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Impact of Systemic Treatment on Local Control for Patients With Lymph Node–Negative Breast Cancer Treated With Breast-Conservation Therapy

From the Departments of Radiation Oncology, Biomathematics, Breast Medical Oncology, and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Thomas A. Buchholz, MD, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 97, Houston, TX 77030; email: tbuchhol{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the impact of tamoxifen and chemotherapy on local control for breast cancer patients treated with breast-conservation therapy.

PATIENTS AND METHODS: The data from 484 breast cancer patients who were treated with breast-conserving surgery and radiation were analyzed. Only patients with lymph node–negative disease were studied to provide comparative groups with a similar stage of disease and a similar competing risk for distant metastases. Actuarial local control rates of the 277 patients treated with systemic therapy (128, chemotherapy with or without tamoxifen; 149, tamoxifen alone) were compared with the rates for the 207 patients who received no systemic treatment. Only 10% of the patients had positive (2%), close (3%), or unknown margin status (5%).

RESULTS: Patients treated with systemic therapy had improved 5-year (97.5% v 89.8%) and 8-year (95.6% v 85.2%) local control rates compared with those that did not receive systemic treatment (P = .004, log-rank test). There was no statistical difference in local control between patients treated with chemotherapy and patients treated with tamoxifen alone (P = .219). Systemic treatment, margin status, young patient age, estrogen and progesterone receptor status, and primary tumor size were analyzed in a Cox regression analysis. The use of systemic treatment was the most powerful predictor of local control: patients who did not receive systemic treatment had a relative risk of local recurrence of 3.3 (95% confidence interval, 1.5 to 7.5; P = .004).

CONCLUSION: In this retrospective analysis, systemic therapy appears to contribute to long-term local control in patients with lymph node–negative breast cancer treated with breast-conservation therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE PERCENTAGE of breast cancer patients diagnosed with early stage disease has significantly increased over the past two decades.¹ Simultaneously, there has been a dramatic increase in the use of breast-conserving local treatments for these women. This change in practice resulted from randomized studies showing that breast conservation therapy provided an outcome equivalent to a modified radical mastectomy for patients with early stage breast cancer.^2,3 The ipsilateral breast recurrence rates in these randomized trials were approximately 1% per year, which permitted 90% of the women treated with breast-conservation therapy to avoid mastectomy during a 10-year period of follow-up.^2,3 Also during this era, clinical trials proved that systemic treatment with chemotherapy and/or tamoxifen improved the probability of survival for both women with lymph node–positive disease and the majority of women with lymph node–negative disease.^4,5

The randomized trials investigating systemic therapy in early stage breast cancer had recurrence-free survival and overall survival as their endpoints. Less information is available concerning the impact of systemic treatment on local recurrence rates after breast-conserving local treatment. This issue is becoming more important as the percentage of breast cancer patients with stage I disease increases. In these patients, local recurrences account for one third to one half of the total number of treatment failures.

In this article, we report the results of a retrospective analysis investigating the impact of systemic therapy on local recurrence rates after breast-conserving surgery and radiation. An inherent difficulty and potential shortcoming of such a retrospective analysis is that a number of clinical and pathologic factors likely influenced the decision to use or not use systemic treatment. To minimize some of the major confounding factors, we elected to study only women with lymph node–negative breast cancer that were treated with breast-conserving surgery and radiation. Since nearly all of the women with lymph node–positive disease treated during the years of this study received systemic treatment, we could not evaluate the impact of systemic treatment on local control in patients with this stage of disease. Focusing our study on patients with lymph node–negative disease also selected a population with a low competing risk for the development of metastatic disease.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between 1987 and 1995, 484 breast cancer patients with pathologically negative lymph nodes were treated with breast-conserving surgery and radiation at our institution. The records from these patients were retrospectively analyzed. We chose the years included in this study, before data abstraction, because they encompassed an era when an attempt to achieve negative surgical margins was the routine.

All patients underwent a segmental mastectomy with axillary lymph node dissection. Final surgical margins were negative ( 2 mm) in 90% of the cases. In the remaining 10% of the cases, 2% had positive margins (tumor cells present at inked margin), 3% had close margins (< 2 mm), and in 5% the margin status was unknown. All patients were treated with radiation involving only the ipsilateral breast. The median dose to the breast was 50 Gy delivered in 25 fractions over a 5-week treatment course with photons from a linear accelerator. A tumor bed boost (median dose, 10 Gy) was delivered in 57%, and only two patients were treated with a brachytherapy boost.

Two hundred seven patients (43%) were treated with surgery and radiation alone, whereas 277 patients received systemic therapy in addition to the surgery and radiation. The decision to use systemic treatment was made by the treating medical oncologist and the patient and was likely influenced by prognostic variables of the particular case. Of those treated systemically, 149 patients were treated with tamoxifen alone and 128 patients were treated with systemic chemotherapy with or without tamoxifen. Doxorubicin-based combination chemotherapy was used in 107 of these patients, with 77 receiving six cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide. An additional 18 patients were treated with cyclophosphamide, methotrexate, and 5-fluorouracil, and three patients were treated with other non–doxorubicin-containing regimens. Of the patients treated with chemotherapy, only 13 were subsequently treated with tamoxifen. Fifty-nine patients received radiation followed by chemotherapy (46%), and 69 patients received chemotherapy followed by radiation (54%). The median time interval from surgery to radiation in patients treated with chemotherapy first was 6.7 months. The median time interval from surgery to chemotherapy in patients treated with radiation first was 3.0 months. We have previously reported the effect of the sequencing of chemotherapy and radiation on clinical outcome in the patients treated with chemotherapy.⁶

The method of Kaplan and Meier⁷ was used to generate actuarial local control curves for various subgroups of patients. All event and follow-up times were measured from the date of diagnosis. Two-sided log-rank tests were used to detect differences in actuarial data. The data were also analyzed using the cumulative incidence methodology.⁸ Because these analyses essentially provided the same results, only the results using the Kaplan-Meier data were reported. A Cox proportional hazards model was used to determine independent variables associated with local control.⁹ Cases with unknown factors were excluded in the initial Cox regression analysis. If a factor did not predict for local control, the cases with unknown values for that factor were again added, and the Cox regression was repeated with that particular factor dropped. A Fisher’s exact test was used to compare clinical and tumor characteristics of populations. Unknown values were not included in the Fisher’s exact tests.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Table 1 lists the patient and tumor characteristics for the patients divided according to the use of systemic treatment. As shown, the two groups (systemic treatment v no systemic treatment) were comparable with respect to the percentage of patients under the age of 40 and the progesterone receptor status. However, within those receiving systemic treatment, the patients treated with chemotherapy had a higher percentage of patients under 40 compared to those treated with tamoxifen alone. As expected, several other prognostic features differed in the two populations. Specifically, the patients treated with systemic therapy more often had primary tumor sizes exceeding 2 cm and more often had close or positive surgical margins. In contrast, the patients who did not receive systemic treatment more often had estrogen receptor–negative disease.

View larger version (17K): [in this window] [in a new window]   Fig 1. Actuarial local control curves according to the use of systemic treatment.

View larger version (16K): [in this window] [in a new window]   Fig 2. Actuarial local control curves for the cohort of patients treated with systemic therapy according to use of tamoxifen alone or chemotherapy.

View larger version (15K): [in this window] [in a new window]   Fig 3. Actuarial local control curves according to patient age < 40 or 40 at the time of diagnosis.

To further account for the different age distributions between the control, chemotherapy, and tamoxifen groups, we also compared the local control rates of the women older than 50 treated with tamoxifen (n = 127) to the women older than 50 in the control group (n = 112). The 8-year local control rates for these two groups were 99% in the tamoxifen group versus 88% in the control group (P = .013). In addition, we compared the local control rates of the women less than or equal to 50 years old treated with chemotherapy (n = 106) to the women less than or equal to 50 in the control group (n = 95). The 8-year local control rates for these two groups were 93% in the chemotherapy group versus 82% in the control group (P = .057).

Figure 4 displays actuarial local control curves for the entire population of patients divided according to both age (< 40 v 40) and the use of systemic treatment. The 5-year local control rates were 95% in the 46 patients less than 40 treated with systemic treatment and 74% in the 29 patients less than 40 who were not treated with systemic therapy (P = .077). The median intervals to local recurrence for the two systemically treated subgroups were 59 months for the younger patients and 34.5 for the older patients. The median intervals to local recurrence for the two subgroups not treated with systemic therapy were 46 months for the younger patients and 39.5 for the older patients.

View larger version (25K): [in this window] [in a new window]   Fig 4. Actuarial local control curves according to patient age < 40 or 40 and the use of systemic treatment.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The randomized data concerning the efficacy of systemic treatment in early stage breast cancer have focused on its role in minimizing the development of distant metastases. Fewer data are available on how the use of systemic therapy affects local control rates after breast-conserving surgery. It is clear that systemic therapy cannot be safely used as a substitute for breast radiation in the treatment of early stage breast cancer. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-06 trial, the 12-year rate of local recurrence in patients treated with lumpectomy and chemotherapy (no radiation) was 40% compared with a 10% rate in patients treated with lumpectomy and radiation.² In the Scottish randomized trial, favorable breast cancers treated with either lumpectomy and tamoxifen or lumpectomy and chemotherapy had higher 6-year local recurrence rates compared with patients receiving breast radiation.¹¹

Although systemic therapy does an inadequate job of preventing local recurrence after treatment with breast-conserving surgery alone, it has a positive impact on local control when it is used in conjunction with surgery and breast radiation. In this report, we found that the use of systemic therapy was the most powerful independent prognostic indicator for achieving local control after treatment with breast-conserving surgery and radiation. This effect was achieved even in a population considered to be at relatively low risk for local recurrence. Specifically, we focused our study on patients treated during the era in which surgical margins were routinely assessed, and we evaluated only patients with lymph node–negative disease.

The patients in this study had a median follow-up of only 66 months, so we cannot rule out the possibility that systemic treatment may delay rather than prevent local recurrences. It should also be noted that the small number of local recurrences that developed in our study population limits the certainty of our results. Another aspect of this study that warrants consideration is our decision to present the majority of our data with all patients treated with systemic therapy combined into one group. We felt this was justified in that there are published data suggesting both types of systemic treatments decrease local recurrence. Indeed, in our Cox regression analyses, both chemotherapy and tamoxifen use were associated with a reduced hazard ratio for local recurrence compared with the patients who did not receive systemic treatment.

The data from this series support the results of a number of randomized trials that have also suggested that systemic therapy has a positive benefit on local control after breast-conserving surgery and radiation. In the NSABP B-06 trial, patients treated with lumpectomy and breast radiation received systemic chemotherapy only if they had lymph node–positive disease. The 12-year local failure rate was less than 5% in lymph node–positive patients treated with lumpectomy, radiation, and chemotherapy compared with 10% in the lymph node–negative patients treated with surgery and radiation alone.² The NSABP B-13 and B-14 trials were randomized studies designed to test the systemic efficacy of chemotherapy (B-13) or tamoxifen (B-14) for women with lymph node–negative breast cancer. Both of these studies showed that systemic treatment decreased ipsilateral breast recurrences. In the patients treated with breast-conservation therapy in the B-13 trial, the use of chemotherapy decreased the 8-year rate of breast recurrences from 13% to 2.6% (P = .001).¹² The B-14 trial showed that tamoxifen use also decreased ipsilateral breast recurrences (10-year recurrence rates of 3.4% for those treated with tamoxifen v 10.3% for those not treated with tamoxifen; P < .001).¹³ In an abstract publication of NSABP B-21, tamoxifen similarly improved local control rates in patients with lymph node–negative breast cancers measuring less than 1 cm. There was only a 0.36% annual breast tumor recurrence rate in women randomized to lumpectomy, radiation, and tamoxifen compared with a 1.2% annual rate in women treated with lumpectomy and radiation alone.¹⁴ Finally, data from a Swedish randomized trial investigating tamoxifen use in early stage disease showed that tamoxifen reduced ipsilateral (hazard ratio, 0.4) and contralateral (hazard ratio, 0.4) breast tumor recurrences in the 432 patients with lymph node–negative disease treated with breast-conserving surgery and radiation.¹⁵

In contrast to these data, Fowble et al¹⁶ did not find a statistically significant decrease in local recurrence according to tamoxifen use in 491 women with estrogen receptor–positive tumors treated with breast-conserving surgery and radiation. The 5-year actuarial local recurrence rate in the 337 patients who did not receive tamoxifen was 7% compared with a 4% rate in the 154 patients treated with tamoxifen (P = .21). In the subgroups of patients with lymph node–negative disease (319, no tamoxifen; 87, tamoxifen) there was also no difference in local recurrence (P = .29). This series differed from ours in that the control group included only patients with estrogen receptor–positive tumors, and therefore the median age of the patients was higher (62 years old). In another retrospective analysis, Wazer et al¹⁷ also reported that tamoxifen was not an independent predictor of local control, although the 10-year rate of local recurrence was only 1.9% for those treated with tamoxifen versus 8.4% in those not treated with tamoxifen. In contrast to these studies and similar to our current study, Haffty et al¹⁸ reported that the use of systemic therapy and age over 35 were independent predictors of local control. The Haffty et al study included both patients with lymph node–negative and lymph node–positive disease, so there was a significant difference in the stage of the two comparison groups.

Our series also differs from the above retrospective studies because only 2% of the study population had positive surgical margins. For example, 36% of the patients in the Fowble et al¹⁶ report had positive, close, or unknown margin status compared with a rate of only 10% in our study. There have been a number of recent articles evaluating whether systemic therapy overcomes the negative prognostic aspect of margin status. A report of 184 patients treated at the Royal Marsden Hospital with lumpectomy, radiotherapy, and chemoendocrine therapy noted a local recurrence rate of only 1.9% (median follow-up, 57 months), even though 38% of their population had unexcised, microscopically involved margins.¹⁹ In a report of 533 patients treated with conservative surgery and radiation at the Joint Center of Radiation Therapy, a multivariate analysis revealed that systemic treatment and margin status were the only two independent predictors of local control.²⁰ Moreover, the crude local recurrence rate at 8 years was 7% in the 45 patients with focally positive margins treated with systemic therapy versus 18% in the 77 patients with focally positive margins who did not receive systemic therapy. For the patients with more extensive margin involvement, the use of systemic therapy did not reduce local recurrence (26% v 29%). Data from Fox Chase Cancer Center suggested that systemic therapy may delay but does not prevent local recurrences in patients with close or positive margins. In this cohort of patients, systemic therapy appeared to reduce the local recurrence at 5 years (11% v 5%), but at 10 years this effect was much less (16% v 12%).²¹ In the Fox Chase study, the use of systemic therapy did not appear to affect local recurrence in their subset of patients with negative margins.²¹

In addition to margin status, young age has been recognized by many authors to be an independent risk factor for breast tumor recurrence.^18,22-25 Our own results corroborate these data and suggest that the negative effect of young age may be minimized by the use of systemic therapy. Specifically, the 5-year local recurrence rate in the patients under 40 who received systemic treatment in addition to surgery and radiation was only 5%. In contrast, the 5-year local recurrence rate in the patients under 40 who did not receive systemic treatment was 26%. Given the small size of the young age groups in our comparison, there is a need for additional data investigating this question.

We did not demonstrate a difference in local control according to the type of systemic treatment (tamoxifen alone v chemotherapy; P = .219). Furthermore, in our Cox regression analyses, both the use of tamoxifen (P = .022) and the use of chemotherapy (P = .057) decreased the hazard ratios for a local recurrence compared to that of the patients not receiving systemic treatment. We did not have sufficient data to compare whether the use of both types of systemic therapy further reduces the risk for local recurrence. However, in the NSABP B-20 trial, which compared the efficacy of chemotherapy and tamoxifen versus tamoxifen alone in lymph node–negative patients treated with breast-conservation therapy, there was a lower local recurrence rate in patients treated with both chemotherapy and tamoxifen (annual rate, 0.22% to 0.48%) versus tamoxifen alone (annual rate, 0.88%; P < .025).²⁶

In conclusion, our data indicate that the 8-year breast local recurrence rate for patients treated with breast-conserving surgery, radiation, and systemic treatment is less than 5%. Tamoxifen is currently advocated for patients with noninvasive breast cancer because of its benefit in reducing local and contralateral breast recurrences.²⁷ Our data add to the accumulating literature suggesting that systemic treatment may have an equally beneficial role in reducing local recurrences in invasive disease. Therefore, clinicians should consider both the degree of reduction in distant metastases and the degree of improvement in local control when making decisions regarding systemic treatment, particularly in young patients.

	ACKNOWLEDGMENTS

 
Supported in part by National Cancer Institute Department of Health and Human Services grant nos. CA16672 and T32CA77050. T.A.B. is supported by grant no. BC980154, an USAMRMC Breast Cancer Research Program Career Development Award.

	NOTES

 
Presented at the Eighty-Second Annual Meeting of the American Radium Society, London, England, April 1-5, 2000.

	REFERENCES

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Submitted May 3, 2000; accepted January 11, 2001.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Buchholz, T. A. Articles by Hunt, K. K. Search for Related Content PubMed PubMed Citation Articles by Buchholz, T. A. Articles by Hunt, K. K. Social Bookmarking                            What's this?