSION: Our results show that local failure is associated with an increase in mortality. The difference in the time distribution of distant metastasis for LF and LC could imply distinct mechanisms of dissemination. Local failure should be considered not only as a marker of occult circulating distant metastases but also as a source for new distant metastases and subsequent mortality.
IT IS OF UTMOST importance to understand the significance of local failure (LF) in breast cancer treated with local excision and radiotherapy, even though it occurs in only 13%1 of patients at 10 years. Considering that two thirds of the 182,000 women with breast cancer in the United States1 are treated with a breast-conservative approach, this translates into 15,600 women with LF every year in this country. This number is greater than the total number of invasive carcinomas of the cervix or Hodgkin's disease. If local failure is responsible for any increase in distant metastasis (DM) and subsequent mortality, its cause and consequences should be carefully analyzed. The impact of local failure on ultimate outcome in breast cancer treated with conservative surgery and postoperative radiotherapy remains controversial. For many investigators, local failure after conservative treatment has no detrimental effect on the survival of patients because breast cancer is a systemic disease that is already disseminated even before diagnosis.2-5 Some risk factors seem to predict both local and distant recurrences, whereas others suggest an increased risk of local recurrence and seem to have little effect on the risk of metastatic disease. Overall, the relation between LF and the risk of systemic metastasis is poorly understood.6 Some authors7-9 have demonstrated that local failure is associated with more chances of distant metastasis, and Whelan et al10 have shown that LF is associated with an increased risk of distant relapse and mortality. Fisher et al7 also showed that patients with local failure have more distant metastases than patients without local failure, but they considered LF to be a marker for distant metastasis, rather than a cause.11 They suggested that mastectomy or breast irradiation after lumpectomy eliminates or reduces the opportunity to identify a marker of risk for distant disease. Because omission of radiotherapy leads to an LF rate of 24%12 to 39%,13 even when adjuvant chemotherapy is used, the implications of LF should be fully understood before accepting such a rationale. In contrast, Arriagada et al14 showed that postmastectomy radiotherapy in node-positive breast cancer patients may decrease the distant metastasis rate by preventing local recurrences and thus avoiding secondary dissemination. This hypothesis was corroborated recently by the findings of two large studies, in which survival was increased in high-risk premenopausal patients receiving postmastectomy radiotherapy after adjuvant chemotherapy.15,16 It remains possible that local failure after breast-conservative treatment has the same deleterious effect on survival as after mastectomy. Therefore, the aim of the present study was to evaluate further the role of local failure in the distant failure and survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis but also a cause. Our main hypothesis is that if local failure is a cause of subsequent metastasis, the time distribution of metastasis in patients with and without LF should be different: the interval preceding the appearance of distant metastasis should be longer for patients with LF than for those with local control (LC). Patients with LC who develop DM must already have DM present at the time of surgery. On the contrary, for patients with LF, the remaining tumor cells in the surgical bed must first multiply and then invade the blood vessels before leading to DM.17 On the other hand, if LF is only a marker of aggressive disease and not a cause of DM, any DM associated with it should occur shortly after surgery.18
The charts of 2,142 women treated between 1969 and 1991 with breast-conservative surgery were reviewed retrospectively. All consecutive patients treated in our department were included except those treated in 1986–1987, because their charts were not available at the time of the review. Patients with American Joint Committee on Cancer stages I to III were included, with the exception of 87 patients with stage T4 tumors. Patients with radiation doses of less than 40 Gy (25 patients) were also excluded from the analysis. Thus, 2,030 patients were available for analysis. The following data were compiled when available: age, menopausal status, clinical and pathologic stage, histologic type and grade, surgical margin status, hormonal receptor status, number of positive and excised nodes, dose and volume of irradiation, delay between lumpectomy and the beginning of radiotherapy, and type of systemic treatment.
Treatment
Statistical Analysis
There were 2,030 patients available for analysis. The median duration of follow-up was 5.2 years (lower quartile, < 4 years; upper quartile, > 7.5 years; only 12% of women who were alive were observed for < 2 years). The mean age was 54.4 years (lower quartile, < 45 years; upper quartile, > 64 years). The mean dose to the breast was 50.8 Gy (lower quartile, < 46 Gy; upper quartile, > 50 Gy). Characteristics of the patients with LF and LC are listed in Table 1, where comparisons are made between the two groups. It can be observed that patients with local failure were younger and more often displayed positive or close surgical margins than patients with local control. They also had more regional failures (RF) (22% v 3%, P < .00) and more distant failures (65% v 19%, P < .00). Hormonal adjuvant therapy was associated with better local control, because only 2% of patients treated with antihormone medication had local failure, in comparison with 10% of the other patients.
Survival Analysis
Factors Associated With Local Control
Local Control in Relation to Survival, Distant Metastasis, and Regional Control
The rate of distant metastasis at 10 years was also higher in the group of patients with local failure than in those with local control (58% v 20%, P < .00). Regional control was also closely associated with failure in the breast (Fig 2). Regional control was 95% when there was local control but only 77% when the breast was uncontrolled (P < .00).
Multivariate Analysis
Time Distribution of Distant Metastasis for Patients With Local Control and Local Failure
The effect of local failure on distant metastasis is indirectly seen in Fig 4, which presents the hazard of having distant metastasis as a function of time. Patients with local control show a peak in the rate of metastasis at about 2 years; after that time point, the rate of DM decreases continually. For patients with local failure, the same peak is observed at 2 years, but it is followed by a second, higher surge in DM at 5 years. This second peak in patients with LF can be explained only by the presence of a second event: local failure. The second peak is not observed in other subgroups of patients with LC (data not shown). The hazard rate of dying follows the same time distribution pattern (not illustrated). It should also be noted that the hazard for metastasis in patients with local failure is always higher than in patients with local control.
We also examined the relationship between the time distribution of metastasis and aggressivity of the disease. The delay from surgery to DM decreases with higher tumor stage (P = .002, ANOVA test) and nodal status (P < .00, ANOVA test). For node-negative patients, the delay was 1,280 days, in comparison to 887 days when more than three nodes were involved; it was 1,334 days for tumor stage T1, in comparison to 1,040 days for stage T2.
Risk Factors for Mortality Among Patients With Local Failure
A high degree of correlation existed between each of these factors. Skin recurrence was associated with higher initial tumor size and nodal stage. The site of local failure was well correlated with the mean delay from initial surgery to LF: it was 2.5, 3.8, and 4.5 years for recurrence in the skin, initial tumor bed, and other sites, respectively (P = .0004, Kruskal-Wallis test). An association was observed between high initial tumor size and nodal stage and a short delay between LF and initial surgery. The only salvage treatment that was associated with survival after LF was hormonal treatment. Salvage mastectomy or lumpectomy led to the same survival, and the addition of chemotherapy had no benefit. Addition or continuation of antiestrogen therapy was associated with a better 10-year survival (47% v 72%, P = .04), particularly in the subgroups of patients with skin lesion (7% v 55%, P = .06), with initial stage T2 (25% v 60%, P = .09), or with regional nodes (20% v 52%, P = .05) (log-rank test).
It may never be possible to prove without any doubt that local failure in breast cancer is responsible for an increase in the rate of distant metastasis. No direct experiment will ever allow women to be randomized to local failure or to local control. Moreover, in contrast with head and neck carcinomas or brain tumors, local failure does not lead directly to death in breast cancer. However, it is important to understand the influence of LF on the ultimate outcome of patients, for at least two reasons. First, even though only 13% of the patients develop LF, this represents a large number of women. Second, misunderstanding of the consequences of LF could lead to inadequate initial locoregional management of breast cancer. In our study, we demonstrated that LF had an impact on the outcome for our patients. This impact is expressed by a rise in the distant metastasis rate, which translates into a reduced survival, with a hazard ratio of 3.6 for our patients with LF, regardless of initial stage. Whelan et al10 also found that LF decreases survival by a factor of 2.8. Veronesi et al8 suggested that LF was only partially related to distant failure. Their assumption was based on the fact that, because some risk factors were not associated with both local failure and distant metastasis, LF was in some cases not related to DM. They made a distinction between local recurrences linked to increased risk of distant spread and those due to inadequate local treatment. Like Veronesi et al, we demonstrated that younger women are more at risk for both LF and DM, but in contrast to their conclusions, we showed that close surgical margins are also associated with DM. Fisher et al7,11 found that LF increases the risk of DM by a factor of 3.41. They stated that LF was a marker of DM and not a cause of DM. They argued that patients with LF had very aggressive disease, which had already led to DM by the time of surgery. In agreement with their results, our findings showed that the initial rate of DM is higher for patients with LF than with LC (Fig 4), indicating that some patients with LF have a greater potential to generate DM than patients with LC. Some investigators have also found that biologic factors usually associated with tumor aggressiveness, like p53 mutation23 and high proliferation rate,24 are both associated with LF and DM. With regard to Fig 4, a point could be made that LF is not only a marker of aggressiveness but also a source of DM. Like Harris et al1 and Veronesi et al,8 we observed a peak in the distant metastasis rate at 2 to 3 years in patients with LC. However, in patients with LF, a second peak, which was much higher, was also observed at 5 to 6 years (Fig 4). This second peak was not seen in any other subgroup of patients with LC. Therefore, at the time of initial surgery, a subset of patients from both groups (with and without LF) will have micrometastatic disease that will become clinically evident within 2 to 3 years (the first peak). In the LF group with a higher hazard for DM, a second peak was observed at 5 to 6 years with a temporal relationship to local recurrence, as the LF rate peaks at around 2 years and 70% of local failures occur before 4 years. Demicheli et al25 (and Veronesi et al8) also observed this second peak of DM at 5 years but in a cohort that included all of their patients (with and without LF). They explained the occurrence of this second peak by the metastasis dormancy hypothesis, which assumes that some micrometastases may remain in a biologic steady state until microenvironmental changes induce metastatic growth.25 We also observed this second peak when we plotted the hazard rate with our entire cohort (Fig 7). Interestingly, this 5-year peak became much smaller when we excluded the patients with LF from our cohort, and the peak disappeared after exclusion of the patients with LF and/or positive margins (Fig 7). Therefore, in contrast to the view of Demicheli et al, our opinion is that this second peak can be explained only by a second event, namely local failure. This second peak is the most direct evidence that LF is the source of subsequent DM.
Moreover, the fact that DM occur later in patients with LF than in patients with LC is not consistent with the hypothesis that LF is only a marker of aggressiveness. In fact, in agreement with results of the study by Koscielny et al,18 we found that the mean time to development of metastases was much shorter for aggressive tumors (high-stage tumor size and nodal status) than for lower-stage tumors. Consequently, if LF were a marker of aggressiveness, metastases in patients with LF would have occurred rapidly, which was not the case. It could be argued that owing to competing events,26 some patients with LC and DM did not have enough time to develop LF, as they died too early. However, this problem of competing events26 is unsolvable. In the same way, Veronesi et al8 observed that the timing of local failure and distant failure differed, and for this reason, they discounted a causal relationship between LF and DM. On the contrary, we observed a close time relationship between LF and DM. Distant metastasis consistently occurred shortly after or at the same time as LF, irrespective of the moment the LF was documented (Fig 6). The nearly simultaneous detection of LF and metastases is consistent with the model developed by Koscielny et al,27 in which metastases grow much faster and are detected at a smaller volume than the primary tumor. This close association would be difficult to explain otherwise than by a cause-effect relationship between LF and DM. It is plausible that some detection bias leads to the early detection of more DM after LF, but in these cases, DM would have been detected a few months later, anyway. A similar relationship for the timing of local failure and regional failure was also observed. This close time relationship between LF and DM is also compatible with the hypothesis presented by O'Reilly et al.28 They proposed that when the primary tumor (in our case, residual tumor cells) is present, metastatic growth is suppressed by a circulating angiogenesis inhibitor. After tumor removal (in our case, the LF), metastases neovascularize and grow. If true, this hypothesis will radically change our concept of cancer. If LF is associated with subsequent DM, it should be reduced. The risk factors should first be identified and then eliminated. Risk factors for LF in our study were young age,29-32 close surgical margins,33-39 absence of hormonal therapy,40 and T3 stage. Obtaining clear surgical margins should be possible. In our series, absence of axillary dissection was associated with positive margins, which implies an association between positive margins and a less aggressive surgical procedure on both axilla and breast. Fein et al41 also found a surgeon-linked factor related to close margins and LF (P = .02). Aggressive local surgery seems to give better local control.36,42 A boost of radiotherapy after 50 Gy to the breast could also reduce the local failure rate,43 but only after appropriate surgery.41,44
We observed an association between DM and close surgical margins. Among the 122 patients in whom there were close surgical margins, 34 of 122 (28%) developed DM, whereas 334 of 1,905 patients (17%) with negative margins developed DM (P = .01, Pearson Local failure could also be reduced by systemic treatment. In our series, hormonal treatment is associated with an LC of 97.5% (399 of 409 patients), adjuvant chemotherapy with an LC of 90% (354 of 390 patients) as compared with 89% (1,105 of 1,231 patients) for those without adjuvant therapy (P = .00001). It is possible that patient selection contributed to the high rate of LC observed in our series with tamoxifen, but our results are consistent with those reported in the literature.1,40,46-49 In our series, chemotherapy did not influence the rate of LF. However, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13, the addition of chemotherapy (CMF), as compared with radiotherapy alone, reduced the rate of LF from 13.4% to only 0.6%.50 Other authors51-54 have found similar results. Interventions to reduce the adverse effects of LF could also be made at the time of LF if risk factors associated with subsequent relapse were identified. In our series, we identified several factors: LF occurring less than 2 years after surgery,7,9,10 initial T2 or positive nodes, and LF with skin invasion or with a size of more than 1.5 cm. As reported by Haffty et al,22 we found that recurrence in a location other than in the initial tumor bed was associated with longer survival. Other high-risk factors at the time of LF include invasive tumor,55 loss of the estrogen receptor56 or the in situ component,57 skin invasion,58,59 and presence of DNA aneuploidy or high S-phase.60 High-risk patients would probably need more aggressive systemic treatment. In our series, only tamoxifen seemed to increase survival, but this finding may be due to patient selection. In a randomized study61 including only low-risk patients with recurrence after mastectomy, tamoxifen increased the disease-free survival. One of the crucial questions that remains to be answered is why the increase in DM after LF does not translate into a survival advantage for patients receiving radiotherapy in some series of patients4,12,13,62,63 treated with lumpectomy or lumpectomy and radiation. We should point out that, in our series, we compared the outcome of patients with and without LF, which is different from the previously cited series, in which comparisons were made between irradiated and nonirradiated patients. It is possible that these series had insufficient power to detect a survival advantage for irradiated patients. Indeed, in a recent meta-analysis,3 radiotherapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94; P = .03) but there was an increased risk of death from other causes (odds ratio, 1.24; P = .002). Moreover, two recent studies15,16 demonstrated a higher survival rate in the group receiving postmastectomy radiotherapy as compared with the group not irradiated. This higher survival rate becomes manifest only after a long follow-up. Yet these two series included only premenopausal women treated with mastectomy and adjuvant chemotherapy, and it is not certain that results from these series are applicable to series of patients treated with lumpectomy without chemotherapy. Nevertheless, as suggested by Hellman,64 it is possible that the increase in local failure and distant metastases observed in the nonirradiated patients in NSABP B-06 will translate into an increase in mortality with longer follow-up. This suggestion is compatible with our data, because DM associated with LF occurred later in time than DM not associated with LF. In conclusion, local failure should be considered not only as a marker of occult circulating distant metastases but also as a source of new distant metastases and subsequent mortality. Every effort should be made to decrease the local failure rate, mainly by obtaining clear surgical margins and possibly by adding antiestrogen therapy.
We wish to acknowledge Guylaine Daigle for her technical assistance.
1. Harris JR, Lippman ME, Morrow M, et al: Diseases of the Breast. Philadelphia, PA, Lippincott-Raven, 1996, p 159 2. Epstein AH, Connolly JL, Gelman R, et al: The predictors of distant relapse following conservative surgery and radiotherapy for early breast cancer are similar to those following mastectomy. Int J Radiat Oncol Biol Phys 17:755-760, 1989[Medline]
3.
Effects of radiotherapy and surgery in early breast cancer: An overview of the randomized trials: Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 333:1444-1456, 1995 4. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with and without irradiation in the treatment of breast cancer. N Engl J Med 320:822-828, 1989[Abstract] 5. Veronesi U, Banfi A, Salvadori B, et al: Breast conservation is the treatment of choice in small breast cancer: Long-term results of a randomised clinical trial. Eur J Cancer 26:668-670, 1990 6. Osteen RT: Risk factors and management of local recurrence following breast conservation surgery. World J Surg 18:76-80, 1994[Medline] 7. Fisher B, Anderson S, Fisher E, et al: Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet 338:327-331, 1991[Medline]
8.
Veronesi U, Marubini E, Del Vecchio Met al: Local recurrences and distant metastases after conservative breast cancer treatments: Partly independent events. J Natl Cancer Inst 87:19-26, 1995 9. Haffty B, Reiss M, Beinfield M, et al: Ipsilateral breast tumor recurrence as predictor of distant disease: Implications for systemic therapy at the time of local relapse. J Clin Oncol 14:52-57, 1996[Abstract] 10. Whelan T, Clark R, Roberts R, et al: Ipsilateral breast tumor recurrence post-lumpectomy is predictive of subsequent mortality: Results from a randomized trial. Int J Radiat Oncol Biol Phys 30:11-16, 1994[Medline] 11. Fisher B, Wickerham DL, Deutsch M, et al: Breast tumor recurrence following lumpectomy with and without breast irradiation: An overview of recent NSABP findings. Semin Surg Oncol 8:153-160, 1992[Medline] 12. Forrest P, Steward HJ, Everington D, et al: Randomised controlled of conservative therapy for breast cancer: 6-year analysis of the Scottish trial. Lancet 348:708-713, 1996[Medline] 13. Levine MN, Bramwell V, Abu-Zahra H, et al: The effect of systemic adjuvant chemotherapy on local breast recurrence in node positive breast cancer patients treated by lumpectomy without radiation. Br J Cancer 65:130-132, 1992[Medline] 14. Arriagada R, Rutqvist LE, Mattsson A, et al: Adequate locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 13:2869-2878, 1995[Abstract]
15.
Ragaz J, Jackson SM, Le N PIet al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997
16.
Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949-955, 1997 17. Chambers AF, Hill RP: Tumor progression and metastasis, in Tannock IF, Hill RP (eds): The Basic Science of Oncology (ed 3). Toronto, Canada, McGraw-Hill, 1998, pp 219-239 18. Koscielny S, Tubiana M, Le MGet al: Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination. Br J Cancer 49:709-715, 1984[Medline] 19. Ng'andu NH: An empirical comparison of statistical tests for assessing the proportional hazards assumption of Cox's model. Stat Med 16:611-626, 1997[Medline] 20. Hill C, Com-Nougué C, Kramar A: Analyse Statistique des Données de Survie. Paris, France, Flammarion, 1990 21. Christensen E: Multivariate survival analysis using Cox's regression model. Hepatology 7:1346-1358, 1987[Medline] 22. Haffty BG, Carter D, Flynn SD, et al: Local recurrence versus new primary: Clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting. Int J Radiat Oncol Biol Phys 27:575-583, 1993[Medline] 23. Noguchi S, Koyama H, Kasugai T, et al: A case-control study on risk factors for local recurrences or distant metastases in breast cancer patients treated with breast-conserving surgery. Oncology 54:468-474, 1997[Medline]
24.
Silvestrini R, Daidone MG, Luisi A, et al: Biologic and clinicopathologic factors as indicators of specific relapse types in node-negative breast cancer. J Clin Oncol 13:697-704, 1997 25. Demicheli R, Abbattista A, Miceli R, et al: Time distribution of the recurrence risk for breast cancer patients undergoing mastectomy: Further support about the concept of tumor dormancy. Breast Cancer Res Treat 41:177-185, 1996[Medline] 26. Gelman R, Gelber R, Henderson G, et al: Improved methodology for analyzing local and distant recurrence. J Clin Oncol 8:548-555, 1990[Abstract] 27. Koscielny S, Tubiana M, Valleron AJ: A simulation model of the natural history of human breast cancer. Br J Cancer 52:515-524, 1985[Medline] 28. O'Reilly MS Holmgren L, Shing Y, et al: Angiostatin: A novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:315-328, 1994[Medline] 29. De la Rochefordiere A, Asselain B, Campana F, et al: Age as prognostic factor in premenopausal breast carcinoma. Lancet 342:1039-1043, 1993
30.
Clarke DH, Martinez AA: Identification of patients who are at high risk for locoregional breast cancer recurrence after conservative surgery and radiotherapy: A review article for surgeons, pathologists, and radiation and medical oncologists. J Clin Oncol 10:474-483, 1992 31. Elkhuizen PH, van de Vijver MJ, Hermans J, et al: Local recurrence after breast-conserving therapy for invasive breast cancer: High incidence in young patients and association with poor survival. Int J Radiat Oncol Biol Phys 40:859-867, 1998[Medline] 32. Fourquet A, Campana F, Zafrani B, et al: Prognostic factors of breast recurrence in the conservative management of early breast cancer: A 25-year follow-up. Int J Radiat Oncol Biol Phys 17:719-725, 1989[Medline] 33. Gage I, Schnitt SJ, Nixon AJ, et al: Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy. Cancer 78:1921-1928, 1996[Medline]
34.
Ghossein NA, Alpert S, Barba J, et al: Breast cancer: Importance of adequate surgical excision prior to radiotherapy in the local control of breast cancer in patients treated conservatively. Arch Surg 127:411-415, 1992 35. Kurtz JM, Jacquemier J, Amalric R, et al: Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancers treated by conservation therapy. Cancer 65:1867-1878, 1990[Medline] 36. Macmillan RD, Purushotham AD, Mallon E, et al: Tumour bed positivity predicts outcome after breast-conservative surgery. Br J Surg 84:1559-1562, 1997[Medline] 37. Schnitt S, Abner A, Gelman R, et al: The relationship between microscopic margins of resection and the risk of local recurrence in breast cancer patients treated with conservative surgery and radiation therapy. Cancer 74:1746-1751, 1994[Medline] 38. Schnitt SJ, Connolly JL, Harris JR, et al: Pathologic predictors of early local recurrence in stage I and II breast cancer treated by primary radiation therapy. Cancer 53:1049-1057, 1994 39. Burke MF, Allison R, Tripcony L: Conservative therapy of breast cancer in Queensland. Int J Radiat Oncol Biol Phys 31:295-303, 1995[Medline] 40. Dalberg K, Johansson H, Johansson U, et al: A randomized trial of long term adjuvant tamoxifen plus postoperative radiation therapy versus radiation therapy alone for patients with early stage breast carcinoma treated with breast-conserving surgery: Stockholm Breast Cancer Study Group. Cancer 82:2204-2211, 1998[Medline] 41. Fein DA, Fowble BL, Hanlon AL, et al: Does the placement of surgical clips within the excision cavity influence local control for patients treated with breast-conserving surgery and irradiation? Int J Radiat Oncol Biol Phys 34:1009-1017, 1996[Medline] 42. Veronesi U, Volterrani F, Luini A, et al: Quadrantectomy versus lumpectomy for small size breast cancer. Eur J Cancer 26:671-673, 1990
43.
Romestaing P, Lehingue Y, Carrie C, et al: Role of a 10-Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 15:963-968, 1997 44. Wazer DE, Schmidt-Ullrich RK, Ruthazer R, et al: Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed. Int J Radiat Oncol Biol Phys 40:851-858, 1998[Medline] 45. DiBiase SJ, Komarnicky LT, Schwartz GF, et al: The number of positive margins influences the outcome of women treated with breast preservation for early stage breast carcinoma. Cancer 82:2212-2220, 1998[Medline] 46. Fisher B, Costantino J, Redmond C, et al: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320:479-484, 1989[Abstract]
47.
Fisher B, Dignam J, Bryant J, et al: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88:1529-1542, 1996 48. Fowble B, Fein DA, Hanlon AL, et al: The impact of tamoxifen on breast recurrence, cosmesis, complications, and survival in estrogen receptor-positive early-stage breast cancer. Int J Radiat Oncol Biol Phys 35:669-677, 1996[Medline] 49. Wazer DE, Morr J, Erban JK, et al: The effects of postradiation treatment with tamoxifen on local control and cosmetic outcome in the conservatively treated breast. Cancer 80:732-740, 1997[Medline]
50.
Fisher B, Dignam J, Costantino JP, et al: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: Eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14:1982-1992, 1996 51. Rose M, Henderson I, Gelman R, et al: Premenopausal breast cancer patients treated with conservative surgery, radiotherapy, and adjuvant chemotherapy have a low risk of local failure. Int J Radiat Oncol Biol Phys 17:711-717, 1989[Medline]
52.
Clahsen PC, van de Velde CJ, Julien JP, et al: Improved local control and disease-free survival after perioperative chemotherapy for early-stage breast cancer: A European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol 14:745-743, 1996
53.
Clahsen PC, van de Velde CJ, Goldhirsch A, et al: Overview of randomized perioperative polychemotherapy trials in women with early-stage breast cancer. J Clin Oncol 15:2526-2535, 1997
54.
Fisher B, Dignam J, Wolmark N, et al: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89:1673-1682, 1997 55. Abner A, Recht A, Eberlein T, et al: Prognosis following salvage mastectomy for recurrence in the breast after conservative surgery and radiation therapy for early-stage breast cancer. J Clin Oncol 11:44-48, 1993[Abstract] 56. Kuukasjärvi T, Kononen J, Heikki H, et al: Loss of estrogen receptor in recurrent breast cancer is associated with poor response to endocrine therapy. J Clin Oncol 14:2584-2589, 1996[Abstract] 57. Chauvet B, Lemseffer A, Fetissoff F, et al: Disappearance of the in situ component: A criterion predictive of metastasis in breast cancer after local relapse. Radiother Oncol 25:181-185, 1992[Medline] 58. Gage I, Schnitt SJ, Recht A, et al: Skin recurrences after breast-conserving therapy for early-stage breast cancer. J Clin Oncol 16:480-486, 1998[Abstract] 59. Clarke DH, Le MG Sarrazin D, et al: Analysis of local-regional relapses in patients with early breast cancers treated by excision and radiotherapy: Experience of the Institut Gustave-Roussy. Int J Radiat Oncol Biol Phys 11:137-145, 1985[Medline] 60. Haffty BG, Toth M, Flynn S, et al: Prognostic value of DNA flow cytometry in the locally recurrent, conservatively treated breast cancer patient. J Clin Oncol 10:1839-1847, 1992[Abstract]
61.
Borner M, Bacchi A, Goldhirsch A, et al: First isolated locoregional recurrence following mastectomy for breast cancer: Result of a phase III multicentric study comparing systemic treatment with observation after excision and radiation. J Clin Oncol 12:2071-2077, 1994
62.
Clark RM, Whelan T, Levine M, et al: Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update: Ontario Clinical Oncology Group. J Natl Cancer Inst 88:1659-1664, 1996
63.
Liljegren G, Holmberg L, Adami H-O, et al: Sector resection with or without postoperative radiotherapy for stage I breast cancer: Five-year results of a randomized trial: Uppsala-Orebro Breast Cancer Study Group. J Natl Cancer Inst 86:712-722, 1994
64.
Hellman S: Stopping metastases at their source. N Engl J Med 337:996-997, 1997 Submitted April 21, 1998; accepted September 3, 1998.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test for categorical data and by the Student's t test for comparison of means. For the comparison of multiple means, the analysis of variance (ANOVA) or Kruskal-Wallis test was used.
