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??Original Contribution

PROGNOSTIC SIGNIFICANCE OF BREAST TREATMENT IN NODE-NEGATIVE

RELAPSE AFTER CONSERVATIVE EARLY BREAST CANCER

BRUNO CHAUVET, M.D.,’ AGNES REYNAUD-BOUGNOUX, M.D.,’ GILLES CALAIS, M.D.,’ NICOLAS PANEL, M.D.,2 JACQUES LANSAC, M.D.,2 PHILIPPE BOUGNOUX, M.D.3 AND OLIVIER LE FLOCH, M.D.’ ‘Clinique d’oncologie et Radiotherapie, ‘Clinique Gyntcologique-Obstetricale et de la Reproduction Humaine, Centre Hospitalier et Universitaire, F 37044 Tours cedex; and 3Laboratoire de Biologie des Tumeurs, FacultC de Medecine, F 37032 Tours cedex, France The prognostic significance of local relapse after conservative treatment of early stage breast carcinoma has been controversial. To determine the incidence and the prognostic value of a breast relapse, we analyzed the results obtained in a series of patients with pTlpN0 presentation of breast carcinoma treated conservatively without adjuvant medical treatment. From 1976 to 1986, 202 patients with invasive breast carcinoma of less than 2 cm without lymph node involvement were treated with surgery and radiation therapy. The overall survival rate was 97.2% at 5 years. Locoregional relapses occurred in 16 patients (7.9%). In these patients, the overall survival rate was significantly decreased as compared to that of patients without local relapse (87.5% versus 98.3% at 5 years, p < 0.001). The probability of remaining metastasis-free was also significantly decreased (80.2% vs 91.3%, p < 0.001). Most relapses (94%) appeared at or close to the primary site. Salvage local treatment was possible in 14/16 patients (87.5%). Age, menopausal status, size and site of primary tumor, histological grade, and boost technique did not influence significantly the risk of local relapse occurrence. We concluded that the occurrence of a breast relapse after a successful local conservative treatment is a pejorative prognostic factor predictive of a high risk of distant metastasis development. There is a need to individualize factors that could allow discrimination of patients with a high probability of local relapse and subsequent metastasis. Breast cancer, Conservative surgery, Radiotherapy,

Local recurrence.

survival rate was found among patients who developed a breast relapse compared to those who did not (24). Moreover, treatment modalities of these local relapses remain controversial, especially with regard to the role of an adjuvant medical treatment. To determine the incidence and the prognostic significance of breast relapse, we performed a retrospective analysis of the results in a population of patients with a pT1 pN0 presentation of invasive breast cancer who received a locoregional treatment, that is, a tumorectomy with axillary dissection followed by radiotherapy without adjuvant medical treatment.

INTRODUCTION Primary conservative treatment of early stage breast cancer has been shown to result in survival rates comparable to those achieved after radical mastectomy (9, 3 1, 36). The long term evolution depends on the occurrence of distant metastasis and is not affected by the type of local treatment, either conservative or not. Local tumor control with good cosmetic result can be obtained through a conservative treatment in a large majority of patients with early stage presentation of breast carcinoma. Although a successful locoregional conservative treatment was achieved, a small percentage of patients will develop a breast relapse. Recent reports indicate a IO-year local recurrence rate of 15 to 25% (5, 26). The prognostic value of a local relapse occurrence is controversial and seems to be different after a conservative treatment or after a mastectomy (2, 14, 33, 34). Some authors have found that a breast relapse after a conservative treatment will not adversely affect survival ( 1,5), but inverse results have been reported in other studies where a significantly lower

METHODS

AND

MATERIALS

From 1976 to 1986, 13 11 patients were referred to our institution for primary breast cancer treatment. After examination by a surgeon and a radiation oncologist, a conservative treatment was proposed when possible according to site and size of tumor, size of the breasts, and patient’s

Presented at the International Congress of Radiology, Paris, France, 1 July 1989.

Reprint requests to: B. Chauvet. Accepted for publication 24 May 1990. 1125

I. J. Radiation Oncology 0 Biology 0 Physics

1126

will. Two hundred fifteen patients with invasive breast carcinoma had a conservative treatment for tumors of less than 2 cm (surgical mensuration) and had no involved lymph node at the axillary dissection (i.e., pT1 pN0 from the TNM classification (35). Among these patients, 13 received chemotherapy or hormonal therapy and were therefore excluded from the study. The studied population consisted of the 202 remaining patients who had a tumorectomy with axillary dissection followed by irradiation without adjuvant medical treatment. When comparing the characteristics of the selected population to those of the 13 excluded patients, no significant difference was found regarding age, menopausal status, site and size of tumor, TNM classification, histologic type, SBR grade, and number of examined nodes on axillary sampling. The mean age of the population was 52.5 years (range 28 to 85 yrs). One hundred four patients (51.5%) were menopausal. The mean size of the tumor (surgical mensuration) was 12.1 mm. The characteristics of the 202 studied patients are presented in Table 1. The majority of patients (69.3%) was clinically evaluated as TlNO according to the TNM classification (35). The proportion of grade 2 tumors, according to the Scarff-Bloom and Richardson grading (4), was high (64%). Since the estrogen receptor status was not performed for the majority of pa-

Table 1. Patient Prognostic

factors

TNM classification TONOMO T 1NOM0 TlNlMO TZNOMO T2NIMO TxNOMO TxNxMO Menopausal status Non menopaused Menopaused Site of tumor Upper-outer quadrant Upper-inner quadrant Downer-outer quadrant Downer-inner quadrant Medial Pathological type Lobular carcinoma Ductal carcinoma Medullar carcinoma Colloid carcinoma N.O.S.* adenocarcinoma Comedocarcinoma Other types Histological grade SBR I SBR II SBR III Not specified * Not otherwise

specified.

features Number

7 140 2 46 4

%

2

3.5 69.3 1.0 22.8 2.0 0.4 1.0

98 104

48.5 51.5

95 49 34 18 6

47.0 24.3 16.8 8.9 3.0

29 144 3 4 11 4 7

14.4 71.3 1.5 2.0 5.4 2.0 3.4

43 114 10 35

21.3 56.4 4.9 17.4

November 1990, Volume 19, Number 5 tients treated before 1984, this prognostic factor was not examined in the present study. Treatment modalities consisted of a large tumorectomy with a margin of 1 cm around the tumor. No histological control of the margins of the excision was performed during the operation. An axillary dissection extended to the limit of the axillary vein (i.e., level 1 of Berg (3)) was performed. The mean number of examined nodes was 13 (S.E. 0.79; range 3 to 31). Subsequent radiation therapy, 3 to 5 weeks after surgery, consisted of a 6oCo irradiation of the entire breast with two tangential fields, the patient lying in a supine position, arm at 90” abduction. Both breast fields were treated daily 4 days a week. Wedge filters were used for 63% of the patients. A dose of 45 Gy was prescribed according to a computerized dosimetry in the isodose which seemed to provide the best homogeneity of dose distribution in the target volume. The 100% isodose was chosen for 170 patients, the 95% isodose for 29 patients, and the 90% isodose for 3 patients. Therefore, 45 to 50 Gy were delivered to the midplane of the breast corresponding to the ICRU point (16). The treatment was given by fractions of 2.25 Gy to 2.50 Gy 4 times a week. Then a boost in the tumor area was delivered for 200 patients, either with external radiotherapy (34 cases) or with brachytherapy ( 166 cases). Brachytherapy consisted of rigid needles implantation afterloaded with ‘921ridium wires, delivering 15 Gy in the 85% reference isodose according to the Paris system (7). External radiolherapy boost was used for patients with small breasts and tumor located in the upper-inner quadrant or for elderly patients to avoid general anesthesia. Boost was done either with a direct electron beam or with small cobalt photon fields. When the tumor was located in the inner quadrants or in the central region of the breast, the internal mammary lymph nodes were irradiated to the dose of 45 to 60 Gy. The internal mammary chain was either included in the tangential fields (87 patients) or separately treated with an anterior beam (7 patients). In addition, 10 patients received an axillosupraclavicular irradiation of 45 Gy. As of December 1988, follow-up time was 1 to 10 years (average 3.2 years, median 3.5 years, 80 pts have been followed 5 years or more). Regular follow-up information was available for 175 patients with periodical mammography and clinical examination. The variables of interest were local control rate, overall actuarial survival, and metastasis-free survival. Survival univariate distributions were estimated using the actuarial method (8) and compared using the log-rank test (19). Characteristics of the studied groups were compared using chi-square test and Student’s t-test ( 19).

RESULTS The 5-year overall survival rate of the whole population was 97.2% (S.E. 4.8%) (Fig. 1). Seventeen patients developed metastasis. Six patients died from metastatic disease. The 5-year metastasis-free survival rate was 90.2% (S.E.

Prognostic significance of breast relapse 0 B. CHAUVET el al.

c

II27

Chi-square = 19.49 p < 0.001

r 04

I

0

1

3

2

4

5

Time from first treatment (years)

Time from first treatment

Fig. 2. Influence of local relapse on overall survival: overall survival was estimated using actuarial method for: 0 16 patients who developed a breast relapse, ??186 patients who had no breast relapse. Population and treatment are as in Figure I.

(years)

Fig. 1. Conservative treatment of lymph node-negative early breast cancer: life-tables. Two-hundred and two patients with less than 2 cm invasive breast cancer without node involvement were treated with surgery and radiation therapy. W Overall survival. 0 Survival without metastasis. A Survival without local relapse.

who developed a breast relapse (37.5%) and 5 patients subsequently died from metastasis. Among 186 patients without local relapse, 11 developed metastasis (5.9%) and one of them died. The overall survival of patients with local relapse was significantly decreased compared to patients without local relapse (87.5% vs 98.3% at 5 years: p < 0.001) (Fig. 2). This difference in overall survival is explained by the higher rate of metastasis among patients with local relapse since the distant disease-free survival was also significantly decreased in patients who had a local relapse compared to patients who had not (80.2% vs 9 1.3%: p < 0.00 1) (Fig. 3). Distant failure rates in patients who did and did not have a local failure have been com-

4.8%) (Fig. 1). Two patients died from intercurrent disease: one from an acute lymphoblastic leukemia, one from cardiac pathology. A controlateral breast cancer occurred in six patients 2 to 5 years after initial treatment. Sixteen patients (7.9%) had a breast relapse confirmed histologically, detected by physical examination in 12 cases and by mammography alone in 5 cases (Table 2). The 5-year actuarial local control rate was 86.5% (S.E. 6.7%) (Fig. 1). Metastasis occurred in 6 out of 16 patients

Table 2. Characteristics

No. 1 2 3 4 5 6 7 8 9 10 I1 12 13 14 15 16

Time to relapse (months) 12 52 21 30 29 43 13 20 30 6 34 37 87 52 56 26

Initial grade* 3 2 2 2 2 2 N.S. 3

1 2 2 N.S. N.S. 2 N.S. 2

Size of tumor recurrence (mm)+ 20 N.P. N.S. N.P. N.S. 25 30 N.S. N.P. 25 N.S. N.P. N.P. 20 20 30

and evolution

of patients

Treatment modalities after local relapse* HT+CT M+RT+CT M + CT M M+HT M M CT + M M M+CT M M + CT M+HT CT + M M M + CT

with local relapse

Evolution

after relapse

Present status (months after initial treatment)

Concomitant metastasis Metastasis 30 months later Metastasis 13 months later Concomitant metastasis Metastasis 7 months later Metastasis 37 months later

* According to Scarff Bloom and Richardson’s classification. N.S. = Not specified. + N.P. = Not palpable (detectable by mammograms). * M = Mastectomy; HT = Hormonal therapy; CT = Chemotherapy: RT = Radiation

therapy;

N.E.D.

= No evidence

Dead ( 17) Dead (95) N.E.D. (5 I) N.E.D. (34) N.E.D. (36) N.E.D. (45) Dead ( 100) Dead (30) N.E.D. (48) N.E.D. (53) N.E.D. (63) N.E.D. (58) N.E.D. (88) Dead (72) N.E.D. (75) Alive (75)

of disease.

I. J. Radiation Oncology 0 Biology 0 Physics

1128 (186)

-c

P

a

Chi-square = 12.83 p < 0.001 0 0

I

I

1

2

I

I 4

3

Time from first treatment

I 5

(years)

Fig. 3. Influence of local relapse occurrence on Ihe probability of remaining metastasis-free: ? ?for patients who developed a breast relapse, I for patients who had no breast relapse. Popu-

lation and treatment are as in Figure 1.

pared according to histological grade and initial tumor size: although metastasis appeared to be more frequent in patients who did have a local relapse whatever the grade and the tumor size compared to patients without local relapse, the small numbers of patients in each group did not allowed actuarial survival estimation and statistical comparisons (Table 3). Breast relapses were invasive carcinomas (14 cases) or predominantly intraductal carcinoma with invasive component (2 cases). No isolated regional relapse was observed. In one patient, breast relapse was associated with a regional relapse (axillary node). The mean time interval from first treatment to occurrence of a local relapse was 34 months (range: 6 to 87). The mean time interval from first treatment to first metastasis development was 3.3 years for six patients who had a local relapse and further developed metastasis. It was 1.5 years for 11 patients who

November 1990, Volume 19, Number 5

developed metastasis without local relapse. The difference is not significant. Most relapses (15/ 16 or 94%) appeared at or close to the primary site (i.e., in the same quadrant). Characteristics and evolution of patients with breast relapse are detailed in Table 2. Two patients had an inflammatory breast relapse (Table 2, n. 8 and 14) and were treated with chemotherapy followed by mastectomy. Another patient with concomitant metastasis received chemotherapy and tamoxifen without local treatment and died from disease 5 months later. Local salvage treatment by mastectomy was possible in 12 remaining patients. Another patient had a limited lumpectomy and further developed a second breast relapse treated by mastectomy. Among patients with local relapse, salvage local treatment was possible in 14/16 patients (87.5%). In terms of local control rate, no significant difference was found regarding age, menopausal status, size and site of primary tumor, SBR grade or boost technique (Table 4). DISCUSSION

These results indicate that the occurrence of a breast relapse after a successful local conservative treatment is a pejorative prognostic factor predictive of a high risk of distant metastasis development. The relapse rate that we found (7.9%) was in the range of 6 to 14%, a finding previously reported in other studies (6,9,25,26,30,3 1,36). It seems greater than that reported after mastectomy for similar patients ( 15). Local recurrence may be understood as the development of another separate focus of cancer in the same breast. This hypothesis is supported by the well-known Table 4. Frequency of local relapse according features and treatment modalities Relapse rate Factors

Table 3. Distant failure according to local relapse occurrence by histological grade and tumor size Distant

failure rate

Patients with local relapse No. Histological grade* 1 2 3 Not specified Tumor size lO mm * According

%

Patients without local relapse No.

%

O/l 319 2/2 l/4

0 33.3 100 25

4142 61105 l/18 o/2 1

9.5 5.7 5.5 0

O/O 218 418

25 50

o/15 2187 9184

0 2.3 10.7

to Scarff Bloom and Richardson

classification.

to patient’s

SBR grade I II III Not specified Size of tumor lO mm Site of tumor Inner and central Outer Upper Downer Boost technique* External RT Brachytherapy Whole population

No. (W)

5-yr actuarial local control rate (%)

l/43 (2.3) 9/l 14 (7.9) 2/20 (10) 4/25 (16)

92.0 84.6 95.0 82.4

N.S.+

O/l5 8195 8/92

(0) (8.4) (8.7)

100 88.8 83.0

N.S.+

7173 91129 1 l/l44 5/58

(9.6) (6.9) (7.6) (8.6)

86.1 89.1 87.0 86.1

N.S.+

4134 12/166

82.8 86.9

N.S.+

161202 (7.9)

86.5

* 2 patients have not received boost. + Not significant (Log-rank test).

N.S.+

Prognostic significance of breast relapse 0 B. CHAUVETet al.

multicentricity of breast cancer found in approximately 29% of mastectomy specimens for all stages (18) and in 7% of mastectomy specimens for Tl tumors (20). However, the site of breast relapse was observed at or close to the site of primary tumor for 94% of the cases in our study as in others (5, 27, 30). This result suggests that local relapse was the consequence of regrowth of a residual tumor. Other foci of multicentric cancer, if existing, have been considered to be eradicated by the whole breast irradiation (13). However, these data on relapse rate and site of recurrence are preliminary, since it may take a longer time for failure to emerge elsewhere in the treated breast (33). As of yet, we have a follow-up of more than 5 years available in only 80 patients and one relapse was observed more than 5 years after the initial treatment. Based on the literature, we would expect to see a 30 to 50% increase in the local recurrence rate in the 5- and IO-year periods (6, 14, 26) and a 5% increase beyond the tenth year ( 17). The pejorative significance of breast relapse on prognosis has already been observed but remains controversial. In a population of 405 patients treated conservatively for T 1T2NON 1 tumors, with a crude relapse rate of 5%, the disease-free survival rate was 88% for patients without local relapse versus 65% for patients with local relapse (24). This result is also in agreement with the low 5-year survival rate generally reported after local relapse in patients with early breast cancer, in the range of 40 to 50% (2 1,27,29). However, our results are different from those of the NSABP B 06 trial comparing total mastectomy with lumpectomy and with lumpectomy plus radiotherapy; despite a higher relapse rate in the lumpectomy group and in the lumpectomy-plus radiotherapy group as compared to the mastectomy group, there was no statistically significant difference in distant-disease-free survival in node-negative patients (9). The data from our study also differ from those of two other reports where no significant survival difference was found between patients with and without local recurrence ( 1, 5). In one of these studies, some patients were treated with conservative surgery without radiotherapy (5). In the other report, some patients received radiotherapy without surgery and not all relapses were infiltrating carcinomas (1). This difference suggests that the modalities of the initial local treatment

1129

may modify the prognostic significance of breast relapse. These recurrences could be due to a fraction of resistant cells selected through the initial local therapy. These cells may have more aggressive behavior, and may have the potential to reccur either locally or at distant sites. The histology of the recurrent tumor also appears to be of prognostic value: local invasive relapses have been demonstrated to have a worse prognosis than non invasive relapses (29). In our study, all relapses were invasive carcinomas. The risk of metastasis occurring in patients with a local relapse may justify an adjuvant medical treatment to be performed after a salvage surgery was realized. But no data are available to support the usefulness of salvage chemotherapy or hormonal therapy for this category of patients. The overall survival of patients with negative node breast cancer, even in studies with a long-term follow-up, is 75 to 85%. Therefore, most patients do not develop distant metastasis and do not require systemic therapy. Randomized trials of such therapy in patients without involved nodes have failed to demonstrate an improvement in overall survival (10, 11, 22). Some studies have shown an improvement in disease-free survival (11, 22, 23) and, in one of these trials, a reduction in treatment failures has been observed for both local and distant relapse (11). In the absence of a proven overall survival benefit, adjuvant treatment does not seem to be justified in all negative-node patients. Several studies have reported the predictive value of initial prognosis factors such as tumor site (25) age (28) tumor size (2 I), extensive intraductal component ( 14,32), or negative hormonal receptors status (12) on breast relapse occurrence. Among the factors that have been studied in the present population without node involvement (i.e., age, tumor size, pathologic grade, or boost technique), no significant difference in risk of breast relapse was found. This may be due in part to the small number of local relapses observed, but, even in studies where the influence of some prognostic factors on relapse occurrence was reported, the magnitude of the differences between low and high risk groups appears to be small. Discriminant factors must be determined to identify the subset of patients to the occurrence of local relapse or distant metastasis, who would be included in adjuvant treatment trials.

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