Treatment results and predictors of local recurrences after breast conserving therapy in early breast carcinoma

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1 Journal of BUON 8: , Zerbinis Medical Publications. Printed in Greece ORIGINAL ARTICLE Treatment results and predictors of local recurrences after breast conserving therapy in early breast carcinoma V. Parvanova, V. Pandova Department of Radiotherapy, National Hospital of Oncology, Sofia, Bulgaria Summary Purpose: The aim of this study was to access the influence of several factors on local control (LC) and overall survival (OS) in patients with early breast cancer after breast-conserving therapy. Patients and methods: 122 early breast cancer patients with tumor (T) up to 3 cm and breast-conserving surgery followed by radiotherapy, chemotherapy, or hormonal therapy were retrospectively analysed. Factors considered to carry possible significance in relation with local recurrence were classified into 3 groups that included characteristics of the patient, of the tumor and the non-surgical treatment methods applied. Results: With a median follow-up of 63.5 months (range months) LC was achieved in 116 (95.1%) patients. The median time to local recurrence was 30.3 months (range months). Of all the factors examined in the 3 groups, a negative statistical impact on LC was found only in high-risk node-negative patients (tumor size over 2 cm, high grade of malignancy, and absence of steroid receptors (SR); p=0.02). Ten-year OS was 95.8%, with statistical significance favoring stage I patients (98.5% versus 87.5% for stage I and II, respectively; p=0.05). Ten-year recurrencefree survival was 89.4%. Postponement of radiotherapy after chemotherapy did not change significantly either LC or OS (p >0.46). Adjuvant chemotherapy was administered to 22 (83.3%) node-positive patients, but only to 1 (12.5%) of node-negative high-risk patients. This resulted in unsatisfactory OS for the latter group of patients (90.2% versus 73.4%; p <0.000). Conclusion: In high-risk node-negative early breast cancer patients, the occurrence of early local recurrences and distant metastasis defines an aggressive disease behavior. Chemotherapy administration and its timing in relation with the delivery of radiotherapy constitutes an issue of future research for this group of patients. Key words: breast-conserving therapy, chemotherapy, local recurrence, predictive factors, radiotherapy without boost, skin recurrence Introduction Some of the key decisions in the current management of primary breast cancer involve the need Received ; Accepted Author and address for correspondence: Dr Vesselina Parvanova National Hospital of Oncology 6 Plovdivsko Pole Street 1756 Sofia Bulgaria Tel: , ext 323 Fax: v_parvanova@yahoo.co.uk for prognostication. The most relevant factors for the estimation of the risk for recurrence remain the nodal status and the number of the involved lymph nodes [1,2]. For patients with node-negative presentation, pathologic tumor size (T), histologic and nuclear grade (G), the absence or presence of SR in the tumor and age are factors considered to define differential prognosis [3-6]. Breast irradiation is clearly indicated after breastconserving surgery, and addition of radiotherapy to surgery has resulted in a 3-fold lower local recurrence rate compared with surgery alone [7,8]. Radiotherapy, as part of such treatment programs, should be delivered with modern techniques designed to reduce the volume of heart and great vessels receiving radiation, and must be coordinated with adjuvant che-

2 242 motherapy and/or hormonal therapy [9]. In most of the studies, high risk for local recurrences after breast -conserving therapy is related to the presence of positive surgical margins, and in some of them with younger patients age (less than 40 years) [6,10,11]. High risk for distant metastasis is associated with early occurrence of local recurrences involving the skin without involvement of the parenchyma of the remaining breast, or with supraclavicular nodal metastasis [12-14]. In this paper we tried to evaluate the effectiveness of radiotherapy and chemotherapy or hormonotherapy in patients with breast-conserving surgery of early breast carcinoma (stages I II) by evaluating factors affecting LC and OS. Patients and methods Between breast cancer patients with T up to 3 cm, N0-1, M0 completed their postoperative therapy at the Department of Radiotherapy, National Hospital of Oncology, Sofia. Breast-preserving operation was followed by radiotherapy, adjuvant chemotherapy, and antiestrogen therapy. Factors considered to carry prognostic significance for local recurrence were classified into 3 groups: 1. Characteristics of the patient: age, menstrual status, breast size, accompanying diseases damaging the small vessels, such as diabetes mellitus and arterial hypertension and related to high risk of irradiation damages, mastopathy, breast cancer family history in 1st and 2nd degree relatives, thyroid dysfunction and tumor localization in the breast. 2. Characteristics of the tumor: tumor size, axillary nodal status (number and level of involved lymph nodes), histological type, grade of malignancy, SR status, presence of extensive intraductal component (EIC), and stage of disease. T, G, and SR status in node-negative patients defined 3 risk groups of patients for distant metastasis, OS and the need for systemic adjuvant therapy (Table 1) [15]. 3. Characteristics of the applied treatment methods: total radiation dose, dose in organs at risk, clinical target volumes (CTV), ± adjuvant chemotherapy, ± adjuvant hormonotherapy, timing of application of radiotherapy and chemotherapy or hormonotherapy. Treatment methods Surgery Surgical treatment comprised quadrantectomy or lumpectomy with histologically confirmed negative resection margins, and radical axillary node dissection (all 3 levels) with more than 10 histologically confirmed resected lymph nodes. Systemic treatment Postoperative adjuvant chemotherapy was administered to 31 (25%) of all patients ( % patients with positive axillary lymph nodes, and 9-9.5%) patients with negative axillary lymph nodes), its application depending on disease stage (Figure 1). Three courses of CMF (cyclophosphamide, methotrexate and 5- fluorouracil) or CEF (cyclophosphamide, epirubicin and 5-fluorouracil) were administered before radiotherapy, and another 3 courses after the completion of radiotherapy. Adjuvant tamoxifen was given to patients with positive SR. In the first years of the study, tamoxifen was also given to some SR-negative or SR-unknown patients. Radiotherapy Radiotherapy was delivered to all of the patients. CTV included the preserved breast and the underlying chest wall (CTV I), and CTV II the supraclavic- Table 1. Risk groups and the need for systemic adjuvant treatment in node-negative patients[15] Tumor factors Low risk Moderate risk High risk T* (cm) <1 1-2 >2 SR Positive Positive Negative G G1 G1-2 G2-3 Systemic No treatment Adjuvant anti- Adjuvant treatment needed in the estrogen therapy chemotherapy presence of all 3 factors *tumor size; steroid receptors; grade of malignancy Figure 1. Patients with chemotherapy according to disease stage.

3 243 ular lymph nodes in patients with more than 3 positive axillary lymph nodes [16]. The prescribed dose in planning target volume (PTV) I was 50 Gy in 25 fractions, 5 times per week with no boost to the tumor bed, and in PTV II 44 Gy in 22 fractions, 5 times per week. Tolerant doses to organs at risk were: lungs 30Gy up to a depth of 3 cm calculated in the central lung distance of the central axis; front wall of the myocardium of the left ventricle 30Gy; and contralateral breast 5Gy. Statistical methods In the statistical analysis parametric methods were used, and proportions and means were compared by the x 2 test of Pearson and Fisher, respectively. Life table analyses were done using the Kaplan-Meier method. All tests were carried out using the SPSS software package. Survival was measured from the date of breast cancer diagnosis. The sufficient number of the studied cases and the adequate length of the follow-up period gave good reliability to the results and conclusions of this study. Results The median patients follow-up period was 63.5 months (range months). Most of the patients were premenopausal with Table 2. Patient characteristics (n=122) Characteristic n (%) Age (years, median 50) (18.9) (45.9) (11.5) >61 29 (23.7) Premenopausal 59 (51.6) Perimenopausal 26 (21.3) Postmenopausal 37 (30.3) Mastopathy 58 (47.5) Thyroid dysfunction 20 (16.4) Family history 20 (16.4) Breast size small 18 (14.8) medium 85 (69.7) large 19 (15.5) Tumor localization upper-lateral 88 (72.0) outer-lateral 22 (18.0) outer-medial 4 (3.0) upper-medial 8 (7.0) Table 3. Tumor characteristics (n=122) Characteristic n (%) Tumor size (cm) T1a < (11.5) T1b (44.3) T1c (38.5) T (5.7) Nodal status N 95 (77.9) N + 27 (22.1) Metastatic axillary lymph nodes (n) 1 21 (17.2) 2 4 (3.3) 3 2 (1.6) Stage I 90 (73.8) IIA 30 (24.6) IIB 2 (1.6) EIC 15 (12.2) Tumor grade G1 50 (41.0) G2 37 (30.3) G3 29 (23.8) unknown 6 (4.9) Steroid receptor status SR+ 85 (69.7) SR- 17 (13.9) unknown 20 (16.4) Risk group* low 41 (33.6) moderate 46 (37.7) high 8 (6.6) * in node-negative patients For abbreviations see text tumors in the upper-lateral quadrant (Table 2). Half of the patients with thyroid dysfunction had stage II disease in contrast with only 21% of those without such a dysfunction (p < 0.01). Most of the patients (55.8%) had tumors up to 1 cm, with negative axilla (77.9%; Table 3). No correlation was found between histological tumor type and age of the patients; however, mucinous carcinomas showed a trend to appear in older patients. Mucinous, papillary, medullary and tubular histologies showed a statistically significant prevalence of low grade malignancy (p=0.03). In our study all of the patients had a negative resection line, and 15 (12.2%) of them an EIC accompanying the invasive tumor. The CTV I was applied in 107 (87.7%) patients, while the additional CTV II was applied in another 15 (12.3%) patients. The latter group represented 46.8% of stage II patients, while the rest of stage II nodepositive patients received chemotherapy without supraclavicular lymph node irradiation.

4 244 An average dose of Gy was applied for CTV I, without boost to the tumor bed. Patients with CTV II received Gy at a depth of 3 cm. In 92 (75.5%) of all patients (91 without chemotherapy and 1 with chemotherapy) radiotherapy started days postoperatively. Thirty (24.5%) patients started radiotherapy approximately 3 months postoperatively, after 3 courses of adjuvant chemotherapy. Chemotherapy in node-negative patients was administered as follows: in the group with low risk for distant metastasis no chemotherapy was given; in the group with moderate risk chemotherapy was given to 8 (17.4%) of the cases; and in patients with high risk it was given only to 1 (12.5%) of them after the end of radiotherapy. Chemotherapy was administered to 22 (83.3%) node-positive patients. Hormonal therapy with tamoxifen was administered to 83 (68%) of all the patients. It was given to 70 (82.4%) patients with positive SR, to 3 (17.6%) with negative SR and to 10 (50%) with unknown SR. Ten-year LC was achieved in 116 (95.1%) of the patients, while 6 (4.91%) patients developed locoregional recurrence (Table 4). The median time to locoregional relapse was 30.3 months (range months). There was no statistically significant correlation between local recurrences and tumor size and disease stage. Three of the local recurrences were skin lesions of the preserved breast without involvement of the breast parenchyma, had the same histology with the primary tumor and measured up to 1.5 cm. One patient developed breast cancer in the remaining breast, with a different histology from the primary tumor. Two patients developed metastatic supraclavicular lymph nodes, without recurrence in the breast. Two patients with skin localization and one with supraclavicular nodal metastasis developed distant metastasis in the lung and liver after 1 and 2.9 months, respectively. Another patient developed cancer in the other breast after 20 months. The tumor had the same histology with the first one. Seven (5.7%) patients developed distant metastasis (2 liver, 3 bone, 1 brain and 1 lung disease), Table 4. Ten-year locoregional recurrence Locoregional recurrence n (%) Remaining breast / skin 1/3 (3.27) Supraclavicular nodes 2 (1.64) Total 6 (4.91) Figure 2. Ten-year recurrence-free survival. after a median of 24.8 months (range months). Only 2 of them had also locoregional relapse. The achieved very good therapeutic results with conservative treatment of early breast carcinoma (Figure 2) did not allow the distinction of risk factors for LC and OS with high statistical value. Factors related to patient characteristics The age of patients, distributed in 4 groups (Table 2), did not show statistical connection with the occurrence of local relapses (p=0.5), distant metastasis (p=0.2) or OS (p=0.3). Also, the menopausal status, presence of mastopathy, and size of the breast did not show any significant relation with LC, distant metastasis or OS. Fifty percent of patients with thyroid dysfunction had stage II disease versus 21% of the patients without thyroid dysfunction (p=0.02). Thirty-seven percent of the patients with thyroid dysfunction developed distant metastasis with statistically significant difference in mortality between patients with or without thyroid dysfunction (10% versus 1.9%, p=0.01), which is a reason for future studies. Patients with family history for breast cancer did not show worse results in terms of LC, distant metastasis or OS compared to those without such a history. The localization of the primary tumor in topographic quadrants of the breast was not connected with LC or distant metastasis (p=0.9). Factors related to tumor characteristics All of the patients in the present study had histologically confirmed negative surgical margins. Cases with EIC accompanying invasive tumor did not show a difference in the occurrence of local recurrences or OS. Tumor size up to 2 cm, the presence of positive axillary lymph nodes and their number, the presence of negative SR and a high grade of malignancy did not differ as single unfavorable risk factors concerning LC as well as OS. The stage of disease did not show any significant relation with LC, but a significant relation with OS was noted (98.5% versus 87.5% for stage I and II, respectively; p=0.05).

5 245 both LC and OS were significantly related with chemotherapy administration in high-risk node-negative patients. Discussion Figure 3. Local recurrence (LR) and overall survival (OS) in different risk node-negative patients and in node-positive patients. Only when the combination of the unfavorable factors in node-negative patients (high grade of malignancy, tumor size >2 cm and absence of SR, forming the high risk group for OS) was taken into account, a statistically significant relation was found for the reduction not only of the OS but also of the LC rate (Figure 3). Factors related to treatment methods The applied doses and the different CTVs did not show any significant influence on treatment results. The administration of chemotherapy in all of the patients who received it did not show a statistically significant improvement of the LC rate, since 3.2% of the patients with postoperative chemotherapy recurred, compared to 4.3% of those without chemotherapy (p=0.30). Only 1 (12.5%) of the high-risk node-negative patients received chemotherapy, which resulted in high mortality (25%), compared to node-positive patients, where mortality was 7.4% (p=0.002; Figure 4). Thus Figure 4. Mortality in different risk node-negative patients and in node-positive patients. The occurrence of local relapses after breastconserving therapy is evaluated at 0.8% annually, which is characteristic for breast-conserving therapy of the early breast cancer. Most often, local failures after breast-conserving treatment are related with the status of the surgical margins and the age of the patient [9,10,17]. The influence of positive margins on the local tumor control is most powerful compared to the other factors (negative SR, G3, EIC), where the results are still controversial [1-4,18-20]. The treatment of node-negative patients varies substantially. In our study, only 1 (12.5%) of high-risk node-negative patients received chemotherapy after the end of radiotherapy because of risk underestimation. In this group of patients the 5-year OS was only 73%, which is even lower than the one observed in node-positive patients (90.2%). The 2 patients with skin recurrence and almost simultaneous development of distant metastasis makes us believe that these cases are not a failure of local treatment, but they may be considered as representing a process of aggressive disease dissemination, requiring the administration of adjuvant chemotherapy [21-24]. The highly selected group of patients in our study with negative surgical margins, tumor size up to 3 cm (only 5.7% of them had a tumor between 2 to 3 cm), and presence of more than 4 positive lymph nodes in 5% of the patients, does not enable a clear distinction of unfavorable factors for the development of local recurrences. Our results are in agreement with relevant studies, showing that early local recurrences and skin relapses are related to an aggressive disease followed by the development of distant metastasis [14,15,19,25]. Published data relate local relapses with reduced OS in node-negative patients with breastpreserving therapy of early breast cancer [21-23,25]; in our study the OS of high-risk node-negative patients reached 73.3% compared to 90.2% of nodepositive patients (Figure 3). The administration of chemotherapy, the combination of the drugs, the number of cycles and the sequence of its administration with radiotherapy or their concurrent application constitute an issue for future research in node-negative high-risk early breast cancer patients with breast-conserving therapy.

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