The second ten years: Long-term risks of breast conservation in early breast cancer

Im. J. Radiation Oncology Biol. Phys.. Vol. 13, pp. 1327-1332 0360-3016/87 $3.00 + .oO Printed in the U.S.A. All rights reserved. Copyright Q 1987 Pergamon Journals Ltd.

??Original Contribution

THE SECOND TEN YEARS: LONG-TERM RISKS OF BREAST CONSERVATION IN EARLY BREAST CANCER

JOHN M. KURTZ, M.D., ’ ROBERT AMALRIC, M.D.,2 GILLES DELOUCHE, M.D.,3 BERNARD PIERQUIN, M.D.,4 JAKOB ROTH, PH.D.’ AND JEAN-MAURICE SPITALIER, M.D.2

‘Departments of Radiation Oncology and Radiation Physics, University Hospital, Basel, Switzerland; %epartments of Radiotherapy and Surgery, Cancer Institute, Marseille; 3Centre De Charlebourg, La Garenne-Colombes;

4Department of Radiotherapy, Henri Mondor Hospital, Creteil, France

A retrospective cooperative study was undertaken to analyze the fate of 300 clinical Stage I and II breast cancer patients who were alive and apparently cured with both breasts preserved, 10 years following primary limited surgery with irradiation. All patients had been treated by tumor excision, with or without axillary dissection, followed by megavolt-age radiation therapy. Follow-up ranged from 10.5 to 26 years, median 14.5 years. The overall actuarial survival (Kaplan-Meier) of the 300 “cured” patients was 86% at 15 years and 78% at 20 years, with 38.5% of deaths attributable to breast cancer. The actuarial probability of remaining free of metastatic disease was 91% at both 15 and 20 years, independent of age or clinical stage. Sixteen patients (5.3%) developed recurrent cancer i,n the treated breast beyond the tenth year, the actuarial probability of remaining free of breast recurrence being 94% and 90% at 15 and 20 years, respectively. Contralateral breast cancers developed during the second decade in 5 patients, with a cumulative risk of 6.5% at 20 years. Significant treatment-related problems appeared during the second decade in 5 patients, including one chest wall sarcoma; all of these patients had received at least 60 Gy to breast and regional nodal areas. A comparison of these results with those in the literature allowed the following conclusions to be drawn: (a) the risk of death, as well as breast cancer mortality during the second decade, are similar for both conservatively and radically treated patients with Stage I and II breast cancer, (b) The risk of contralateral breast cancer is not greater than that observed following primary radical surgery without radiation therapy; (c) Ipsilateral breast “recurrences” continue to occur at about 1% per year during the second decade. Such late recurrences are highly operable and have a favorable prognosis; (d) Late progression of treatment-related sequelae is uncommon. This analysis supports the continued use of breast-conserving surgery with radiation therapy in the treatment of Stage I and II breast cancer.

Breast cancer treatment, Breast conservation, Breast radiotherapy, Breast recurrence.

INTR:ODUCI’ION from numerous retrospective studies,3~‘0~12,22~28,35 that breast-conserving treatment can be applied with equal

There is growing evidence to support the notion, long held by a minority of authors,6,25,29*33 that survival in op erable mammary cancer is not prejudiced by therapies which preserve the breast, provided that such conservative treatments are adequate to control local and regional disease. This evidence is particularly convincing for the most favorable clinical Stage I patients, for which pro- spective, randomized clinical trials have demonstrated the equivalence of both breast-conserving and radical treatments, at least for the first 8 years post-therapy.38340 More recently, preliminary results from a large randomized trial by the National Surgical Adjuvant Breast Proj- ect (NSABP) have confirmed the impression, gained

success for more moderately extensive lesions, with or without axillary adenopathy.”

Since previous experience with randomized breast cancer trials has demonstrated that 5-year disease-free survival rates are highly predictive of IO-year results,” there is little reason to doubt that the favorable conclusions of these studies will be confirmed by the IO-year analyses. However, even assuming equivalent 1 O-year results, it is possible that patients treated successfully with preservation of the affected breast are subject to certain long-term risks not shared by patients having undergone primary breast amputation.

To shed light on this question, a cooperative, retro-

Presented at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, Octo- ber 41985, and at the Annual Meeting of the European Society for Therapeutic Radiology and Oncology, Baden-Baden, Sep- tember 10,1986.

Reprint requests to: John Kurt~, M.D., Department of Radi- ation Oncology, University Hospital Base& Petersgraben 4, CH-403 1 Bawl, Switzerland.

Accepted for publication 30 March 1987.

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1328 I. J. Radiation Oncology 0 Biology 0 Physics September 1987, Volume 13, Number 9

spective study was undertaken at three French treatment centers having long experience with breast-conserving therapy. The purpose of this study was to investigate the fate of patients considered cured of early breast cancer 10 years following conservative surgery with radiation therapy. The overall survival, as well as the probability of developing metastatic disease or recurrent cancer in the treated or contralateral breast, was analyzed for the second decade post-treatment.

METHODS AND MATERIALS

Between December 1956 and January 1973, 597 patients with clinical Stages I and II breast cancer were treated at the three participating institutions (Cancer In- stitute and associated clinics in Marseille, Centre de Charlebourg in La Garenne-Colombes, Hopital Hemi Mondor in Creteil) employing megavoltage radiation therapy following conservative surgery. Treatment techniques, as well as lo-year treatment results, have appeared in previous publications.3,4,‘4,35 Of these 597 patients, 351 (59%) survived with both breasts preserved, and without evidence of distant metastases, for a mini- mum of 10 years. Fifty-one of these “cured” patients were excluded from the study because of inadequate follow-up information. The remaining 300 patients form the basis for the following analysis. Their average age at time of primary treatment was 49 years.

Surgery generally involved simple excision of the primary tumor, without attempt at wide resection margins. In only 31 patients did the initial operation include an axillary dissection. One hundred seventy patients were in clinical Stage I (T,NO, American Joint Committee),5 and 130 patients in clinical Stage II (TIN, or T2No_,). Twenty-seven patients had histologic or clinical evidence for axillary lymph node involvement. Radiation therapy was performed with telecesium or telecobalt equipment, generally applying 45-60 Gy (4500-6000 rad) to breast as well as to regional and supraclavicular nodal areas. Although this therapy was carried out in most patients at a dose rate of 8-l 1 Gy/week, treatment was unusually protracted in 76 patients, using either small daily frac- tions or a split-course technique. Supplemental irradiation to the tumor bed was applied in all but 77 patients, using either an external radiation beam or interstitial cu- rietherapy. The great majority of patients received a total dose of between 60-80 Gy to the primary tumor area, only 3 patients receiving less than 60 Gy.

Patients were generally followed by the responsible radiation oncologist or surgeon, with follow-up examinations beyond 10 years often taking place at 2 year inter- vals. In a small minority, follow-up information was ob- tained from the patient’s personal physicians. The number of patients having had recent mammographic examinations was not recorded for this study.

Follow-up for living patients ranged from 10.5 to 26 years, with a median follow-up of 14.5 years. Statistical

analysis was performed using the Kaplan-Meier method,24 with survival rates set at 100% at the IO-year mark. Overall survival takes into account all causes of death. The probability of developing distant metastases (“metastasis-free survival”) was calculated using the diagnosis of metastatic disease as end-point, patients not developing distant metastases being censored at last follow-up or at time of death. The probability of remaining free of breast recurrence was calculated using analogous methodology, with the diagnosis of recurrent cancer in the treated breast as end-point. Similarly, the probability of remaining free of contralateral cancer was based upon the development of histologically proven cancer in the opposite breast. The log-rank test was employed to test for significant differences between survival curves.34

RESULTS

As of this writing (July 1985), two hundred sixty-one of the 300 patients (87.3%) remain alive. Of 39 deaths, 17 (43.6%) were due to intercurrent disease while free from cancer, fifteen (38.5%) were due to breast cancer, and for 7 patients the cause of death was unknown. Fif- teen of the 17 patients (90%) dying of intercurrent disease were 60 years or older at the time of primary treatment.

The overall survival was 86% at 15 years and 78% at 20 years (Fig. 1). The overall survival curves did not differ significantly for Stage I compared to Stage II patients (20- year survival rates of 80% and 76% respectively). Patients who were 50 years or older at time of primary treatment had a significantly poorer survival ( 15- and 20-year survivals 73% and 56%) than younger patients (15- and 20- year survivals 94% and 90%, p-value less than 0.001). This difference was due entirely to a larger number of intercurrent deaths in the older group.

Nineteen patients (6.3%) are known to have developed distant metastatic disease. All but one of these metastases were diagnosed prior to 15 years, the single exception having developed metastases at 20 years, 4 months. The metastasis-free survival was 9 1% at both 15 and 20 years

Fig. 1. Actuarial overall survival during second decade post- treatment, including all causes of death. Numbers below the time axis represent the number of patients at risk. Error bars represent 95% confidence limits at 15 and 20 years.

Breast preservation risks ??J. M. KURTZ et al. 1329

(Fig. 2). The probability of remaining free of distant metastases was essentially identical for pre- and post-meno- pausal patients (91% and 92%, respectively) and for patients in Stages I or II (93% and 89% respectively).

Sixteen patients (5.3%) were diagnosed as having recurrent cancer in the treated breast beyond the tenth year. Three of these recurrences were observed beyond the fifteenth year, the latest at 22 years, 7 months. The probability of remaining free of breast recurrence was 94% at 15 years and 90% at 20 years (Fig. 3).

As far as could be determined from the patient’s records, twelve of the 16 recurrences (75%) were described as being in the vicinity of the original primary tumor. Fourteen of the patients with breast recurrences were able to have a salvage operation. Axillary nodes were involved at the time of th’e secondary operation in 4 patients, and two additional patients developed axillary adenopathy without breast recurrence. Distant metastases were subsequently diagnosed in 4 of the patients with local-regional recurrences. One of the breast “recurrences” proved histologically to be a malignant fibrous histiocy- toma, occurring 10 years and 6 months following therapy. This patient is curre:ntly alive and well more than 4 years following secondary surgery and chemotherapy.

Contralateral breast cancers were observed in six patients (2%). The probability of remaining free of contralateral breast cancer was; 98% at 15 years and 93.5% at 20 years (Fig. 4). Two of the patients with contralateral cancers subsequently developed metastatic disease.

An attempt was made to identify patients in whom radiation-related changes were thought to have pro- gressed in severity beyond the tenth year. In 64 of the patients such a judgment was not possible, most commonly because some patients were being followed by physicians outside the treatment center. For the remaining 236 patients, the individual study participants judged 11 patients (4.7%) to have suffered progressive treatment-induced changes beyond the tenth year. In six in- stances this consisted of progressive skin telangiectasias or breast fibrosis. In five cases, however, more distressing problems became apparent in the second decade, includ-

Fig. 2. Actuarial probability of remaining free of distant metas- Fig. 4. Actuarial probability of remaining free of contralateral tasis during the second decade. Numbers below the time axis breast cancer during the second decade. Numbers below the represent the number of patients at risk. Error bars represent time axis represent the number of patients at risk. Error bars 95% confidence limits at 15 and 20 years. represent 95% confidence limits at 15 and 20 years.

0 , , , , , , , , , , , , , / , , , 1 , ,

10 II 12 “EP, II Pk:,,,” ;“,,,dl II 19 10

FOLLDYiNG

_ ,w 29, 2,s 2% I.3 216 I08 111 101 139 129 8, 82 7s 70 $0 ,I 1* 3, *i *o

Fig. 3. Actuarial probability of remaining free of ipsilateral breast recurrence during the second decade. Numbers below the time axis represent the number of patients at risk. Error bars represent 95% confidence limits at 15 and 20 years.

ing skin ulceration (1 patient), arm edema (2 patients), arm plexus lesion (1 patient), and chest wall sarcoma (1 patient).

DISCUSSION

It is generally recognized that patients remain at risk of dying of breast cancer long after the 1 O-year mark, so commonly used as a measure of “cure” in the surgical literature. Excess breast cancer mortality has been well documented for as long as 40 years following primary therapy, rendering the definition of cure controver- sia1.8,27,37 Nevertheless, a rather consistent picture of the second decade after radical surgical therapy can be gained from the small number of long-term analyses in the literature.

Although the risk of breast cancer death during the first decade post-treatment is a strong function of stage, these differences become much less marked during the second 10 years. Rutqvist and Wallgren found the breast cancer hazard rates to remain somewhat higher for node- positive than for node-negative patients even beyond the tenth year. 36 Langlands et al., however, found no clear distinction between the subsequent death rates of patients in Stages I and II who had survived for 10 years.27 Similarly, Ferguson et al. reported that 36% of the lo-

1330 1. J. Radiation Oncology 0 Biology 0 Physics September 1987, Volume 13, Number 9

year survivors in Stage I and 34% in Stage II died during the second decade.16 This is consistent with our results, which show no significant difference in prognosis during the second decade for patients in clinical Stages I and II. Thus the absence of pathological staging does not detract from the validity of this study, and it is reasonable to assume that our conclusions can be applied in a general way to all operable patients, at least in clinical Stages I and II.

to show any particular tendency to occur outside the originally involved quadrant.

An estimation of the percentage of lo-year survivors dying of breast cancer during the second decade after radical surgical therapy can be gained by comparing the lo- and 20-year relative survival rates reported in the literature, assuming that breast cancer patients are not sub- jected to other sources of excess mortality. Using this methodology, about 20% of the IO-year survivors in the study of Adair et al. ’ and 24% in the study of Adami et al.* died of breast cancer during the second 10 years. Similarly, Hibberd et al. estimate the excess mortality at 26.8% during the second decade.23 Since 5-10% of 10 year survivors already have overt metastatic disease at the 10 year mark,36 and are destined to die during the second decade, it follows that the probability of a “cured” patient dying of breast cancer before 20 years is five to ten percentage points lower than the mortality figures cited above. It is thus reasonable to assume that the residual breast cancer mortality during the second decade is between 10 and 15%, which is consistent with the calculations of Rutqvist and Wallgren.36

It is likely that the probability of late breast recurrence exceeds that of late chest wall recurrence following primary breast amputation. A valid comparison of these risks, however, awaits long-term analyses of randomized studies which have only recently finished accruing patients, 18,38,40 results which will not be available until the 1990’s. Therefore, it is of considerable importance to rec- ognize the markedly different prognoses of these two types of recurrences. Late chest wail recurrence is associated with an approximately 50% incidence of simulta- neous distant metastases,32 and an average survival time of 2 years, despite the long disease-free interval.30~32 Even apparently isolated chest wall recurrences occurring after 10 years have a prognosis similar to that of recurrences diagnosed 5 or 6 years after mastectomy, with a median survival of about 5 years.“,3’ In contrast, a recent analysis of 49 patients having failed locally 5 or more years following breast-conserving therapy has demonstrated a remarkably favorable prognosis for such late failures, with 5- and lo-year survivals of 84% and 67% following salvage surgery (Spitalier, J.M. and Kurtz, J.M., unpub- lished data, January 1986). The small number of local failures in the present study, along with the short post- recurrence follow-up time, suggest that a more detailed analysis of this series would be of little value.

The survival analysis of our patients suggests that breast conservation is not associated with an inordinate mortality or excessive risk of metastases during the second decade after treatment. The 22% death rate from all causes and the 9% probability of developing metastatic disease are consistent with the results cited above for radically-treated patients.

Late local-regional recurrences following primary radical treatment of breast cancer are well recognized, and recurrences during the second decade are thought to rep resent approximately 5% of local-regional failures. ’ 5*32 Although the risk of such late recurrences is assumed to be very small, we are unaware of reports in the literature allowing calculation of the actuarial probability of chest wall or nodal recurrences 10 or more years following radical surgical management.

The literature concerning the risks of developing bilat- eral breast cancer has recently been extensively reviewed by Haagensen.*’ The probability of a second breast cancer occurring during the second decade following primary radical surgery without radiotherapy varies between 0.6% and 0.9% per year. Concern has recently been expressed in the literature that scattered radiation might lead to a higher incidence of contralateral cancers in patients treated in combination with radiation therapy. *’ The actuarial probability of 6.5% of developing contralateral cancer in the present study is consistent with the results from the surgical literature cited above. Thus we have been unable to demonstrate an increased risk for irradiated patients during the second decade. However, it is recognized that breast cancer induction by ionizing irradiation may have a longer latent period, and longer follow-up with larger numbers of patients will be required to settle this issue.

The present analysis suggests that tumor formation in The cosmetic results of breast-conserving therapy as the treated breast continues at a rate of about 1% per year well as the complications of irradiation employed in this during the second decade after conservation therapy. setting have been extensively studied.7*‘3 Using current Since two recurrences have thus far been observed be- treatment concepts and techniques, the incidence of seri- yond the twentieth year, there is no evidence to support ous complications is very 10w.~~‘~ This study represents the notion that the therapeutically irradiated breast the first attempt to quantitate the progression of radia- ceases to be at risk at a certain point in time. This should tion injury beyond the tenth year in conservatively not be surprising, since it is analogous to the known pro- treated breast patients, and any conclusions should be pensity of the contralateral breast to new tumor forma- drawn with caution. Many patients during the 1950’s tion for the remainder of the patient’s lifetime.*’ Al- and 1960’s were treated to large volumes using high though breast “recurrences” during the second decade doses (60-70 Gy) currently reserved exclusively for sup might best be regarded as new tumors, we were unable plemental irradiation of small volumes. Consequently

some patients have suffered marked radiation changes of an extent only rarely observed using current techniques. The five patients who manifested serious radiation-related problems after the t’enth year all received at least 60 Gy to the entire breast, as well as to nodal areas. We would not expect to observe progressive late radiation injury after application of 45-50 Gy in 5 weeks, a dose which corresponds to current standard treatment prac- tice. In addition, although 6 patients were identified who suffered progression of relatively minor radiation sequelae after the tenth year, the records also indicate 4 patients whose radiation changes were judged to have become less severe during the second decade. This most likely reflects the element of subjectivity inherent in at- tempting to make qualitative judgments in the frame- work of a retrospective analysis.

The chest wall sarcoma observed 10.5 years following radiation therapy in one of our patients fulfills the estab- lished criteria for an irradiation-induced neoplasm. Al- though chest wall sarcomas have been reported as uncommon complications of radiation therapy following mastectomy, ‘7,26,39 we are unaware of any previously reported cases occurring after breast-conserving treatment. Of course, based on this single case, it is difficult to gain

an appreciation of the statistical risk of this event among long-term survivors of conservative therapy. This observation simply confirms that secondary malignant neo- plasms will occasionally be encountered in the irradiated tissues of patients treated with radiotherapy.

In summary, this study suggests that Stage I and II patients treated by breast-conserving surgery with radiotherapy have the same breast cancer mortality and the same risk of developing contralateral breast cancer during the second decade as patients treated by primary radical surgery with or without irradiation. The only long- term risk unique to conservatively treated patients is the continued development of cancer foci in the preserved breast, whereas after mastectomy only the contralateral breast is exposed to such risks. We have found such late “recurrences” to have a very favorable outlook and do not consider this risk to represent an important argu- ment against conservative management. Late progression of radiation-induced changes appears to be confined to patients having received very high doses to large volumes, and can be avoided by adhering to generally accepted current treatment practices. Our analysis supports the continued use of this form of therapy for Stage I and II breast cancer.

Breast preservation risks 0 J. M. KURTZ et al. 1331

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The second ten years: Long-term risks of breast conservation in early breast cancer