Conservative treatment of breast cancer: A report on 108 patients

Inr J Radmmn O,ldO~J~ Bid Phy Vol Pnnted 1” the U S.A. All rights reserved.

IO,

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0360.3016184 $03.00 + ..I0 C 1984 Pergamon Press Ltd.

0 Original Contribution CONSERVATIVE TREATMENT OF BREAST CANCER: A REPORT ON 108 PATIENTS MICHEL JEAN MONTICELLI,

M.D., MOISE NAMER,

H~RY, M.D.,

JEAN-LOUIS

Centre

Antoine

M.D., JACQUES VERSCHOORE,

BOUBLIL,

Lacassagne,

M.D.

AND CLAUDE

MICHEL

M.D., LALANNE,

M.D.

36 Voie Romaine, 06054 Nice, France

Between 1975 and 1980, 108 breast cancers (Tl and small T2) were treated at the Centre Antoine-Lacassagne (Nice, France) by a combination of conservative surgery and irradiation. Ninety-two of these patients underwent axillary node dissection; 17% of them presented with nodal involvement. All irradiation was given by telecobalt:

45 Gy to the entire breast, 60 Gy to the site of the tumor. All cosmetic results were acceptable. Intramammary recurrences were rare (6%) and independent of the tumor site or size or of any dodal involvement. Solitary metastases (not associated with a local recurrence) were extremely rare (4%) and were observed in patients who had had no nodal involvement. The actuarial survival rate at 5 years is 90%. Breast cancer, Conservative surgery, Irradiation.

metastasis was found in the remaining 16 patients (N+ = 17%). Sixteen patients did not undergo node dissection since such surgery was not initially part of the treatment protocol. Tables 1 and 2 summarize tumor distribution data as a function of size and nodal status.

INTRODUCTION Conservative treatment of small breast cancers of less than 3 cm (T 1, small T2) remains a subject of controversy

despite the favorable results reported by numerous authors.2,3,5,‘3Two randomized studies conducted in Italy” and in FranceI unquestionably demonstrate the value of treatment combining conservative surgery with irradiation. The present study describes our own results obtained using this conservative therapeutic strategy.

METHODS During the patients with and small T2) vative surgery

AND

Irradiation Breast. Telecobalt was used to deliver 45 Gy to the entire breast with two symmetrical, opposed beams, compensator wedges and without bolus at a rate of 10 Gy per week over 4 or 5 sessions. Boost doses to the tumor bed were also given by telecobalt: a small beam (5 X 5 cm) was employed to deliver 15 Gy, without a bolus, to the scar area. Very large breasts received 45 Gy over 5 weeks, but the boost dose never exceeded 10 Gy. The daily dose was 180 rad per fraction. Nodal regions. From 1975 to 1977, all patients with positive axillary nodes were treated by irradiation of the supraclavicular and axillary nodes 3 times a week using an anterior field (2.5 Gy, average depth 6 to 7 cm); a posterior axillary portal was used to deliver additional irradiation to the axilla (2.5 Gy once a week). Details of irradiation were as follows:

MATERIALS

5 year period from 1975 to 1980, 108 breast cancers smaller than 3.5 cm (Tl were treated by a combination of conserand irradiation.

Population The population consisted of 83 patients classified as Tl (UICC classification, tumor between 0 and 2 cm) and 25 patients classified as T2 (tumor between 2 and 3.5 cm). All 108 patients were classified as NO, Nl.

axillary dose: 45Gy

Conservative surgery Surgery consisted of segmentectomy with cutaneous resection for superficial tumors. Ninety-two of the 108 patients had axillary node dissection: 76 of these dissections did not reveal any metastasis (N- = 83%) while

Reprint

requests

18 sessions 4% weeks

NSD: 1598 TDF 81 supraclavicular dose: 45 Gy 14 sessions 4% weeks NSD: 1673 TDF 91

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to: Dr. M. H&y. 2185

for publication

3 July 1984.

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RESULTS

Table 1. Study population No. of cases

Characteristics Size

83 25

0 to 2 cm 2 to 3.5 cm

Tl NO Nla (St I) T2 NO Nla (St II) Nodal status Clinical (NO, Nl) Histological*

NNf

* Only 92 patients underwent

Beginning in 1978, Gy at an average axillary-supraclavicular week over 5 weeks. deliver a daily boost 45 Gy (NSD: 1460;

108 = 76 (83%) = 16 (17%)

node dissection.

the technique was modified to 45 depth of 3 cm using an anterior beam at a rate of 10 Gy per A posterior axillary beam is used to in order to arrive at a total dose of TDF 74 for both volumes). In the

absence of any axillary dissection, a direct axillary beam is used to deliver 10 Gy in 5 sessions at a depth of 3 cm. An anterior sternal beam was always employed for separate irradiation of the internal mammary nodes: 35 Gy by telecobalt at a depth of 3 cm plus a 10 Gy boost by 10 Mev electrons (isodose 90%). In the absence of axillary irradiation, the supraclavicular and internal mammary regions are irradiated with a single anterior “hockey stick” beam. Irradiation of the nodal regions varied depending on whether dissection was performed. If no dissection was performed, axillary nodes received 60 Gy while the supraclavicular and internal mammary nodes received 45 Gy, regardless of nodal status (NO or Nl ). For patients who underwent dissection, irradiation was modulated as a function of nodal status; N+ patients received 45 Gy to the axillary, supraclavicular and internal mammary regions. N- patients with a central or internal tumor received 45 Gy to the internal mammary and supraclavicular regions.

Table 2. Studv nonulation N-

N+

No dissection

Total

T2

57 19

11 5

15 1

83 25

Total

76

16

16

108

Tl

N+ 1 to 3 4 or more Total

Tl

December 1984, Volume 10, Number 12

T2

Total

8 3

4 1

12

11

5

16

4

Cosmetic outcome concerning the breasts At 3 years, 10 1 of the 108 irradiated patients had no sequela (3 patients were lost to follow-up, 3 patients had undergone mastectomy for early recurrence, and 1 death had occurred from metastasis). At 4 years, 82 patients were available for follow-up: there were 8 1 good cosmetic results, including 1 case of discrete telangiectasia. The remaining patient had required mastectomy for recurrent disease. For patients followed to 5 years or more, 64 had no important sequela. One patient presented with a discrete retraction of the scar during the fifth year. Two other patients developed telangiectasia and slight sclerosis during the seventh year. The majority of patients were treated at a rate of 4 sessions of 2.5 Gy per week; the other patients received 5 sessions of 2 Gy per week. The total dose delivered to the entire breast never exceeded 45 Gy for any patient. No differences were observed in results. Only a slight depth of breast was irradiated since the internal mammary chain was irradiated separately with an anterior sternal beam. Very large breasts, however, were treated somewhat differently: 9 Gy per week in 5 sessions, 45 Gy to the entire breast, boost dose not exceeding 10 Gy. Cosmetic outcome concerning the nodal regions In the group of 16 patients who did not undergo axillary dissection, 2 presented complications during the fifth year (1 marked axillary sclerosis, 1 radiation-induced plexitis). Four complications were observed in the group of 50 patients who had axillary dissection (N+ or an insufficient number of N-). Two of these 4 patients were T 1, 2 N+; one developed proximal edema of the arm 1 year after irradiation without any adjuvant chemotherapy; the other patient developed moderate but unesthetic sclerosis of the pectoral muscle during the fourth year, without any impairment of arm mobility, after having received 60 Gy. The other two patients were T2, N+; one developed plexitis during the eighth year (45 Gy in 14 sessions over 4% weeks) while the other developed moderate supraclavicular fibrosis. Survival Four patients died and two others were lost to followup. Two of the deaths were caused by diffise metastasis without local recurrence; the other two deaths involved mammary recurrence plus concomitant nodal and visceral metastases. The actuarial survival rate at 5 years is 90%; the median length of follow-up is 60 months. Mammary recurrences A total of 71108 recurrences were observed; three out of 83 Tl patients (4%) and four out of 25 T2 patients (16%) relapsed. This difference is not statistically significant. The site of the primary tumor did not influence

Conservative treatment of breast cancer 0 M. H~RY ef nl.

the probability of recurrence: four of the relapses concerned the outer quadrant while the three others were in the inner quadrant. Mammary recurrence was not conditioned by axillary node involvement. None of the 16 N+ patients relapsed, but six of the 76 N- patients (8%) had recurrence in the breast. One of these six patients developed enlarged nodes free of metastasis; the total of 14 nodes examined for the remaining five patients were all free of involvement. A seventh case of recurrence occurred in a patient who did not undergo node dissection. The dose of irradiation received appears to play an important role in whether recurrence occurs: one of the three patients who received less than 45 Gy relapsed. Despite appropriate doses (60 Gy), however, 6/85 patients (7%) also relapsed. Table 3 summarizes data on mammary recurrences as a function of various parameters. In view of the low number of analyses performed, we were unable to evaluate recurrence as a function of hormone receptors. Date of recurrence While mammary recurrence can occur years after treatment, four of our seven cases of recurrence were observed in the first 2 years of follow-up: one patient relapsed at 1 year, three patients relapsed at two years, one patient relapsed at three years, one patient relapsed at four years, and one patient relapsed at five years. Site of recurrence The site of recurrence varied. Three of the 7 relapses involved the tumor bed, and two of these three cases were associated with metastases which rapidly proved fatal. Two other recurrences were seen at the tumorectomy scar, in the form of small (1 cm), benign granulomas. The last two recurrences concerned diffuse intra-

galactophoric cations.

epithelioma

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with extensive microcalcifi-

Treatment of recurrences Conservative treatment was possible for the two patients with nodules on tumorectomy scars. Four other patients required a mastectomy. The last patient’s disease evolved rapidly, and treatment solely by chemotherapy was unsuccessful. Solitary axillary recurrences Three of our 108 patients developed a solitary axillary recurrence. All three patients had undergone node dissection which did not reveal any nodal involvement; thus they did not receive any axillary radiotherapy. These recurrences can be explained by the insufficient number of nodes examined (one patient had one Nnode; the other two each had 4 N- nodes), which vitiates the predictive value of dissection. Isolated metastases without local recurrence Five of the 108 patients (4%) developed isolated metastases without any accompanying local recurrence. No correlation was seen with tumor volume: three of the 83 patients with Tl disease relapsed while two of the 25 patients with T2 lesions relapsed. No correlation was seen either with the Scarff and Bloom grade: four of the patients were classified Grade II while one patient was classified Grade III. Although none of our 16 N+ patients developed metastases, certain received an adjuvant medical treatment. Of the 76 N- patients, five (6%) developed metastases. One of these five patients had only one negative node; for the other four patients, 14 enlarged nodes were examined, and all were free of metastases. The usual sites of metastases were the lungs (two patients) or bone (three patients), and such metastases generally showed up at an early date (within two years).

Table 3. Mammary recurrence 7/108 patients (6%)

Size Tl T2 Site Outer quadrant Inner quadrant Nodal Status NO N+ NBreast irradiation Total dose zz 45 Gy Total dose > 45 to 60 Gy

No. of cases

Percentage

3183 4125

4% 16% NS

4 3 l/16 O/16 6/76*

8%

l/3 61105

5%

* Of the six N- patients who relapsed, one had 5 N- and the other five patients had 14 N-.

Chemotherapy Patients who benefited from chemotherapy were the subject of special study since the influence of such treatment on local cure and cosmetic results remains a topic of controversy. Five patients received chemotherapy due to nodal involvement. Three of these patients were classified Tl ; one patient had one N+ node, one patient had 14 N+ nodes, and one patient had 10 N+ nodes. These patients received a polychemotherapy for one year: type CMF for the patient with one N+ node, and a combination of adriamycin, vincristine, cyclophosphamide and fluorouracil for the other two patients. The remaining two patients with nodal involvement were classified T2; one patient had two N+ nodes, the other had four N+ nodes. During one year, one of these patients received a CMF treatment; the other was given

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a combination of adriamycin, vincristine, cyclophosphamide and fluorouracil. Five additional patients who developed metastases were also given chemotherapy once the lesions were discovered. No differences as concerns complications or cosmetic outcomes were observed between patients who received adjuvant chemotherapy and those who were not treated. None of our 16 patients with nodal involvement developed local recurrence; five of these patients received adjuvant chemotherapy for a one year period. This number is too small to allow any conclusions to be drawn as to the influence of chemotherapy on local control. DISCUSSION Conservative surgery versus mastectomy Two recent European trials have demonstrated that conservative surgery is as effective as mastectomy. The trial conducted by the Tumor Institute in Milan, Italy” included 701 patients with a breast cancer smaller than 2 cm, classified NO, treated between 1973 and 1980. Radical mastectomy (Halsted) (349 patients) was compared to quadrantectomy plus axillary node dissection and mammary irradiation (352 patients). The actuarial survival rate was 90% at 5 years for both groups. Furthermore, no significant differences were observed in the rate of local recurrence or metastases. The second trial, conducted at the Institut Gustave-Roussy in Villejuif, France,16 covered 179 patients with Tl or small T2 tumors seen from Oct. 1972 to 1980. Eighty-eight patients underwent tumorectomy, while 91 others were treated by mastectomy. Surgery of the axilla was identical for both groups: axillary sampling plus dissection were performed if extemporaneous examination of the lower nodes was positive. The actuarial survival rate at five years was 9 1% for the mastectomy group and 95% for the tumorectomy group. Our results concur with these figures. Quadrantectomy versus tumorectomy Patients in the Villejuif trial treated by tumorectomy had the same crude survival/relapse free survival rate as the Milan patients treated by quadrantectomy.16,‘7 Patients who had a histologically insufficient excision” relapsed more frequently. In such cases, excellent local control can be obtained with iridium treatment of the tumor bed; this solution has the advantage of preserving the cosmetic result, in contrast to extensive resection. Scope of application of conservative surgery At the present time, we feel it reasonable to propose conservative surgery for tumors measuring over 2 cm. In our series, as in those of Baeza et al2 and Harris et al.,” no significant differences were noted in the rates of local recurrence for Tl and T2 tumors. The essential parameter appears to be the ratio between tumor volume

December 1984, Volume 10, Number 12

and breast size; in other words, excision of a 3 cm tumor should be avoided for small breasts, even though some patients prefer to “keep their breast” regardless of the cosmetic outcome. The preferred procedure is thus tumorectomy or segmentectomy, by a direct incision, with careful hemostasis, and excision of the gland down to the muscle layer. Cutaneous resection opposite the tumor does not seem obligatory. Axillary investigation Clinical examination of the axillary region allows initial evaluation of any nodal involvement (NO, Nl to Ml), despite a 20 to 35% margin of error. Surgical exploration offers better insight into the natural history of Tl and T2 breast cancers: 15 to 30% of such patients exhibit nodal involvement (N+).‘,16 Axillary sampling also provides important prognostic data as a function of the number of nodes involved. In addition, it furnishes useful information for radiotherapy by obviating the need for “blind” irradiation of 70 to 80% of those axillary nodes that are free of metastases. Treatment as a function of findings is as follows. N- nodes in the outer quadrant receive no irradiation. N- nodes in the central quadrant call for inner mammary irradiation plus supraclavicular or inner irradiation. When N+ nodes are discovered, certain authors16 advise complete axillary dissection without any subsequent irradiation in order to avoid functional complications. Other authors” feel that irradiation with sufficient doses is required to reduce the rate of recurrence and metastasis. Finally, surgery provides data which is useful for decisionmaking concerning adjuvant medical treatment (hormone therapy or chemotherapy). Since Vogt-Homer and Contesso” published the results of their work, axillary node involvement has been known to progress by steps, from level 1 to level 3. Axillary sampling was thus proposed as a means of reducing the risks of edema resulting from complete dissection while still allowing satisfactory assessment of nodal status. Kissin et al.12 criticized this procedure, however, on the grounds that the average number of nodes examined was only four in axillary sampling versus 14 during extensive dissection. Axillary sampling was also criticized for three other reasons: no nodes were found for 10% of patients, false negatives were obtained for 8% of patients, and the number of N+ nodes were underestimated for 6% of patients. Rose et al. I5 reported on a series of 132 axillary investigations for NO, N la patients. When one to five nodes were examined, 11% were found to be involved; this percentage rose to 22% when six to 10 nodes were checked. In a series of 200 axillary dissections, Boova et a1.4 found seven patients (3.5%) with solitary nodal metastases in the second or third levels. The average number of nodes examined for these patients in the first level was only 3.4, whereas the average for the entire series was

Conservative treatment of breast cancer 0 M. H~RY ef al.

14. In contrast, the average number of nodes examined in the second and third levels (12 and 7 respectively) was identical. A sufficient number of nodes must therefore be examined in level 1 to ensure the full predictive value for the status of the entire axillary chain. The three cases of axillary recurrence in our series concerned patients for whom only four nodes had been examined, thus corroborating the results of Boova et al4 Mammary recurrence Irradiation of the breast with a sufficient dose is mandatory, since approximately 30 to 40% of patients have subclinical disease sites disseminated throughout the breast. Two important studies by Atkins et al. ’ and Chu et al.* have demonstrated that breast irradiation with a dose of less than 40 Gy leads to a 30% recurrence rate. By contrast, overall results published in the literature indicate a relapse rate of only 8% with irradiation doses over 45 Gy, and optimum control with 70 Gy. The problem thus involves arriving at a compromise between optimum local control with high doses (70 Gy), which may affect cosmesis, and local control at lower doses (60 Gy) with an 8% risk of local recurrence but an excellent cosmetic outcome. Harris et al. lo did not find any significant relationship between mammary recurrence and clinical node involvement. As a reminder, none of our 16 patients with histologically confirmed node involvement (N+) developed local recurrence. Finally, recurrence limited strictly to the breast does not reduce the survival rate.6 Five of our patients had disease recurrence limited to the breast, and they are still free of metastases after three years without having received any adjuvant treatment. Cosmetic results Three factors influence the quality of the cosmetic result: the surgical procedure, the dose of irradiation and breast size. Unfortunately, no mathematical formula exists to define the optimum volume of excision for a given breast size. Nevertheless, cosmetic outcomes are less satisfactory with quandrantectomy than with tumorectomy. “,I6 For Sarrazin et al., I6tumorectomy gave 95% satisfactory results versus only 60 to 70% with more extensive tumorectomy. Direct arciform incisions are preferable for upper quadrants. Radial incisions are advisable for lower quadrants, as suggested by the N.S.A.B.P.,3 with separate incisions being made for dissection.

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Irradiation The higher the dose of irradiation, the higher the rate of complications. Delouche et aL9 reported that the use of 6000 rad had a 13% complication rate while 7000 rad resulted in a 56% complication rate. Use of telecobalt for irradiation of the entire breast and boost doses gives excellent functional results.2*5,16Other authors10,‘3 have obtained equally good results using curietherapy for boost purposes. At present, despite the satisfactory results obtained by Ray and Fish,14 many radiotherapists have abandoned the use of electrons for supplementation due to the sequela observed. The best cosmetic results appear to be obtained with a dose of 45 to 60 Gy to the breast and a boost dose of 10 to 15 Gy by cobalt or iridium. Our patients were all treated by telecobalt, and none received more than 45 Gy to the entire breast, which gave good cosmetic results. As for breast size, the cosmetic result of post-tumorectomy irradiation of a large, pendulous breast is always mediocre, and even moderate irradiation (50 Gy) will cause sclerosis with accompanying retraction and rise of the breast. Very few (six) of our patients had large breasts, which undoubtedly explains our good results. We were, however, surprised by our good results with small breasts. CONCLUSION Tl-T2 breast cancers can be cured while conserving the mammary gland by combining surgery and irradiation according to certain specific guidelines: Mammary surgery should consist of tumorectomy, since this affects the cosmetic outcome. Local recurrence is not correlated with tumor volume, site or axillary involvement. Axillary surgery must be sufficient (dissection of the first level and examination of at least seven nodes) in order for it to have an excellent predictive value; this affects the planning for nodal irradiation and adjuvant medical treatment. Irradiation should deliver 45 to 50 Gy to the entire breast, and 60 to 65 Gy to the tumor bed, using cobalt therapy or curietherapy for boost purposes. Globally speaking, mammary conservation is possible in 95% of patients with excellent cosmetic results and an actuarial survival rate identical to that for mutilating radical surgery. Prognosis is not linked to the conservative or mutilating nature of surgery.

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of the breast. Znt. J. 1982. 3. Bedwinek, J.: Treatment of stage I and II adenocarcinoma of the breast by tumor excision and irradiation. Znt. J. Radiat. Oncol. Biol. Phys. 7: 1553-1559, 1981. management

of stage I carcinoma

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4. Boova, R.S., Bonanni, R., Rosato, F.E.: Patterns of axillary nodal involvement in breast cancer. Predictability of level one dissection. Ann. Surg. 196(6): 642-644, 1982. 5. Calle, R., Pilleron, J.P., Schlienger, P., Vilcoq, J.R.: Conservative management of operable breast cancer. Ten years experience at the Fondation Curie. Cancer 42(4): 20452053, 1978. 6. Clark, R.M.: Treating breast cancer conservatively: dissension, contention continue. JAMA 248: 1793-1802, 1982.

7. Clark, R.M., Wilkinson, R.H., Mahoney, L.J., Reid, J.G., MacDonald, W.D.: Breast cancer: A 21 year experience with conservative surgery and radiation. Int. J. Radiat. Oncol. Biol. Phys. 8: 967-975, 1982. 8. Chu, A.M., Cope, O., Russo, R., Wang, C.C., Schultz,

M.D., Wang, C.A., Rodkey, G.: Treatment of early stage breast cancer by limited surgery and radical irradiation. Int. J. Radiat. Oncol. Biol. Phys. 6: 25-30, 1980. 9. Delouche, G., Picard, J.D., Boucher-Laborderie,

J., Le Houerou, G., Bachelot, F., Gest, J.: L’association tumorectomie-cobaltherapie. Rbultats dans les cancers du sein de petite taille. Nouv. Presse Med. 2( 11): 709-7 13, 1973. 10. Harris, J.R., Botnick, L., Bloomer, W.D., Chaffey, J.T., Hellman, S.: Primary radiation therapy for early breast cancer: The experience at the Joint Center for Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 7: 1549-1552, 1981.

11. Host, H., Brenn Houd, I.: The effect of post-operative radiotherapy in breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 2: 1061-1067, 1977.

December 1984, Volume 10, Number 12 12. Kissin, M.W., Thompson, E.M., Price, A.B., Slavin, G., Kark, A.E.: The inadequacy of axillary sampling in breast cancer. Lancet 8283: 1210-1211, 1982. 13. Pierquin, B., Owen, R., Maylin, C., Otmezguine, R.M., Mueller, W., Hannoun, S.: Radical radiation therapy of breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 6: 17-24, 1980.

14. Ray, G.R., Fish, V.J.: Biopsy and definitive radiation therapy in Stage I and II adenocarcinoma of the female breast: Analysis of cosmesis and the role of electron beam supplementation. Int. J. Radiat. Oncol. Biol. Phys. 9: 813818, 1983. 15. Rose, CM., Botnick, L.E., Weinstein, M., Harris, J.R., Koufman, C., Silen, W., Hellman, S.: Axillary sampling in the definitive treatment of breast cancer by radiation therapy and lumpectomy. Int. J. Radiat. Oncol. Biol. Phys. 9: 339-344, 1983. 16. Sarrazin, D., L& M., Fontaine, F., Lasser, P., Aniagada, R.: Le traitement conservateur des cancers du sein, Tl, petits T2. A propos de 459 cas trait& a l’1.G.R. Actualitb Carcinologiques Institut Gustave Roussy. 1983, pp. 5566. 17. Veronesi, U., Saccozzi, R., Delvecchio, M.: Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. New Engl. J. Med. 305: 6-l 1, 198 1. 18. Vogt-Homer, G., Contesso, G.: Repartition des ganglions axillaires metastatiques. Memoires AC. Chir. 26: 795-799, 1967.