Copyright
0360.3016191 $3.00 + .I0 (CI 1991 Pergamon Prey plc
l Original Contribution
EXTERNAL IRRADIATION PRIOR TO CONSERVATIVE FOR BREAST CANCER TREATMENT
SURGERY
E. CALITCHI, M.D.,* Y. OTMEZGUINE, M.D.,* F. FEUILHADE, M.D.,* P. PIEDBOIS, M.D.,* J.-M. PAVLOVITCH, M.D.,* B. BRUN, M.D.,* J.-J. MAZERON, M.D.,* J.-P. LE BOURGEOIS,M.D.,* M. JULIEN, M.D.+ AND B. PIERQUIN, M.D.* HBpital Hemi Mondor, 5 1 Avenue du Mar&ha1 de Lattre de Tassigny, 94010 Crete& France From 1981 to 1987, 138 patients with breast cancer unsuitable for primary tumorectomy received initial external radiotherapy (45 Gy/2Sf/35d) in order to reduce the tumor volume so that secondary limited surgery could be performed. There were 81 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. After completion of the radiotherapy, 22 patients (16%) showed no more evidence of a tumor either clinically or radiologically and received a boost of 25 Gy. In 52 cases (38%) the tumor regression allowed for secondary tumorectomy followed by a boost of 20 Gy. Sixty-four patients (46%) showed either little or no tumor regression: radical surgery was performed in 14 cases (10%) and high dose boost curietherapy (37 Gy) in the 50 (36%) remaining patients who refused mastectomy. Breast conservation in good condition was thus obtained in 74 patients (54%). Sufficient tumor regression to allow secondary tumorectomy was more often observed in T2 than in T3, in poorly differentiated tumors or mutinous type, and in tumor with well defined mammographic aspects. Actuarial 5year local control and disease-free survival rates after limited surgery were, respectively, 90% and 73%. No particular complications were observed after secondary tumorectomy. This therapeutic approach is encouraging in patients with large T2 and T3 breast tumors, but a longer follow-up is required to assess definitive conclusions. Breast cancer, Preoperative radiotherapy, Secondary tumorectomy.
INTRODUCTION
METHODS
The combination of limited surgery and radiotherapy is currently a well accepted option for the treatment of early breast cancer (1, 2, 4, 6, 12, 13, 14, 15). This treatment approach is generally recommended for tumors less than 4 cm in size that do not involve the nipple-areolar complex. The most important criterion for achieving good cosmetic results is the ratio between the volume of the tumor and that of the mammary gland (9, 11). The usual recommendation for patients with larger tumors is radical surgery. If surgery is refused, exclusive radiotherapy is always possible, but cosmetic results are generally not as good and local recurrences often occur, necessitating salvage mastectomy (8, 12). We tried to improve local control and cosmetic results for large T2 and T3 by combining limited surgery with radiotherapy as is currently done for Tl and small T2. To maximize the use of conservative rather than radical surgery, we inversed the therapeutic sequence, beginning with external irradiation, in order to reduce the tumor volume so that secondary limited surgery could be performed.
AND MATERIALS
From 198 1 to 1987, 138 consecutive patients with unifocal non-inflammatory and non-metastatic breast cancer unsuitable for primary tumorectomy (T2 and T3) were treated in our institution. Patients’ and tumor characteristics are presented in Tables 1 to 3. In all cases, diagnosis was established histologically by incisional biopsy. The median follow-up was 50 months (range 8 to 118). According to the 1987 UICC TNM classification, there were 8 1 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. In about 10% of the cases (13/138), the tumor size did not exceed 3.5 cm but the breast was not large enough for primary excision of the tumor. Treatment modalities Treatment of the breast. All patients were treated with a telecobalt unit. Briefly, the breast was treated to 45 Gy using opposed tangential portals, 5 fractions/week, 1.8 Gy each fraction. Six weeks after completion of the radiotherapy course, the tumor response was evaluated
* Department of radiotherapy. +Department of surgery.
Reprint request to: E. Calitchi. Accepted for publication 25 January 325
199 1.
326
1. J. Radiation Oncology 0 Biology 0 Physics
Table 1. Patients
and tumor
Menstrual status Premenopausal Postmenopausal Average tumor size (cm) Clinical lymph node status NO Nl
July 1991. Volume 21. Number 2
characteristics
T2 (81)
T3 (57)
Total (138)
29 52 4
28 29 6
57 81
EXTERNAL
45ty 12X/354)
66 15
30 27
25
-
-
-
PR +
. Culetnarapy
type T3 (57)
Total
16 28 18 10
5 21 20 9
21 49 38 19
6 0 3
1 1 0
7
I 3
* The biopsy specimens were too small to allow for histologic grade specification. ( 1) = Well differentiated; (2) = Moderately differentiated; (3) = Poorly differentiated.
status and mammographic
Receptor status* ER+PR+ ER+PRER-PR+ ER-PRMammographic findings Star shaped Nodular Microcalcifications Blurred opacity
- B
20 Gy
T2 (81) Histologic type: histologic grade Infiltrating ductal carcinoma (N.O.S.) I(1) II (2) III (3) Unknown* Other type Mutinous Medullary Lobular
(221
Tumorectomy
6 weeks
96 42
clinically and radiologically to decide on further treatment modalities (Fig. 1): (A) In case of complete regression (complete response: CR) with no further evidence of the tumor either clinically or radiologically, no surgery was performed and treatment was completed with a moderate boost of 25 Gy (group A). (B) If tumor regression was incomplete (partial response: PR) but sufficient to allow for limited surgery, secondary tumorectomy was carried out followed by a postoperative boost of 20 Gy. It must be stressed that in
Table 2. Histologic
Gy
IRRADIATION
MR or NR
Table 3. Receptor
Curlelllerlple- A
CR PRIMARY
findings
T2
T3
Total
24 9 7 11
17 5 6 13
41 14 13 24
43 14 10 14
24 13 16 14
67 27 26 28
* Steroid receptor determination (superior or inferior to IO fmol) was available only in 92 patients, as it was not performed on a routine basis at the beginning of the study.
_ \
(521
Mastectomy
- Cl II41
\ y
Cunetnerapy 37 GY
Fig. 1. Treatment
’
- c2 I501
protocol.
order to obtain good cosmetic results, the surgical procedure removed only the residual tumor with a margin of macroscopic normal surrounding tissue (group B). No formal microscopic peroperative margin assessment was performed. (C) In case of poor regression (no response: NR or minimal response: MR) we recommended radical surgery (group C 1). Patients who refused it were given a high dose boost (37 Gy), being fully informed of its uncertain outcome (group C2). All the boosts were delivered by Iridium 192 afterloading interstitial techniques. In most cases the implant consisted of two planes unless, after tumorectomy, the mammary volume only allowed for one plane. Treatment of the regional lymph nodes. The attitude adopted toward the regional nodes was modified during the study. Until 1984, in conformity with our previous practice, radiotherapy alone was used in the management of the draining lymph nodes areas. They received 45 Gy by telecobalt followed by a boost of 24 Gy to the lower axilla and of 15 Gy to the internal mammary nodes using direct 10 MeV electron beams. Axillary dissection was only performed when large nodes showed insufficient regression after radiation therapy. According to our previous experience (8), this protocol led to very high local control in the axilla and internal mammary chain. However, it did not provide any information with regard to axillary lymph node involvement, which remains the most important prognostic criteria in deciding any adjuvant medical treatment (3). Therefore, from 1984 primary axillary dissection was routinely performed to evaluate his-
Table 4. Response
to primary
CR = 22/138 (16%) PR = 52/138 (38%) NR or MR = 64/138 (46%)
external
irradiation
Group A Group B Group Cl + C2
321
Breast cancer treatment 0 E. CALITCHI eta/
Table 5. Tumor response according to tumor size and histology Histology T
Good responders* (group A and B) Poor responders+ (group Cl and C2)
T2
T3
Grade I (1)
:2I)
III (3)
45
29
I
28
23
5
1
2
36
28
14
21
15
2
0
1
Mutinous
Medullary
Lobular
* CR or PR. + MR or NR. (1) = Well differentiated:
(2) = Moderately
differentiated;
(3) = Poorly differentiated.
be accurate. On the other hand, well defined mammographic aspects (stellar or nodular) usually were associated with good response to radiotherapy in 59 out of 94 (63%) cases. In cases of blurred opacities or abundant microcalcifications, only 15 out of 44 showed good response to radiotherapy. In all 52 secondary tumorectomy specimens, the tumor margins were microscopically negative; moreover, 8 of those cases ( 15%) did not show any residual tumor. Fifty-nine axillary dissections were performed to remove the nodes of Berg level I and II (21 before radiotherapy; 38 after delivering 45 Gy). Fifteen out of 30 T2 patients (50%) and 22 out of T3 patients (76%) were found positive, giving a total of 37 positive axillary dissection (63%). Secondary surgery after 45 Gy did not cause any particular complications. In three cases there was a breach of the surgical scar: spontaneous healing occurred in 6 to 8 weeks. Compared to primary tumorectomy, no particular complications were observed. Provided that the surgical procedure only removed the residual tumor with 1 cm of surrounding macroscopic normal tissue, the cosmetic results after secondary tumorectomy were, on the whole. satisfactory. In the two main therapeutic groups (B and C2) among patients with more than 3 years follow-up, poor cosmetic results were more often observed after exclusive irradiation with high dose boost (C2: 4/3 1 = 13%) than after secondary tumorectomy (B: 2/38 = 5%). In conformity with our previous experience (8) in cases of local recurrence, salvage surgery could always be performed without any particular difficulties even after high dose boost (C2). Actuarial local control and disease-free survival at 5 years according to therapeutic subgroups and tumor size are shown in Figures 2 to 5.
tological nodal status. Postoperative axillary irradiation (45 Gy) was then only delivered in case of nodal involvement. Supraclavicular and internal mammary regions were irradiated in N- patients with a central or medial tumor or N+ patients regardless of the site of the primary tumor. Adjuvant chemotherapy, if indicated, was only delivered following completion of locoregional treatment.
RESULTS Table 4 shows the tumor response to primary external irradiation, which formed the basis of our therapeutic sequence. In 54% of the cases (74/138), a satisfactory response was observed, enabling exclusive irradiation with a moderate dose boost (group A: 22/ 138- 16%) or limited secondary surgery (group B: 52/138-38%). The remaining patients (64/138: 46%) did not respond well. They most often chose exclusive irradiation with a high dose boost (group C2: 50/ 138-36%) rather than radical surgery (group C 1: 14/l 38-lo%), perhaps because of the reputation of our institution for breast preservation. In fact, many patients who had been refused breast conservation elsewhere came to us totally opposed to primary mastectomy and ready to try breast conservation. Analysis of the tumor response as a function of initial size, histology, receptor status, and mammographic findings is shown in Tables 5 and 6. Total or partial regression sufficient to allow secondary tumorectomy was observed more often in T2 rather than in T3. Similarly, the response rate was higher in the moderate or poorly differentiated tumors (grade II and III) and in the mutinous type than in the well differentiated tumors (grade I). Since hormone receptor determination only applied to part of the population, interpretation of tumor response as a function of receptor status would not Table 6. Tumor
Good responders* Poor responderst
* CR or PR. t MR or NR.
response
according
ER+PR+
ER-PR+
ER+PR-
23141 18141
6113 7113
3114 1 l/l4
to receptor ER-PR12124 I2124
status and mammographic Stellar
Nodular
44167 23167
I5127 12127
findings
Microcalcifications 6126 10126
Blurred opacity 9128 19128
I. J. Radiation Oncology 0 Biology 0 Physics
328
July 1991, Volume 21, Number 2
90
70
,I...... 0
2
I
4
3 YEARS
S
6
Fig. 2. Local control according to therapeutic groups.
.I_&___ 0
2
3
4
S
6
"EARS
Fig. 4. Disease-free survival according to therapeutic subgroups.
the two main therapeutic groups (B and C2), actuarial local control for patients at 5 years seems to be higher after secondary tumorectomy (90%) than after exclusive irradiation with high dose iridium implantation (76%). Similar results were observed for disease-free survival (73% vs 65%). However, the difference did not reach statistical significance (p = 0.08). Considering the small number of the two other therapeutic subgroups (A and Cl), it is difficult to interpret the disease-free survival data. After radical surgery we did not observe any chest wall skin recurrence. If we consider
(i.e., the poor responders in terms of radiosensitivity) received high dose iridium brachytherapy. Recently, Durand et al. (5) published their results of conservative surgery after preoperative external irradiation. Although dealing only with T2 they conclude that 15% of the cases could benefit from a secondary tumorectomy, some of which had postoperative complications. In addition to preoperative radiotherapy, some authors investigated two other treatment modalities in order to improve
DISCUSSION
This protocol enabled preservation of the breast in good condition in 56% of the large T2 (45/8 1) and 5 1% of the T3 (29/57) cases in which mastectomy is classically performed because of the large tumor volume. The response to primary external radiotherapy seems to be the best criterion of tumor radiosensitivity and consequently of the possibility of conservative treatment. The high rate of local recurrence observed in this series after exclusive high dose irradiation is greater than that found in our previous published data (8) dealing with T2 and T3 without any selection regarding tumor radiosensitivity. As stated above, in this series, only the patients who refused radical surgery
conservative
management
of large tumors:
x
,
OJ 0
I
2
3
4
S
6
YEARS
Fig. 3. Local control according to tumor size.
in-
traoperative brachytherapy ( 10) and neoadjuvant chemotherapy (7). Intraoperative brachytherapy renders possible an “economical” excision of the tumor since the radiotherapist has an exact measure of the macroscopic tumor margins during the implantation. Nevertheless, a tumor larger than 5 cm cannot benefit from this technique. In fact, the removal of a tumor of such a size induces a surgical defect which would definitively affect the cosmetic result. Neoadjuvant chemotherapy has two advantages: its preventive effect on microscopic spread and its frequent effect on the local tumor regression. On the other hand, imposing primary chemotherapy on all patients on the sole basis of tumor size without taking into account the
04 0
/
2
3
4
S
6
Fig. 5. Disease-free survival according to tumor size.
Breast cancer treatment l E. CALIT~HI d al.
other prognostic parameters seems too harsh an attitude, especially in post-menopausal women (3). It must be stressed that in our series a third of the patients who underwent an axillary dissection (59 patients) did not show any node involvement. Nevertheless, if systemic adjuvant therapy (chemo or hormonotherapy) is indicated (particularly in the case of positive nodes), it should be done immediately. Therefore, in our current protocol, after axillary dissection, locoregional radiotherapy is performed simultaneously with the eventual adjuvant treatment.
329
CONCLUSION Nowadays conservative management of breast cancer is well accepted for small lesions but reservations are made for larger tumors. Preoperative radiotherapy enables the use of conservative surgery in large T2 and T3 cases. Our results are preliminary and require more cases with a longer follow-up to assess definitive conclusions. Nevertheless, our protocol enables women to conserve their breasts in about half the cases where radical surgery would usually be recommended.
REFERENCES I. Almaric, R.; Santa Maraia, F.; Robert, F.; Seigle, Y.: Altschuler. H.; Ayme, Y.; Pallet, J. F.; Burmeister, R.; Abed, R. Radiation therapy with or without primary limited surgery for operable breast cancer: a 20 year experience at the Marseille Cancer Institute. Cancer 49:30-34; 1982. 2. Calle, R.; Pilleron, J. P.; Schlienger, P.; Vilcoq, J. R. Conservative management of operable breast cancer10 years experience at the Foundation Curie. Cancer 42:2045-2053: 1978. 3. Consensus conference. Directed by the “National Cancer Institute.” Adjuvant chemotherapy for breast cancer. JAM.4 254:3461-3463; 1985. 4. Delouche, G.; Bachelot, F.; Premont, M.; Kurtz, J. M. Conservation treatment of early breast cancer: long term results and complications. lnt. J. Radiat. Oncol. Biol. Phys. 13:2934; 1986. 5. Durand, J. C.; Solalinde, V.; Mathieu, G.; Salmon, R. Y.; Bataini, P.; Vilcoq, J. R.; Hamelin, J. P.; Pilleron, J. P. La chirurgie conservative apres radiotherapie a doses prt-operatoires dans le traitement des cancers du sein. indications et resultats. Bull. Cancer 74:641-646; 1987. 6. Fisher, B.; Bauer, M.; Margolese, R.; Poisson, R.; Pilch, Y.: Redmond, C.; Fisher, E.; Wolmark, N.; Deutsch, M.; Montagne, E.; Saffer, E.; Wickermam, L.; Lerner, H.; Glass, A.; Shibata, H.; Deckers, P.; Ketcham, A.; Oischi, R.; Russel. I. Five year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N. Engl. J. Med. 11:665-673; 1985. I. Jacquillat, C.; Weil, M.; Baillet, F.; Borel, Ch.; Auclerc, G.; De Maublanc, M. A.; Housset, T.; Forget, G.; Till, L.; Soub-
rane, C.: Khayat, D. Results of neoadjuvant chemotherapy and radiation therapy in the breast conserving treatment of 250 patients with all stages of infiltrative breast cancer. Cancer 66:119-129; 1990. Y.; Calitchi, E.; Mazeron, J. J.; Le 8. Leung, S.; Otmezguine, Bourgeois, J. P.; Pierquin, B. Locoregional recurrences following radical external beam irradiation and interstitial implantation for operable breast cancer. A twenty three year experience. Radioth. Oncol. 5: l-10; 1986. for early breast cancer. 9. Limited surgery and radiotherapy Special Report. N. Engl. J. Med. 21:1365-1368; 1985. IO. Maylin, C.; Baillet, F.; Clot, P.; Mignot. L. Inter&t de l’association tumorectomie-curietherapie per-operatoire dans le cancer du sein. J. Eur. Radiother. I: 139-141: 1980.
I I. Pierquin,
12.
13.
14. 15.
B.; Huart, J.: Raynal, M.; Otmezguine, Y.; Mazeron, J.-J.: Calitchi, E.: Le Bourgeois, J. P.; Marinello, G. Radiation therapy a primary treatment of cancer of the breast. Br. J. Radiol. 22(Suppl.):67-76; 1987. Pierquin, B.; Marin, L. The past and future of conservative treatment of breast cancer. Am. J. Clin. Oncol. 9:476-480; 1986. Sarrazin, D.; Dewar, J. A.; Arriagada, R.; Benhamou, S.; Lasser, P.; Fontaine, F.; Travagli, J. P.; Spielmann, M.; Le Chevalier, T.: Contesso, G. Conservative management of breast cancer. Br. J. Surg. 73:604-606; 1986. Tobias, J. S. Radiotherapy and breast conservation. Br. J. Radial. 59:653-666; 1986. Veronesi, U.; Zucali, R.; Luini, A. Local control and survival in early breast cancer: the milan trial. Int. J. Radiat. Oncol. Biol. Phys. l2:7 17-720: 1986.
0360.3016191 $3.00 + .I0 (CI 1991 Pergamon Prey plc
l Original Contribution
EXTERNAL IRRADIATION PRIOR TO CONSERVATIVE FOR BREAST CANCER TREATMENT
SURGERY
E. CALITCHI, M.D.,* Y. OTMEZGUINE, M.D.,* F. FEUILHADE, M.D.,* P. PIEDBOIS, M.D.,* J.-M. PAVLOVITCH, M.D.,* B. BRUN, M.D.,* J.-J. MAZERON, M.D.,* J.-P. LE BOURGEOIS,M.D.,* M. JULIEN, M.D.+ AND B. PIERQUIN, M.D.* HBpital Hemi Mondor, 5 1 Avenue du Mar&ha1 de Lattre de Tassigny, 94010 Crete& France From 1981 to 1987, 138 patients with breast cancer unsuitable for primary tumorectomy received initial external radiotherapy (45 Gy/2Sf/35d) in order to reduce the tumor volume so that secondary limited surgery could be performed. There were 81 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. After completion of the radiotherapy, 22 patients (16%) showed no more evidence of a tumor either clinically or radiologically and received a boost of 25 Gy. In 52 cases (38%) the tumor regression allowed for secondary tumorectomy followed by a boost of 20 Gy. Sixty-four patients (46%) showed either little or no tumor regression: radical surgery was performed in 14 cases (10%) and high dose boost curietherapy (37 Gy) in the 50 (36%) remaining patients who refused mastectomy. Breast conservation in good condition was thus obtained in 74 patients (54%). Sufficient tumor regression to allow secondary tumorectomy was more often observed in T2 than in T3, in poorly differentiated tumors or mutinous type, and in tumor with well defined mammographic aspects. Actuarial 5year local control and disease-free survival rates after limited surgery were, respectively, 90% and 73%. No particular complications were observed after secondary tumorectomy. This therapeutic approach is encouraging in patients with large T2 and T3 breast tumors, but a longer follow-up is required to assess definitive conclusions. Breast cancer, Preoperative radiotherapy, Secondary tumorectomy.
INTRODUCTION
METHODS
The combination of limited surgery and radiotherapy is currently a well accepted option for the treatment of early breast cancer (1, 2, 4, 6, 12, 13, 14, 15). This treatment approach is generally recommended for tumors less than 4 cm in size that do not involve the nipple-areolar complex. The most important criterion for achieving good cosmetic results is the ratio between the volume of the tumor and that of the mammary gland (9, 11). The usual recommendation for patients with larger tumors is radical surgery. If surgery is refused, exclusive radiotherapy is always possible, but cosmetic results are generally not as good and local recurrences often occur, necessitating salvage mastectomy (8, 12). We tried to improve local control and cosmetic results for large T2 and T3 by combining limited surgery with radiotherapy as is currently done for Tl and small T2. To maximize the use of conservative rather than radical surgery, we inversed the therapeutic sequence, beginning with external irradiation, in order to reduce the tumor volume so that secondary limited surgery could be performed.
AND MATERIALS
From 198 1 to 1987, 138 consecutive patients with unifocal non-inflammatory and non-metastatic breast cancer unsuitable for primary tumorectomy (T2 and T3) were treated in our institution. Patients’ and tumor characteristics are presented in Tables 1 to 3. In all cases, diagnosis was established histologically by incisional biopsy. The median follow-up was 50 months (range 8 to 118). According to the 1987 UICC TNM classification, there were 8 1 T2 and 57 T3. Fifty-seven percent of the patients had a tumor larger than 4.5 cm. In about 10% of the cases (13/138), the tumor size did not exceed 3.5 cm but the breast was not large enough for primary excision of the tumor. Treatment modalities Treatment of the breast. All patients were treated with a telecobalt unit. Briefly, the breast was treated to 45 Gy using opposed tangential portals, 5 fractions/week, 1.8 Gy each fraction. Six weeks after completion of the radiotherapy course, the tumor response was evaluated
* Department of radiotherapy. +Department of surgery.
Reprint request to: E. Calitchi. Accepted for publication 25 January 325
199 1.
326
1. J. Radiation Oncology 0 Biology 0 Physics
Table 1. Patients
and tumor
Menstrual status Premenopausal Postmenopausal Average tumor size (cm) Clinical lymph node status NO Nl
July 1991. Volume 21. Number 2
characteristics
T2 (81)
T3 (57)
Total (138)
29 52 4
28 29 6
57 81
EXTERNAL
45ty 12X/354)
66 15
30 27
25
-
-
-
PR +
. Culetnarapy
type T3 (57)
Total
16 28 18 10
5 21 20 9
21 49 38 19
6 0 3
1 1 0
7
I 3
* The biopsy specimens were too small to allow for histologic grade specification. ( 1) = Well differentiated; (2) = Moderately differentiated; (3) = Poorly differentiated.
status and mammographic
Receptor status* ER+PR+ ER+PRER-PR+ ER-PRMammographic findings Star shaped Nodular Microcalcifications Blurred opacity
- B
20 Gy
T2 (81) Histologic type: histologic grade Infiltrating ductal carcinoma (N.O.S.) I(1) II (2) III (3) Unknown* Other type Mutinous Medullary Lobular
(221
Tumorectomy
6 weeks
96 42
clinically and radiologically to decide on further treatment modalities (Fig. 1): (A) In case of complete regression (complete response: CR) with no further evidence of the tumor either clinically or radiologically, no surgery was performed and treatment was completed with a moderate boost of 25 Gy (group A). (B) If tumor regression was incomplete (partial response: PR) but sufficient to allow for limited surgery, secondary tumorectomy was carried out followed by a postoperative boost of 20 Gy. It must be stressed that in
Table 2. Histologic
Gy
IRRADIATION
MR or NR
Table 3. Receptor
Curlelllerlple- A
CR PRIMARY
findings
T2
T3
Total
24 9 7 11
17 5 6 13
41 14 13 24
43 14 10 14
24 13 16 14
67 27 26 28
* Steroid receptor determination (superior or inferior to IO fmol) was available only in 92 patients, as it was not performed on a routine basis at the beginning of the study.
_ \
(521
Mastectomy
- Cl II41
\ y
Cunetnerapy 37 GY
Fig. 1. Treatment
’
- c2 I501
protocol.
order to obtain good cosmetic results, the surgical procedure removed only the residual tumor with a margin of macroscopic normal surrounding tissue (group B). No formal microscopic peroperative margin assessment was performed. (C) In case of poor regression (no response: NR or minimal response: MR) we recommended radical surgery (group C 1). Patients who refused it were given a high dose boost (37 Gy), being fully informed of its uncertain outcome (group C2). All the boosts were delivered by Iridium 192 afterloading interstitial techniques. In most cases the implant consisted of two planes unless, after tumorectomy, the mammary volume only allowed for one plane. Treatment of the regional lymph nodes. The attitude adopted toward the regional nodes was modified during the study. Until 1984, in conformity with our previous practice, radiotherapy alone was used in the management of the draining lymph nodes areas. They received 45 Gy by telecobalt followed by a boost of 24 Gy to the lower axilla and of 15 Gy to the internal mammary nodes using direct 10 MeV electron beams. Axillary dissection was only performed when large nodes showed insufficient regression after radiation therapy. According to our previous experience (8), this protocol led to very high local control in the axilla and internal mammary chain. However, it did not provide any information with regard to axillary lymph node involvement, which remains the most important prognostic criteria in deciding any adjuvant medical treatment (3). Therefore, from 1984 primary axillary dissection was routinely performed to evaluate his-
Table 4. Response
to primary
CR = 22/138 (16%) PR = 52/138 (38%) NR or MR = 64/138 (46%)
external
irradiation
Group A Group B Group Cl + C2
321
Breast cancer treatment 0 E. CALITCHI eta/
Table 5. Tumor response according to tumor size and histology Histology T
Good responders* (group A and B) Poor responders+ (group Cl and C2)
T2
T3
Grade I (1)
:2I)
III (3)
45
29
I
28
23
5
1
2
36
28
14
21
15
2
0
1
Mutinous
Medullary
Lobular
* CR or PR. + MR or NR. (1) = Well differentiated:
(2) = Moderately
differentiated;
(3) = Poorly differentiated.
be accurate. On the other hand, well defined mammographic aspects (stellar or nodular) usually were associated with good response to radiotherapy in 59 out of 94 (63%) cases. In cases of blurred opacities or abundant microcalcifications, only 15 out of 44 showed good response to radiotherapy. In all 52 secondary tumorectomy specimens, the tumor margins were microscopically negative; moreover, 8 of those cases ( 15%) did not show any residual tumor. Fifty-nine axillary dissections were performed to remove the nodes of Berg level I and II (21 before radiotherapy; 38 after delivering 45 Gy). Fifteen out of 30 T2 patients (50%) and 22 out of T3 patients (76%) were found positive, giving a total of 37 positive axillary dissection (63%). Secondary surgery after 45 Gy did not cause any particular complications. In three cases there was a breach of the surgical scar: spontaneous healing occurred in 6 to 8 weeks. Compared to primary tumorectomy, no particular complications were observed. Provided that the surgical procedure only removed the residual tumor with 1 cm of surrounding macroscopic normal tissue, the cosmetic results after secondary tumorectomy were, on the whole. satisfactory. In the two main therapeutic groups (B and C2) among patients with more than 3 years follow-up, poor cosmetic results were more often observed after exclusive irradiation with high dose boost (C2: 4/3 1 = 13%) than after secondary tumorectomy (B: 2/38 = 5%). In conformity with our previous experience (8) in cases of local recurrence, salvage surgery could always be performed without any particular difficulties even after high dose boost (C2). Actuarial local control and disease-free survival at 5 years according to therapeutic subgroups and tumor size are shown in Figures 2 to 5.
tological nodal status. Postoperative axillary irradiation (45 Gy) was then only delivered in case of nodal involvement. Supraclavicular and internal mammary regions were irradiated in N- patients with a central or medial tumor or N+ patients regardless of the site of the primary tumor. Adjuvant chemotherapy, if indicated, was only delivered following completion of locoregional treatment.
RESULTS Table 4 shows the tumor response to primary external irradiation, which formed the basis of our therapeutic sequence. In 54% of the cases (74/138), a satisfactory response was observed, enabling exclusive irradiation with a moderate dose boost (group A: 22/ 138- 16%) or limited secondary surgery (group B: 52/138-38%). The remaining patients (64/138: 46%) did not respond well. They most often chose exclusive irradiation with a high dose boost (group C2: 50/ 138-36%) rather than radical surgery (group C 1: 14/l 38-lo%), perhaps because of the reputation of our institution for breast preservation. In fact, many patients who had been refused breast conservation elsewhere came to us totally opposed to primary mastectomy and ready to try breast conservation. Analysis of the tumor response as a function of initial size, histology, receptor status, and mammographic findings is shown in Tables 5 and 6. Total or partial regression sufficient to allow secondary tumorectomy was observed more often in T2 rather than in T3. Similarly, the response rate was higher in the moderate or poorly differentiated tumors (grade II and III) and in the mutinous type than in the well differentiated tumors (grade I). Since hormone receptor determination only applied to part of the population, interpretation of tumor response as a function of receptor status would not Table 6. Tumor
Good responders* Poor responderst
* CR or PR. t MR or NR.
response
according
ER+PR+
ER-PR+
ER+PR-
23141 18141
6113 7113
3114 1 l/l4
to receptor ER-PR12124 I2124
status and mammographic Stellar
Nodular
44167 23167
I5127 12127
findings
Microcalcifications 6126 10126
Blurred opacity 9128 19128
I. J. Radiation Oncology 0 Biology 0 Physics
328
July 1991, Volume 21, Number 2
90
70
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2
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4
3 YEARS
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Fig. 2. Local control according to therapeutic groups.
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Fig. 4. Disease-free survival according to therapeutic subgroups.
the two main therapeutic groups (B and C2), actuarial local control for patients at 5 years seems to be higher after secondary tumorectomy (90%) than after exclusive irradiation with high dose iridium implantation (76%). Similar results were observed for disease-free survival (73% vs 65%). However, the difference did not reach statistical significance (p = 0.08). Considering the small number of the two other therapeutic subgroups (A and Cl), it is difficult to interpret the disease-free survival data. After radical surgery we did not observe any chest wall skin recurrence. If we consider
(i.e., the poor responders in terms of radiosensitivity) received high dose iridium brachytherapy. Recently, Durand et al. (5) published their results of conservative surgery after preoperative external irradiation. Although dealing only with T2 they conclude that 15% of the cases could benefit from a secondary tumorectomy, some of which had postoperative complications. In addition to preoperative radiotherapy, some authors investigated two other treatment modalities in order to improve
DISCUSSION
This protocol enabled preservation of the breast in good condition in 56% of the large T2 (45/8 1) and 5 1% of the T3 (29/57) cases in which mastectomy is classically performed because of the large tumor volume. The response to primary external radiotherapy seems to be the best criterion of tumor radiosensitivity and consequently of the possibility of conservative treatment. The high rate of local recurrence observed in this series after exclusive high dose irradiation is greater than that found in our previous published data (8) dealing with T2 and T3 without any selection regarding tumor radiosensitivity. As stated above, in this series, only the patients who refused radical surgery
conservative
management
of large tumors:
x
,
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4
S
6
YEARS
Fig. 3. Local control according to tumor size.
in-
traoperative brachytherapy ( 10) and neoadjuvant chemotherapy (7). Intraoperative brachytherapy renders possible an “economical” excision of the tumor since the radiotherapist has an exact measure of the macroscopic tumor margins during the implantation. Nevertheless, a tumor larger than 5 cm cannot benefit from this technique. In fact, the removal of a tumor of such a size induces a surgical defect which would definitively affect the cosmetic result. Neoadjuvant chemotherapy has two advantages: its preventive effect on microscopic spread and its frequent effect on the local tumor regression. On the other hand, imposing primary chemotherapy on all patients on the sole basis of tumor size without taking into account the
04 0
/
2
3
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S
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Fig. 5. Disease-free survival according to tumor size.
Breast cancer treatment l E. CALIT~HI d al.
other prognostic parameters seems too harsh an attitude, especially in post-menopausal women (3). It must be stressed that in our series a third of the patients who underwent an axillary dissection (59 patients) did not show any node involvement. Nevertheless, if systemic adjuvant therapy (chemo or hormonotherapy) is indicated (particularly in the case of positive nodes), it should be done immediately. Therefore, in our current protocol, after axillary dissection, locoregional radiotherapy is performed simultaneously with the eventual adjuvant treatment.
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CONCLUSION Nowadays conservative management of breast cancer is well accepted for small lesions but reservations are made for larger tumors. Preoperative radiotherapy enables the use of conservative surgery in large T2 and T3 cases. Our results are preliminary and require more cases with a longer follow-up to assess definitive conclusions. Nevertheless, our protocol enables women to conserve their breasts in about half the cases where radical surgery would usually be recommended.
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