The role of postoperative radiotherapy in node negative breast cancer patients with pT3–T4 disease

EJSO 33 (2007) 285e293

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The role of postoperative radiotherapy in node negative breast cancer patients with pT3eT4 disease G. Aksu a,*, S. Kucucuk b, M. Fayda a, M. Saynak c, S. Baskaya b, P. Saip d, N. Ozturk d, I. Aslay b a

Kocaeli University Faculty of Medicine, Radiation Oncology Department, Yahyakaptan Mahallesi F 29 Blok Daire: 12, Kocaeli, Turkey b Istanbul University Oncology Institute, Radiation Oncology Department, Istanbul, Turkey c Trakya University, Faculty of Medicine, Radiation Oncology Department, Edirne, Turkey d Istanbul University Oncology Institute, Medical Oncology Department, Istanbul, Turkey Accepted 24 October 2006 Available online 4 December 2006

Abstract Aims: To evaluate the role of postmastectomy radiotherapy (PMRT) in patients with pT3eT4N0M0 breast cancer. Methods: 156 patients with T3eT4N0M0 breast cancer were retrospectively analyzed. Results: Locoregional recurrences were seen in 17 of 156 patients with a median time for development of 27 months (5.7e248.7 months). Two of 9 patients who were not treated with post-operative radiation therapy had locoregional recurrence as compared with 16 of 147 patients receiving radiotherapy. In multivariate analysis, presence of locoregional recurrence was the only significant prognostic factor for overall survival (18% vs. 86%, p < 0.001, RR ¼ 9.05). The patients with a median number of dissected lymph nodes 10 had a significantly better locoregional disease free survival rate as compared with patients with dissected lymph nodes <10 (90% vs. 78%, p ¼ 0.04). Chest wall recurrences were clearly higher in patients without chest wall RT since 5 of 49 patients without RT had recurrences in the chest wall region while only 4 of 107 who received chest wall RT had recurrence. However receiving RT to peripherical lymphatic regions had no additional effect on reducing recurrences in these regions (5% vs. 4%). Conclusions: Due to the lack of phase III randomized trials directly addressing the role of postmastectomy radiotherapy in these stages, our series suggest that postmastectomy radiotherapy to the ipsilateral chest wall is recommended for patients with PT3N0 and T4N0 breast cancer. The need for irradiating axillary or supraclavicular region shall be neglected in patients who undergo sufficient axillary sampling. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; T3N0; Node-negative disease; Radiotherapy; Prognostic factors; Locoregional recurrence

Introduction Most of the patients with breast cancer without nodal involvement have T1 or T2 disease and T3N0M0 or T4N0M0 breast cancer is relatively rare. In a recent population based study from Denmark and Sweden that analyzed 3148 breast cancer patients treated between 1983 and 1989 only 33 patients were classified as pT3N0M0.1 Another trial from Finland confirmed these findings by informing that only 38 patients had pathologically proven T3N0 disease among 4190 breast cancer patients.2 Trudeau et al. also recently reported that of 415 patients with node-negative breast cancer

* Corresponding author. Tel.: þ90 533 687 5814. E-mail address: [email protected] (G. Aksu). 0748-7983/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2006.10.037

during a 10 years period only 18 patients had pathologically proven T3N0 disease.3 As seen the true pathological T3e4N0M0 breast cancer is relatively rare and the identification of patients with node negative breast cancer that are likely to develop locoregional or systemic disease and might benefit from adjuvant therapy still remains a challenge. Especially for breast cancer patients who have a primary tumor larger than 5 cm in diameter without regional lymph node metastases (pT3N0M0) there is little data in the literature for decision making to regard whether to give post-operative radiotherapy or not. In most of the series these tumors are evaluated together either with T4 cancers or axillary lymph node positive cancers reflecting the relative rarity of such patients and still in many centers treatment decision is made depending on the local practice.

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In the present study we retrospectively analyzed 156 patients with pT3N0M0 and pT4N0M0 disease admitted to Istanbul University Oncology Institute regarding the prognostic factors and the role of radiotherapy in these subgroups separately with a comparison of the results with the literature. Methods 156 female patients with histopathologically proven T3N0 and T4N0 breast cancer without any detectable distant metastasis (4% of the 3400 breast cancer patients referred to Istanbul University Oncology Institute between 1975 and 2000) were retrospectively analyzed. Among these patients, 133 had pT3N0 disease and 23 patients had pT4N0 disease. The median age of the whole group was 47 (26e78) and the median follow-up was 90 months (6e263 months). The patients were divided into two groups and Group A consisted of patients with pT3N0 disease and Group B consisted of patients with PT4N0 disease. Group A (PT3N0M0) (133 patients) Group A consisted of 133 patients with pT3N0M0 breast cancer. Radical mastectomy was performed in 24 patients, modified radical mastectomy in 101 patients and the remaining 8 patients were treated with breast conserving surgery (BCS). All patients had Level I and II axillary dissection. The median number of pathologically examined axillary nodes was 11 (5e40). The characteristics of patients with pT3N0M0 disease are shown in Table 1. Radiotherapy

Table 1 Characteristics of patients with pT3N0M0 disease (Group A) Patients

Whole group, n ¼ 133

Radiotherapy given, n ¼ 125

Age (median ¼ 47) <50 50e65 >65

78 40 15

75 37 13

Menopause status Premenapausal Postmenapausal

78 55

75 50

Histopathology Invasive ductal carcinoma (IDC) Invasive lobular carcinoma (ILC) Others

108 5 20

101 5 20

Surgery type MRM BCS RM

101 8 24

93 8 24

Pathologically examined axillary nodes <10 10

30 103

27 98

Surgical margins <3 mm 3 mm

20 113

20 108

Systemic therapy Only CT Only HT CT þ HT No systemic treatment

16 40 36 41

15 34 35 41

Radiotherapy type Only chest wall/breast Chest wall/breast þ Peripheral lymphatics Only peripheral lymphatics No RT

42 52 31 8

42 52 31

Of these 133 patients, 125 received postoperative radiotherapy so the remaining 8 patients were excluded from statistical analysis for disease-free and overall survivals for Group A. A total dose of 45e50 Gy to the chest wall and/or peripheral lymphatics was administered with 2 Gy daily fractions by Co60e6 MV photon beams and electron beams after mastectomy. In patients treated with BCS, following 50 Gy whole breast irradiation with 2 Gy daily fractions with Co60 or 6 MV photon beams, a boost dose of 10 Gy with electron beams of 8e12 MeV energy was applied to the tumor bed. Among these 125 patients, only chest wall or whole breast was irradiated in 42 patients, chest wall and peripherical lymphatics were irradiated in 52 patients and only peripheral lymphatics were irradiated in 31 patients (all of the patients receiving radiotherapy to only peripheral lymphatics without chest wall were treated before 1987).

patients used tamoxifen (TMX) (20 mg/daily) for 2e5 years. Thirty-six patients received both chemotherapy (CT) and hormonotherapy (HT) and 41 patients received no systemic treatment. The staging examinations of chest X-ray, bilateral mammography, liver ultrasound examination, isotope bone scan, and blood tests including the liver chemistry profile were performed to evaluate the presence of distant metastatic disease at diagnosis. The median follow-up time was 90 months. The local and regional recurrences were defined as any recurrence in the skin or the soft tissue over the chest wall or in the breast and in the regional lymphatics (axilla, internal mammary, supraclavicular, infraclavicular). Distant recurrence was defined as a recurrence outside the ipsilateral chest wall or regional lymphatics.

Chemotherapy and hormonotherapy

Group B (pT4N0M0) (23 patients)

Totally 52 patients received adjuvant chemotherapy. Chemotherapy protocols are shown in Table 1. Seventy-six

Group B consisted of 23 patients with pathologically proven T4N0M0 disease. All of the patients were treated

G. Aksu et al. / EJSO 33 (2007) 285e293 Table 2 Characteristics of patients with pT4N0M0 disease (Group B) Patients

n ¼ 23

Age (median ¼ 47) <50 50e65 >65

15 5 3

Menopause status Premenopausal Postmenopausal

13 10

Surgery type MRM BCS RM

22 0 1

287

times were calculated with the KaplaneMeier method and compared with the log-rank test. Independent factors that adversely affect survival and time to progression were determined with the Cox proportional ratio. The chi-square (c2) test was used for comparison of qualitative variables, and to evaluate the linear relationship between pairs of quantitative variables. A value of p < 0.05 was considered to be statistically significant. Results Prognosis and recurrence

All of the 23 patients with pT4N0M0 disease received systemic therapy. Of these patients 13 received both CT and HT, 6 only CT and 4 patients received only HT. Totally 52 patients received adjuvant chemotherapy.

At the median follow-up time of 90 months, 15-year overall survival, disease free survival and locoregional disease-free survivals for all 156 patients were 72.5%, 74% and 87.5% ( p ¼ NS). In subgroup analysis, 10-year overall survivals for patients with pT3N0 and pT4N0 disease were 79.4% and 71.4% respectively with no significant difference ( p ¼ NS). Ten-year locoregional disease-free survivals were 87% and 90%, respectively ( p ¼ NS). Ten-year disease-free survivals for the both groups were 73% and 72% again with no significant difference ( p ¼ NS). Distant metastases occurred in 30 of 156 patients during follow-up. The most frequent metastatic site was lung (11 patients) followed by bone (10 patients) and liver (7 patients). The median time to development of distant metastases was 29.4 months (3.83e114 months) and 65% of distant metastases had developed during the first 5 years following surgery. The median survival following systemic recurrences was 17.2 months. Locoregional recurrences were seen in 17 of 156 patients. The median time for development was 27 months (5.7e248.7 months) and % 77 of locoregional recurrences had developed during first 5 years. The median survival following locoregional recurrences was 41.1 months. Two of 9 patients who were not treated with post-operative radiation therapy had locoregional recurrence as compared with 16 of 147 patients receiving radiotherapy. However, 15-year OS of the both groups were similar (72.7% vs. 72.9%). There were also no significant differences between disease-free survivals (73.4% vs. 88.9%) and locoregional disease-free survivals (77.8% vs. 88%) ( p ¼ NS). Ten of 17 locoregional recurrences were located in the chest wall only, 5 in the ipsilateral axillary region and 2 recurrences were located in the ipsilateral supraclavicular region. There were no clinical internal mammarian node chain recurrences. The distribution of locoregional failures according to sites is shown in Table 4.

Statistical analyses

Prognostic factors

All statistical analyses were carried out with SPSS package program, version 7.5. The survival and progression

Age at diagnosis (<50 vs. 50 years), tumor size (5e7 cm vs. >7 cm), number of dissected axillary lymph

Pathologically examined axillary nodes <10 10

4 19

Surgical margins <3 mm >3 mm

2 21

Systemic therapy Only CT Only HT CT þ HT

6 4 13

Radiotherapy type Only chest wall Chest wall þ Peripheral lymphatics Only peripheral lymphatics No RT

8 14 0 1

with mastectomy and axillary dissection. The median number of pathologically examined axillary nodes was 11 (7e35). The patient characteristics of Group B are shown in Table 2. Radiotherapy Of these 23 patients all but one patient received postoperative radiotherapy since only 1 patient refused RT. Among these 22 patients receiving RT, only chest wall was irradiated in 8 patients and chest wall and peripherical lymphatics were irradiated in 14 patients. A total dose of 45e50 Gy to the chest wall and/or peripheral lymphatics was administered with 2 Gy daily fractions by Co60e6 MV photon beams or electron beams after mastectomy. Chemotherapy and hormonotherapy

G. Aksu et al. / EJSO 33 (2007) 285e293

288

Table 3 The relationship between prognostic factors and 15-year overall and locoregional disease-free survivals in 156 patients N

15 year locoregional disease free survival

Univariate Log-rank p

15 year overall survival

Univariate Log-rank p

Age >50 50

58 98

87,6% 87,4%

NS

86% 65%

0.28

Menopausal status Pre-menopausal Post-menopausal

91 65

85,7% 90,2%

NS

68% 80%

0.86

*Stage T3N0 T4N0

133 23

87% 90%

NS

73% 71%

0.6

Histopathology Invasive ductal Ca. Invasive lobular Ca. Other

124 7 25

87% 68% 91%

NS (Between ductal-lobular p ¼ 0.05)

74% 64% 68%

0.24

Tumor size £7 cm >7 cm

130 26

78,8% 89,1%

NS

78% 62%

0.21

Total number of dissected nodes <10 10

34 122

78% 90%

0.04

60% 74%

0.82

Surgical margin 3 mm <3 mm

134 22

88% 82%

NS

75% 50%

0.38

RT type Only chest wall-breast Chestwall/breast þ peripheral lymphatics Only peripheric lymphatic No RT

50 66 31 9

93% 87% 79% 77%

NS

85% 65% 70% 72%

0.26

Systemic treatment Only chemotherapy (CT) Only hormonotherapy (HT) CT þ HT No systemic treatment

22 44 49 41

90% 88% 88% 82%

NS

69% 84% 61% 72%

0.18

e

18% 86%

Locoregional recurrence Present Absent

17 139

e

nodes (<10 vs. 10), locoregional recurrence status (absent vs. present), radiotherapy (absent vs. present) hormonotherapy (absent vs. present), chemotherapy (absent vs. present) and stage were analyzed as prognostic factors. In multivariate analysis, presence of locoregional recurrence was the only significant prognostic factor for overall survival. The patients with locoregional recurrence had a significantly lower overall survival rate as compared with Table 4 The distribution of locoregional failures according to the RT fields Sites of failure

Number of locoregional recurrences

Chest wall Axilla Supraclavicular region Internal mammarian chain

10* 5 3 e

*One of the recurrences is outside the RT field.

<0.001

patients with no recurrences (18% vs. 86%, p < 0.001, RR ¼ 9.05). Regarding locoregional disease-free survival, number of dissected axillary lymph nodes was found as the only significant prognostic factor. The patients with a median number of dissected lymph nodes 10 had a significantly better locoregional disease free survival rate as compared with patients with dissected lymph nodes <10 (90% vs. 78%, p ¼ 0.04). The relationship between prognostic factors and overall and locoregional disease-free survivals for the whole group are shown in Table 3. Group A (patients with pT3N0M0 disease) 15-year overall and disease-free survival rates of patients with pT3N0 disease were 73% and 87% respectively.

G. Aksu et al. / EJSO 33 (2007) 285e293

Group B (patients with pT4N0M0 disease) Ten-year OS and locoregional DFS were 71% and 90% respectively.

1.0 .9

Locoregional recurrence absent

Surviving fraction

.8 .7 p<0.0001

.6 .5 .4 .3

Locoregional recurrence .2 .1

0

30

60

90

120

150

180

210

240

270

300

Months Figure 1. Locoregional recurrence and survival relationship in 125 T3N0 irradiated patients.

1.0 p=NS

.9 5-7 cm n =112

.8 .7

Cum Survival

Locoregional recurrence was also the only significant prognostic factors affecting overall survival in patients with T3 node negative disease. Fourteen of 125 patients who received radiotherapy had locoregional recurrences and these patients had a significantly lower 15-year overall survival rate as compared with patients without locoregional recurrences (21% vs. 85%, p < 0.0001) (Fig. 1). Of these 14 patients with locoregional recurrences, 3 patients had only locoregional recurrences and the remaining 11 patients had both locoregional and systemic recurrences. In 3 cases, distant and locoregional recurrences were diagnosed at the same time and in the remaining 8 cases local recurrence was followed by systemic recurrence. The time interval between both recurrences was shorter than 1 year in 5 cases and ranged between 46e91 months in the other 3 patients. Systemic recurrence had occurred in 24 of 125 patients and 15-year disease-specific survival (DSS) rate was 6% in this group. The 15-year overall survival for the patients with tumors >7 cm was lower than patients with 5e7 cm tumors but the difference did not reach a statistical significance (61.6 vs. 80%, p ¼ NS) (Fig. 2). None of the prognostic factors had a significant effect on locoregional disease-free survival. The association between prognostic factors and locoregional recurrence, systemic recurrence, DFS and OS in all group including patients with pT3N0 disease is shown in Table 3.

289

.6 .5 >7cm n = 13

.4 .3 .2 .1 0.0

0

30

60

90

120

150

180

210

240

270

300

Months Figure 2. The relationship between tumor size and disease-free survival in pT3N0 breast cancer patients treated with radiotherapy.

Locoregional recurrence was present in 2 patients. One of the locoregional recurrences occurred in the patient who refused radiotherapy and the other case was in the RT receiving group. In both patients with locoregional recurrences, systemic recurrence occurred during the following 4 and 19 months. Systemic recurrence was present in 5 cases and lungs were the most frequent metastatic sites (3 of 5 cases). The association between prognostic factors and locoregional recurrence, systemic recurrence, DFS and OS in all group including patients with pT4N0 disease is shown in Table 3. Distribution of locoregional recurrences according to the RT fields Locoregional recurrences were present in 14 of 125 patients receiving radiotherapy and in 1 of 8 patients who did not receive radiotherapy during a median follow-up time of 90 months in patients with T3N0 disease. As mentioned above; radiotherapy type was not standard in all of the patients since only chest wall or whole breast was irradiated in 42 patients, chest wall and peripheral lymphatics were irradiated in 52 patients and only peripheral lymphatics were irradiated in 31 patients (all of the patients receiving radiotherapy to only peripheral lymphatics without chest wall were treated before 1987). Also there were only 8 patients in the no RT group which did not enable us to make significant statistical comparisons between the patients with or without RT. Therefore; regarding these two considerable points, we reviewed the distribution of locoregional recurrences according to the RT fields by separating patients into groups as receiving chest wall RT or not and peripheral lymphatics RT or not. The 8 patients who did not receive RT to any field were also included.

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290

Table 5 Distribution of recurrences in the chest wall according to the chest wall RT status in patients with pT3 and T4N0 disease

Chest wall Recurrence Whole Group RT (+)

RT(-)

4/107 pt.*

5/49 pt. p=0.1 T4N0 patients

T3N0 patients RT (+)

RT (-)

3/86 pt.

4/47 pt.

RT (+)

RT (-)

1/19 pt.

p=NS

1/4 pt. p=NS

* pt= patients

The association between chest wall RT and the recurrences in the chest wall was the primary point for analysis. Among 133 patients, 86 patients received chest wall RT and only 3 chest wall recurrences developed in this group. On the other hand; although not reaching a statistically significance, chest wall recurrences were clearly higher in patients without chest wall RT since 4 of 47 patients in this subgroup had recurrences in the chest wall region ( p ¼ 0.21) (Table 5). These results show that, patients with T3N0 breast cancer without chest wall RT have a greater risk of developing locoregional recurrences and as the number of recurrences increases by time as stated in the literature, with a longer follow-up time, the difference between the groups can also become statistically significant favoring RT. Radiotherapy to the chest wall also reduced the risk of locoregional recurrences in T4-node-negative disease since only 1 chest wall recurrence was seen in 18 patients receiving chest wall RT while 1 of 5 patients without RT had developed recurrence. The irradiation of peripheral lymphatics has also been a matter of debate among radiation oncologists in patients with T3N0 and some centers in Europe still irradiate peripheral lymphatic regions in such patients. Therefore, we also analyzed the association between locoregional recurrences and peripheral lymphatic RT. Eighty-two patients received RT to peripheral lymphatics and 4 of these patients had recurrences in supraclavicular or axillary region. However the number of recurrences were similar in patients who

did not receive peripheral lymphatics RT with only 3 recurrences among 74 patients ( p ¼ NS) (Table 6). These findings show that, postmastectomy radiotherapy to the ipsilateral chest wall must be recommended for patients with PT3N0 and T4N0 breast cancer since it significantly lowers the locoregional recurrence rate in these subgroups but there seems to be no need for irradiating axillary or supraclavicular region in patients who undergo sufficient axillary sampling like our series.

Discussion Since the majority of breast cancers that are larger than 5 cm or that invade chest wall or skin have either axillary node or distant metastases at the time of the diagnosis the true pathological T3e4N0M0 disease is a rare entity. In addition, there is also little information about the value of post-operative radiotherapy separately in pT3N0M0 breast cancer since in most of the series that address post-operative radiotherapy these cancers have been lumped together either with T4 cancers or axillary lymph node positive cancers. Therefore although postoperative radiation therapy given after mastectomy to the chest wall and to the regional lymphatics reduces the risk of locoregional recurrence to about one third as compared to patients who do not receive radiotherapy whether the same benefit will be achieved in patients with T3N0M0 disease or the clinical target volume should include the axillary and the supraclavicular lymph

Table 6 Distribution of recurrences in the peripheric lymphatic regions according to the peripheric lymphatic RT status in the whole group

Recurrence in peripheric lymphatic regions RT (+)

RT(-)

4/82 pt.

3/74 pt. p=0.1

G. Aksu et al. / EJSO 33 (2007) 285e293

nodes as well as the chest wall are still under debate reflecting the relative rarity of these patients.4e6 Prognostic factors in breast cancer In 1999 The College of American Pathologists presented a Consensus Statement summarizing prognostic factors in breast cancer by dividing into three categories. Factors in category I were proven to be of prognostic importance and useful in clinical pain management and included tumor size, lymph node status, micrometastasis, histologic grade, mitotic count and hormonal receptor status. Her-2 Neu expression, p-53 mutations, lymphovascular invasion and DNA ploidy were included in category II and tumor angiogenesis, epidermal growth factor (EGF) receptor, transforming growth factor-alpha, Bcl-2 and overexpression of cathepsin-D were included in category III.7 Significance of axillary nodal involvement Among these factors the most significant prognostic indicator for patients with early-stage breast cancer is the presence or absence of axillary lymph node involvement. According to the National Surgical Adjuvant Breast and Bowel Project (NSABP) data the 5-year survival for patients with node-negative disease is 82.8% compared with 73% for 1e3 positive nodes, 45.7% for 4e12 positive nodes, and 28.4% for 13 positive nodes demonstrating that patients with node-negative disease have significantly better prognosis.8. Haagensen et al. demonstrated a direct relation between axillary nodal involvement and chest wall recurrence and an inverse correlation with survival. Fisher et al. also showed that survival diminished with a greater number of metastatic axillary lymph nodes.9,10 Correlation between tumor size and locoregional and systemic recurrences Tumor size is the most powerful prognostic factor in patients without nodal involvement.11 Tumor size correlates with the presence and number of involved axillary lymph nodes and distant recurrence rates increases with larger tumor size. According to The SEER database that included 13,464 patients with node-negative breast cancer, patients with tumors <1 cm had a 5-year overall survival of 99% compared with 89% for tumors between 1 cm and 3 cm and 86% for tumors between 3 cm and 5 cm.12 Rosen et al. showed that 20-year recurrence-free survival was significantly better for tumors 1 cm when compared with tumors between 3.1 cm and 5 cm (88% vs. 59%).13 Median time to the development of metastatic disease was also shorter in patients who had larger tumor sizes in these trials.12e14 In our series, 15-year overall survival for the patients with tumors >7 cm was also lower than patients with 5e7 cm tumors but the difference did not reach a statistical significance (61.6 vs. 80%, p ¼ NS).

291

The other significant adverse prognostic factors in our T3N0 group for overall survival were presence of systemic and locoregional recurrences. Surgical margins closer than 3 mm had also a borderline adverse affect on OS ( p ¼ 0.06). However in multivariate analysis, presence of locoregional recurrence was the only significant prognostic factor for overall survival. The patients with locoregional recurrence had a significantly lower overall survival rate as compared with patients with no recurrences (18% vs. 86%, p < 0.001, RR ¼ 9.05). An important finding of our study was also the presence of the close relationship between locoregional and systemic recurrences since 12 of 15 patients with locoregional recurrences in T3N0 group had also systemic recurrence. In a recent trial by Grillo et al. it was showed that breast cancer patients presenting with a local recurrence within 2 years after surgery had significantly lower distant disease-free and overall survivals.15 Abner et al. analyzed 118 breast cancer patients who were treated with surgery and radiotherapy and reported that the 10-year disease-free survival rates was 91% for nodenegative patients with tumors < ¼ 1 cm ( p ¼ 0.07).16 In a different trial which investigated skin changes including edema, erythema, and ulceration of the breast in patients treated with mastectomy only edema was statistically significant for increased local recurrence.17 The role of radiotherapy in pT3N0M0 breast cancer Up-to date there is only a few prospective randomized trials directly addressing the role of radiotherapy in T3N0M0 breast cancer. In Danish Breast Cancer Cooperative Group 82B trial 135 patients with T3N0 disease were randomized to chemotherapy plus postmastectomy radiotherapy or chemotherapy alone arms. During a follow-up period of 10 years in radiotherapy receiving group 3 of 58 patients had locoregional recurrences while 17 of 77 patients had locoregional failure in chemotherapy alone group. Ten-year overall survival was also better in patients who received radiotherapy (82% vs. 70%).18 In a different trial by Klefstro¨m et al. that totally analyzed 120 patients with stage III breast cancer, 40 patients with pathologically confirmed T3N0M0 disease were randomized to receive either postoperative radiotherapy or chemotherapy, or a combination of these, with or without levamisole immunotherapy. While only 2 of 27 patients had locoregional recurrences in postmastectomy radiotherapy group, 5 of 13 patients had locoregional failure in no radiotherapy group. The authors also declined that only 2% of all breast cancers treated at their institute was staged as T3N0M0 disease.19 Helinto et al. retrospectively analyzed 38 patients with T3N0M0 disease and showed that 3 of the 5 patients who were not treated with post-operative radiation therapy developed locoregional recurrence as compared with only 3 of the 33 patients who were given post-operative radiotherapy during a median follow-up of 58 months ( p ¼ 0.0003). The authors also reported that patients who were given post-operative

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radiotherapy had a better distant disease-free survival rate ( p ¼ 0.04) and overall survival rate ( p ¼ 0.03) than the ones who were not treated with radiation therapy.2 In a large retrospective trial that analyzed the natural history of node negative breast cancer in 826 patients with a median follow-up period of 162 months (9e532 months) the strongest predictor factor for outcome and time to relapse was found as pathologic tumor size and it was shown that patients with tumors less than 2 cm had significantly a better 20-year disease-free survival (DFS) as compared with patients with tumors greater than 2 cm (79% vs. 64%, p < 0.001). The median time to recurrence was also significantly longer in patients with smaller tumors (48 months vs. 37 months, p ¼ 0.01).20 Recently, Jagsi et al. evaluated the locoregional recurrence rates and prognostic factors in 877 node-negative patients treated with mastectomy and implications for PMRT. Median follow-up was 100 months. Their results showed that; close margins (<2 mm), T2 or larger tumors, premenopausal status, and LVI were the risk factors for local recurrence in node-negative patients and 10-year locoregional recurrence rate was 1% for those with 0 risk factors, 10% for those with 1 risk factor, 18% for those with 2 risk factors, and 40% for those with 3 risk factors. The chest wall was the most common site of failure (80%) and the authors stated that treating the chest wall alone in these patients was a reasonable treatment approach.21 In a different recent trial by Garg et al. from M.D. Anderson Cancer Center that evaluated the outcomes of 132 patients with Stage I or II breast cancer treated with neoadjuvant chemotherapy and mastectomy without radiotherapy it was reported that T3 disease at presentation was a significant predictor for locoregional recurrence and warranted the addition of radiotherapy to the postmastectomy treatment regimen. In this trial, the locoregional recurrence rate of 14% for patients with T3N0 disease was greater than in those with T2N1 disease (11%) or T1eT2N0 disease (2%) ( p ¼ 0.0057).22 Gurkaynak et al. also reported that among 40 breast cancer patients with T3N0M0 disease whom all received postmastectomy radiotherapy, only 1 patient experienced a locoregional recurrence located in the chest wall.23 As seen above our series including totally 156 patients with pathologically proven T3eT4N0M0 disease is one of the largest series reported in the literature yet with a median follow-up time of 90 months. The receptor status, lymphovascular invasion status and histological and nuclear grades were unknown in an important part of the patients since a considerable number of patients were treated in 70’s and early 80’s. There was no significant difference in OS between the RT receiving group and the remaining patients but postoperative radiotherapy significantly reduced locoregional recurrence. Totally, locoregional recurrences were seen in 17 of 156 patients. Two of 9 patients who were not treated with post-operative radiation therapy had locoregional

recurrence as compared with 16 of 147 patients receiving radiotherapy. In subgroup analysis, 14 of 125 patients with T3N0 disease who had locoregional recurrences had a significantly lower 15-year overall survival rate when compared with patients with no locoregional recurrences (21% vs. 85%, p < 0.0001). Another importance of our study was the evaluation of the distribution of locoregional recurrences in patients with T3N0 disease according to the RT fields by separating patients into groups as with or without chest wall and peripheral lymphatics RT. Our findings showed that patients with T3N0 breast cancer without chest wall RT have a greater risk of developing locoregional recurrences since only 3 chest wall recurrences developed among 86 patients receiving chest wall RT as compared to 4 recurrences among 47 patients whose chest walls were not irradiated. Since locoregional recurrence risk increases by time in breast cancer, the longer median follow-up times can reveal a greater and significant difference. Irradiation of the chest wall also reduced the risk of locoregional recurrences in T4-node-negative disease since only 1 chest wall recurrence was seen in 19 patients receiving chest wall RT while 1 of 4 patients without RT had developed recurrence. However receiving RT to peripherical lymphatic regions had no additional effect on reducing recurrences in these regions since the recurrence rates were similar in both groups (5% vs. 4%, p ¼ NS). Conclusions Due to the lack of phase III randomized trials directly addressing the role of postmastectomy radiotherapy in these stages, our series as being one of the largest in the literature that evaluated these subgroups also suggest that postmastectomy radiotherapy to the ipsilateral chest wall must be recommended for patients with PT3N0 and T4N0 breast cancer since PMRT significantly lowers the locoregional recurrence rate in these subgroups in accordance with the literature. The need for irradiating axillary or supraclavicular region shall be neglected in patients who undergo sufficient axillary sampling.

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