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Breast-conserving therapy ‘avant la lettre’: a long-term follow-up study after radical partial mastectomy and low-dose orthovoltage irradiation for stage I and II breast cancer
The Breast (1998) 7, 22&226 Q 1998 Harcotrt Brace & Co. Ltd
ORIGINAL ARTICLE
Breast-conserving therapy ‘avant la lettre’: a long-term follow-up study after radical partial mastectomy and low-dose orthovoltage irradiation for stage I and II breast cancer H. W. P. M. Kemperman”, J. H. Borger+, J. L. Peteme*, E. A. van Slooten* and J. A. van Dongen* Department of Surgery*, Department of Radiotherapyf, Department of Pathology$, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hut’s, Amsterdam, The Netherlands
S U MMA R Y. From 1954 to 1966, 32 patients with a small, well-outlined breast cancer mostly located in the upper outer quadrant, were treated with a radical partial mastectomy followed by low-dose orthovoltage irradiation. In this series with an almost complete follow-up of median 18.4 years, disease-specific survival was 85% at 5 years and 81% at 10 years. In this small number of patients, no statistically significant prognostic factors for survival could be identified, but data suggest an adverse effect of young age. Thirteen breast recurrences occurred, after an interval of 0.6-29.7 (mean 9.7, median 8.6) years. The actuarial breast recurrence rate at 5 years was 10% (10 years, 33%; 20 years, 47%). The only risk factor for local recurrence identified was an incomplete or doubtfully complete tumourectomy. We believe that the low dose of irradiation contributed to the high breast recurrence rate. In breast-conserving therapy, an adequate radiation dose is important to prevent breast recurrence.
In the Netherlands Cancer Institute, it was believed early in the 1950s that limited breast surgery followed by the postoperative radiotherapy regimen which was standard at that time might be appropriate for a small subgroup of patients. Starting in 1954, 28 patients were selected for this treatment. Alarmed by a number of local recurrences in this and other series, the method was abandoned as an appropriate treatment option in 1961. The disappointing results in the first 28 patients, 12 of whom developed a breast recurrence, were reported before, and were considered to constitute an argument against partial conservation of the breast.‘,” In view of current notions on indications and limitations of BCT, it seems appropriate to report on this patient group with longer follow-up, now up to 40 years after treatment. Long-term data of BCT are rare and might give information on some important aspects of breast conservation, such as the risk of local recurrence and the importance of adequate radiotherapy.
INTRODUCTION Breast conservation by irradiation as primary treatment for early breast cancer was initiated soon after the introduction of radiotherapy. In the 1920s large series of patients were treated with various techniques of irradiation, with or without preceding tumourectomy.‘” In some centres, patients were preferably treated by radiotherapy,2S4whereas in other centres the method was considered a justifiable second option for patients who refused mastectomy.6 In those times, Halsted’s radical mastectomy,’ often followed by locoregional radiotherapy, was the gold standard for primary breast cancer treatment. Many considered the replacement of any part of the operation by radiotherapy as a violation of the basic principles of cancer treatment, and a true leap backward. A conference in Strasbourg in 1972,8 where several French centres presented results of breastconserving therapy (BCT), marked a change of opinion. However, not before large randomized studies had demonstrated comparable results of BCT and mastectomy for patients with small operable breast cancers, was the new treatment generally accepted. Address correspondence to: H. W. P. M. Kemperman, Ziekenhuis, Boerhaavelaan 25, 4708 AE Roosendaal,
PATIENTS
AND METHODS
The radical partial mastectomy, as introduced in our institute in 1954, included a wide excision and resection of the
Surgeon, Franciscus The Netherlands
220
Breast-conserving therapy sternal part of the pectoralis major and the complete removal of the pectoralis minor muscle. The operation was started with a frozen section biopsy of the axillary apex; in cases of apical lymph node metastasis, patients were considered incurable and were treated only with radiotherapy.“,‘* Only patients with sharply outlined tumours, preferably situated in the upper-outer quadrant of the breast, were selected for this partial radical mastectomy. Most tumours were smaller than 2 cm, but a few patients with larger tumours were included, provided that the size of the breast permitted an excision with adequate margins. The surgeon aimed at resecting a margin of at least 2 cm of normal (at inspection and palpation) breast tissue around the lesion. Wide excision of the involved quadrant was performed en bloc with a complete axillary clearance. The remaining part of the breast was lifted to give access for the resection of the pectoralis muscles (Figs 1 and 2). Radiotherapy was started approximately 2 weeks after operation. It consisted of two or three (depending on the chosen total dose) series of four fractions of 200 roentgen on consecutive days, delivered by two opposing beams to the whole breast and to the axillary and supraclavicular regions, by 240 kV roentgen beams. The interval between series was 5-6 weeks. The cumulative dose for each of the fields was 1600 or 2400 roentgen. The total absorbed dose is estimated at either 15 or 20-25 Gy. Before 1957, this BCT schedule was applied to a few patients who refused ablative therapy. From 1957 to 1961, this option was offered to all eligible patients, with an explanation of its
glandular
22 1
tissue
Fig. 2
experimental nature; not all eligible patients chose to be treated by breast conservation. After 1961, BCT was no longer offered as an option, because of the number of breast recurrences that had occurred. However, a small number of patients adamantly declined mastectomy and were treated with radical partial mastectomy plus irradiation. From November 1954 to November 1966, 32 patients were treated according to the technique described. Patient files have been reviewed and updated. Twenty-three patients have died. Some patients are still in regular followup at our clinic. If necessary, follow-up data were collected by contacting the family doctor. The histological slides of the primary tumour were available for review in 27 cases, including 11 of the patients who developed a breast recurrence. Because of the small number of cases, a descriptive approach rather than a formal statistical one has been performed. However, an attempt is made to identify significant risk factors for local recurrence. If calculated expected frequencies are all ~2, and not more than one is < 5, the P value is estimated by calculation of x2, and for all distributions Fisher’s exact test is applied. RESULTS
Fig. 1
The median age at diagnosis was 46 (range 26-80) years. In 24 cases the tumour was located in the upper outer quadrant; in 7 cases with the tumour located in other quadrants an en bloc procedure was still feasible with reasonable cosmetic effect. In 1 case, the tumour in the upper medial part and the axillary lymph nodes were removed using
222 Table
The Breast 1
Stage (n = 32)
Clinical
Pathological
T,No T,N, TIN, TzN, Incomplete
record
14 4 5 4 5
TIN, TINI T,N, T,N,
12 6 6 3 5
separate incisions. The clinical and pathological stages13are presented in Table 1. Nineteen tumours were of the invasive ductal type, 3 of which had an extensive intraductal component (EIC); 4 tumours were invasive lobular carcinomas; 2 medullary and 1 mutinous carcinoma were found, 1 case was a carcinoma in situ (DCIS), poorly differentiated with comedo necrosis. Completeness of the tumour excision was evaluable in 22 cases; in 8 at review the margins were considered involved. Twenty patients were irradiated to cumulative field doses of 1600 roentgen. Three patients (one because of wound complications, two others for untraceable reasons) did not complete the full series of radiation and received only 600-1000 roentgen. Six patients were irradiated to cumulative field doses of 2400 roentgen; the reason for this higher dose was not clear from the files. Three of these patients were treated in the period 1956-1959 and had centrally or medially located tumours; all 3 on histological review showed high grade of malignancy and/or doubtful radicality of the excision. The other 3 patients receiving higher radiation doses were among 4 patients treated after 1961 (the fourth patient treated after 1961 declined radiotherapy). Two patients refused
irradiation following surgery, and in 1 case (DCIS) radiotherapy was deliberately omitted. In the 1950s and 1960s no standard evaluation of quality of life and of the cosmetic result was performed. In spite of the loss of a large part of the glandular tissue, remodelling of the breast shape often gave an excellent result and, according to the notes in patient files at various intervals, the cosmetic result in most cases was judged as satisfactory by patients and doctors (Figs 3 & 4). Median duration of follow-up was 18.4 (range 0.6-37.9) years. One patient was lost to follow-up 19.3 years after treatment at age 26; another, aged 57 at primary treatment, was lost to follow-up after 7.7 years. Survival for patients aged under 40 at the time of primary treatment (median 15.6, range 0.6-36.3, mean 17.1 years), did not differ significantly from that of the older patients (median 20.0, range 1.2-37.9, mean 18.4 years). Quantitative data of this series are presented in Table 2 and Figures 5-8. Table
2
Quantitative
data (SE = standard
Endpoint Overall At risk
survival
Disease-specific At risk Disease-free At risk Local control At risk
(SE) survival
survival (SE)
(SE)
(SE)
error)
5-year
lo-year
15-year
20-year
81 (7) 26
72 (8) 22
59 (9) 18
49 (9) 14
85 (6) 26
81 (7) 22
70 (8) 18
58 (9) 14
72 (8) 23
47 (9) 15
38 (9) 12
31 (8) 9
90 (5) 24
67 (9) 16
62 (10) 14
53 (10) 9
Breast-conserving therapy
223
Fig. 4
d,
4kI
!il3 Xme from treatment
Fig. 5
8
Survival
-I 192
240
d0
48
96 Time from treatment
(months)
(all patients).
Fig. 7
Disease-free
survival
I 144
192
240
(months)
(all patients).
I 0
49
9%
144
Time from treatment
Fig. 6
164
Disease-specific
survival
192
48
240
(months)
(all patients).
96 Time from treatment
Fig. 8
Local
control
(all patients).
144 (months)
192
240
224
The Breast Table 3 Survival for age at primary treatment Age < 40 years Age 2 40 years
5-year
lo-year
15-year
20-year
25-year
7/8 (88%) 19/24 (79%)
6/S (75%) 16/23 (70%)
4/8 (50%) 14123 (61%)
2/7 (29%) 12/23 (52%)
2/7 (29%) 8/23 (35%)
Survival The equal duration of follow-up for younger and older patients suggests a poorer age-corrected survival for younger patients, neutralizing the better life expectancy normally associated with younger age. Table 3 shows the survival at different intervals for patients aged under 40 years at primary treatment and those above that age. Thirteen patients died from breast cancer, 0.6-20.7 (median 11.3) years after diagnosis. This number includes 1 patient who developed a contralateral breast tumour 2 years after primary treatment. Of 8 patients who were under the age of 40 years at primary treatment, 5 died during follow-up, all of them from breast cancer. Of 19 patients treated under the age of 50, 13 died, 10 of them from breast cancer, 2 from causes unrelated to breast cancer, and 1 from an unknown cause. Of the 13 patients aged over 50 at primary treatment, 10 died during follow-up: only 3 of them from breast cancer; 4 died from confiied other causes; and 3 from unknown causes, at very old age. The numbers are too small to correlate factors other than age, such as clinical or pathological tumour size, axillary nodal status, histological grade or angio-invasion, with survival.
Local control No regional (axillary, supraclavicular or parastemal) recurrences occurred. Any evidence of further tumour in the remaining breast tissue was considered as a local treatment failure. Thirteen breast recurrences were observed, after an interval of 0.6-29.7 (median 8.6) years. All breast recurrences occurred without previous or simultaneous evidence of distant relapse. Of the 12 patients followed up after local recurrence, 7 eventually developed distant metastases, 0.9-20.5 (median 12.8) years after primary treatment and 0.3-10.5 (median 3.3) years after local relapse. In 11 of the 12 patients with non-diffuse breast recurrences, the tumour
was situated in the quadrant of the location of the primary tumour or in an immediately adjacent quadrant. One patient had an inflammatory relapse which was unsuitable for further surgery, and was treated systemically. Two of the other 12 patients declined mastectomy and were treated by segmental resection and tamoxifen. Eventually, both underwent a mastectomy for a second breast recurrence. One patient was lost to follow-up shortly after the detection of her breast recurrence. Eleven patients were followed up after intentionally curative treatment of a breast recurrence. Five years after breast recurrence, 7 of them (64%) were alive; at 10 years, 4 of 10 patients (40%) were alive. One patient was alive and well at the closure of the study, 8.3 years after a late breast recurrence (29.7 years after primary treatment). The small numbers do not allow correlation between the interval to local recurrence and subsequent survival. Overall and disease-specific survival from time of primary treatment for patients who developed a breast recurrence during follow-up and those who remained free of local recurrence is displayed in Table 4. Risk factors for local recurrence Owing to the small number of cases, a complete assessment of risk factors for local recurrence was not possible. Using x2 and/or Fisher’s exact test, a variety of possible prognostic factors was examined, including: age at diagnosis; tumour location, clinical and pathological tumour size, microscopically (in) complete excision; histological type; extensive intraductal component (EIC); histological grade; angioinvasion; axillary node involvement; and irradiation dose. The only factor with a relatively low P value (0.03, Fisher exact) was microscopic margin involvement (other data not shown). No notable difference was seen between patients treated with ‘high’ or ‘low’ radiation doses or even no irradiation, Breast recurrence was observed 5.3 years after partial mastectomy in 1 of the 3 patients who refused radio-
Table 4 Overall and disease-specific survival from diagnosis, patients without and with local recurrence 5-year
lo-year
15-year
20-year
25-year
No local recurrence Overall Disease-specific
14/19 (74%) 14/17 (82%)
KY19 (63%) 12/16 (75%)
1 l/19 (58%) 11/15 (73%)
9/19 (47%) 9/15 (60%)
7/18 (39%) 7/13 (54%)
Local recurrence Overall Disease-specific
lU13 (92%) 1213 (92%)
IO/12 (83%) lO/ll (91%)
7/12 (58%) 7/11 (64%)
6/12 (50%) 6/11 (55%)
302 (25%) 3/10 (30%)
Breast-conserving therapy therapy. In this patient, histological review revealed doubtful completeness of excision combined with EIC. The one patient with pure DCIS remained free of disease, despite the fact that histological review showed DCIS extending to all excision margins. This patient had not been irradiated.
225
As expected in a series with such a long follow-up, a number of second primary malignancies occurred. Four nonmammary cancers were seen after 5, 9, 16 and 33 years, respectively; 2 of these patients were thought to have died from the second malignancy. Three patients developed a second primary malignancy in the contralateral breast following 2, 10 and 24 years. These were all treated with radical mastectomy.
in this treatment schedule. The dose of irradiation did not correlate with breast recurrence, but we are convinced that even the higher dose given to some patients was inadequate to provide local control. One may even consider that some of the late breast recurrences are related to the tumourigenic effect of the irradiation.‘g*20 Limited surgery for breast cancer requires adequate radiotherapy; more limited surgery may require even higher doses of irradiation. In this small series, no impact of breast recurrence on survival could be demonstrated. Remarkably, however, no local recurrences occurred after or simultaneously with distant metastasis, and some locally relapsing patients who eventually developed distant disease only did so after a very long interval, This does not support the hypothesis proposed by some, that local recurrence and distant relapse are two different expressions of the same, as yet unidentified, relapse-prone biological characteristic of some turnours.*’
DISCUSSION
References
Other malignancies
The small numbers in this series do not allow a thorough statistical analysis, but the similar duration of follow-up for ‘younger’ and ‘older’ (referring to age at diagnosis) patients is suggestive of a poorer disease-specific survival in younger patients. This is also reflected in the exclusiveness of breast cancer as cause of death for the young women and when comparing the overall survival of different age groups: younger patients had a better survival at 5 and 10 years, but a poorer survival at long-term follow-up, when normally one would expect the better life expectancy of the younger patients to become evident. Young age has been identified as a risk factor for disease-specific survival of breast cancer in many studies.14-‘8 Despite strict selection of patients and the technique of wide excision, a substantial number of breast recurrences was seen. In fact, only 2 recurrences had occurred when the treatment schedule was discontinued in 1961, but several more were observed in the following years, resulting in a local control rate of 90% at 5 and only 67% at 10 years. This prompted us to present a negative report at the Strasbourg conference.g The finding of several recurrences after very long intervals indicates the persisting risk of ipsilateral breast tumour recurrence. The fact that most recurrences were located near the excision site suggests that most of the breast recurrences originated from residual tumour or in a premalignant area. This is compatible with the fact that, in these small numbers, incomplete tumour excision was the only factor significantly correlated with local recurrence. The importance of a microscopically radical tumourectomy may not be so important when modem irradiation techniques and high doses are used, but it certainly appears to be a major factor
4. 5. 6. I. 8. 9.
10. 11. 12.
13. 14.
15.
16.
Keynes G. The treatment of primary carcinoma of the breast with radium. Acta Radio1 1929; 10: 393402. Keynes G. Conservative treatment of cancer of the breast. BMJ 1937; 2: 643-647. Mustakallio S. Treatment of breast cancer by tumour extirpation and Roentgen therapy instead of radical operation, .I Fat Radio1 1954; 6: 23-26. Mustakallio S. Conservative treatment of breast carcinoma - review of 25 years follow up. Clin Radio1 1972; 23: 110-l 16. Baclesse F. Roentgen therapy as the sole method of treatment of cancer of the breast. Am J Roentgen01 Radium Ther 1949; 62: 311-319. Baclesse F, Ennuyer A, Cheguillaume J. Est-on autorise a pratiquer une tumorectomie simple suivie de radiotherapie en cas de tumeur mammaire? J Radio1 1960; 41: 137-139. Halsted W S. The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889 to January, 1894. Johns Hopkins Hosp Bull 1894-1895; 4: 297-350. Gros G M. Thtrapeutiques non mutilantes des car&reuses du sein; Congress Report, Strasbourg 1972. Paris: Masson & Cie, 1973. van Dongen J A, Hampe J F, van Slooten E A. Are there indications for a radical partial mastectomy? Frequency of re(oc)cutrences in the remaining part of the breast. Therapeutiques non-mutilantes des cancereuses du sein, Strasbourg, 1972, abstr. van Dongen J A, Pemot J H M. Breast carcinoma-arguments for aggressive treatment. Archivum Chimrgicum Neerlandicum 1973; 25: 399-412. van Dongen J A. Subclavicular biopsy as a guideline for the treatment of breast cancer. World J Surg 1977; 1: 306-308. van Dongen J A, van Slooten E A. Infraclavicular exploration as a prognostic criterion and as a selection criterion for choice of treatment in breast cancer. Ned Tijdschr Geneeskd 1983; 127: 714-711. International Union Against Cancer. TNM atlas, 3rd ed, 2nd rev. Springer Verlag, 1992. Nemoto T, Vana J, Bedwani R N, Baker H W, McGregor F H, Murphy G P. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 1980; 45: 2917-2924. Matthews R H, McNeese M D, Montague E D, Oswald M J. Prognostic implications of age in breast cancer patients treated with tumorectomy and irradiation or with mastectomy. Int J Radiat Oncol Biol Phys 1988; 14: 659-663. de la Rochefordiere A, Asselain B, Campana F et al. Age as
226
The Breast
prognostic factor in premenopausal breast carcinoma. Lancet 1993; 341: 1039-1043. 17. Nixon A J, Neuberg D, Hayes D F et al. Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 1994; 12: 888-894. 18. Albain K S, Allred D C, Clark Cl M. Breast cancer outcome and predictors of outcome: are there age differentials? Monogr Nat1 Cancer Inst 1994: 16: 3542.
19. Lipsztein R, Dalton J F, Bloomer W D. Sequelae of breast irradiation. JAMA 1985; 253: 3582-3584. 20. Modan B, Chetrit A, Alfandary E, Katz L. Increased risk of breast cancer after low-dose irradiation. Lancet 1989; i(8639): 6299631. 21. Fisher B, Anderson S, Fisher E R et al. Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet 1991, 338: 327-331.
ORIGINAL ARTICLE
Breast-conserving therapy ‘avant la lettre’: a long-term follow-up study after radical partial mastectomy and low-dose orthovoltage irradiation for stage I and II breast cancer H. W. P. M. Kemperman”, J. H. Borger+, J. L. Peteme*, E. A. van Slooten* and J. A. van Dongen* Department of Surgery*, Department of Radiotherapyf, Department of Pathology$, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hut’s, Amsterdam, The Netherlands
S U MMA R Y. From 1954 to 1966, 32 patients with a small, well-outlined breast cancer mostly located in the upper outer quadrant, were treated with a radical partial mastectomy followed by low-dose orthovoltage irradiation. In this series with an almost complete follow-up of median 18.4 years, disease-specific survival was 85% at 5 years and 81% at 10 years. In this small number of patients, no statistically significant prognostic factors for survival could be identified, but data suggest an adverse effect of young age. Thirteen breast recurrences occurred, after an interval of 0.6-29.7 (mean 9.7, median 8.6) years. The actuarial breast recurrence rate at 5 years was 10% (10 years, 33%; 20 years, 47%). The only risk factor for local recurrence identified was an incomplete or doubtfully complete tumourectomy. We believe that the low dose of irradiation contributed to the high breast recurrence rate. In breast-conserving therapy, an adequate radiation dose is important to prevent breast recurrence.
In the Netherlands Cancer Institute, it was believed early in the 1950s that limited breast surgery followed by the postoperative radiotherapy regimen which was standard at that time might be appropriate for a small subgroup of patients. Starting in 1954, 28 patients were selected for this treatment. Alarmed by a number of local recurrences in this and other series, the method was abandoned as an appropriate treatment option in 1961. The disappointing results in the first 28 patients, 12 of whom developed a breast recurrence, were reported before, and were considered to constitute an argument against partial conservation of the breast.‘,” In view of current notions on indications and limitations of BCT, it seems appropriate to report on this patient group with longer follow-up, now up to 40 years after treatment. Long-term data of BCT are rare and might give information on some important aspects of breast conservation, such as the risk of local recurrence and the importance of adequate radiotherapy.
INTRODUCTION Breast conservation by irradiation as primary treatment for early breast cancer was initiated soon after the introduction of radiotherapy. In the 1920s large series of patients were treated with various techniques of irradiation, with or without preceding tumourectomy.‘” In some centres, patients were preferably treated by radiotherapy,2S4whereas in other centres the method was considered a justifiable second option for patients who refused mastectomy.6 In those times, Halsted’s radical mastectomy,’ often followed by locoregional radiotherapy, was the gold standard for primary breast cancer treatment. Many considered the replacement of any part of the operation by radiotherapy as a violation of the basic principles of cancer treatment, and a true leap backward. A conference in Strasbourg in 1972,8 where several French centres presented results of breastconserving therapy (BCT), marked a change of opinion. However, not before large randomized studies had demonstrated comparable results of BCT and mastectomy for patients with small operable breast cancers, was the new treatment generally accepted. Address correspondence to: H. W. P. M. Kemperman, Ziekenhuis, Boerhaavelaan 25, 4708 AE Roosendaal,
PATIENTS
AND METHODS
The radical partial mastectomy, as introduced in our institute in 1954, included a wide excision and resection of the
Surgeon, Franciscus The Netherlands
220
Breast-conserving therapy sternal part of the pectoralis major and the complete removal of the pectoralis minor muscle. The operation was started with a frozen section biopsy of the axillary apex; in cases of apical lymph node metastasis, patients were considered incurable and were treated only with radiotherapy.“,‘* Only patients with sharply outlined tumours, preferably situated in the upper-outer quadrant of the breast, were selected for this partial radical mastectomy. Most tumours were smaller than 2 cm, but a few patients with larger tumours were included, provided that the size of the breast permitted an excision with adequate margins. The surgeon aimed at resecting a margin of at least 2 cm of normal (at inspection and palpation) breast tissue around the lesion. Wide excision of the involved quadrant was performed en bloc with a complete axillary clearance. The remaining part of the breast was lifted to give access for the resection of the pectoralis muscles (Figs 1 and 2). Radiotherapy was started approximately 2 weeks after operation. It consisted of two or three (depending on the chosen total dose) series of four fractions of 200 roentgen on consecutive days, delivered by two opposing beams to the whole breast and to the axillary and supraclavicular regions, by 240 kV roentgen beams. The interval between series was 5-6 weeks. The cumulative dose for each of the fields was 1600 or 2400 roentgen. The total absorbed dose is estimated at either 15 or 20-25 Gy. Before 1957, this BCT schedule was applied to a few patients who refused ablative therapy. From 1957 to 1961, this option was offered to all eligible patients, with an explanation of its
glandular
22 1
tissue
Fig. 2
experimental nature; not all eligible patients chose to be treated by breast conservation. After 1961, BCT was no longer offered as an option, because of the number of breast recurrences that had occurred. However, a small number of patients adamantly declined mastectomy and were treated with radical partial mastectomy plus irradiation. From November 1954 to November 1966, 32 patients were treated according to the technique described. Patient files have been reviewed and updated. Twenty-three patients have died. Some patients are still in regular followup at our clinic. If necessary, follow-up data were collected by contacting the family doctor. The histological slides of the primary tumour were available for review in 27 cases, including 11 of the patients who developed a breast recurrence. Because of the small number of cases, a descriptive approach rather than a formal statistical one has been performed. However, an attempt is made to identify significant risk factors for local recurrence. If calculated expected frequencies are all ~2, and not more than one is < 5, the P value is estimated by calculation of x2, and for all distributions Fisher’s exact test is applied. RESULTS
Fig. 1
The median age at diagnosis was 46 (range 26-80) years. In 24 cases the tumour was located in the upper outer quadrant; in 7 cases with the tumour located in other quadrants an en bloc procedure was still feasible with reasonable cosmetic effect. In 1 case, the tumour in the upper medial part and the axillary lymph nodes were removed using
222 Table
The Breast 1
Stage (n = 32)
Clinical
Pathological
T,No T,N, TIN, TzN, Incomplete
record
14 4 5 4 5
TIN, TINI T,N, T,N,
12 6 6 3 5
separate incisions. The clinical and pathological stages13are presented in Table 1. Nineteen tumours were of the invasive ductal type, 3 of which had an extensive intraductal component (EIC); 4 tumours were invasive lobular carcinomas; 2 medullary and 1 mutinous carcinoma were found, 1 case was a carcinoma in situ (DCIS), poorly differentiated with comedo necrosis. Completeness of the tumour excision was evaluable in 22 cases; in 8 at review the margins were considered involved. Twenty patients were irradiated to cumulative field doses of 1600 roentgen. Three patients (one because of wound complications, two others for untraceable reasons) did not complete the full series of radiation and received only 600-1000 roentgen. Six patients were irradiated to cumulative field doses of 2400 roentgen; the reason for this higher dose was not clear from the files. Three of these patients were treated in the period 1956-1959 and had centrally or medially located tumours; all 3 on histological review showed high grade of malignancy and/or doubtful radicality of the excision. The other 3 patients receiving higher radiation doses were among 4 patients treated after 1961 (the fourth patient treated after 1961 declined radiotherapy). Two patients refused
irradiation following surgery, and in 1 case (DCIS) radiotherapy was deliberately omitted. In the 1950s and 1960s no standard evaluation of quality of life and of the cosmetic result was performed. In spite of the loss of a large part of the glandular tissue, remodelling of the breast shape often gave an excellent result and, according to the notes in patient files at various intervals, the cosmetic result in most cases was judged as satisfactory by patients and doctors (Figs 3 & 4). Median duration of follow-up was 18.4 (range 0.6-37.9) years. One patient was lost to follow-up 19.3 years after treatment at age 26; another, aged 57 at primary treatment, was lost to follow-up after 7.7 years. Survival for patients aged under 40 at the time of primary treatment (median 15.6, range 0.6-36.3, mean 17.1 years), did not differ significantly from that of the older patients (median 20.0, range 1.2-37.9, mean 18.4 years). Quantitative data of this series are presented in Table 2 and Figures 5-8. Table
2
Quantitative
data (SE = standard
Endpoint Overall At risk
survival
Disease-specific At risk Disease-free At risk Local control At risk
(SE) survival
survival (SE)
(SE)
(SE)
error)
5-year
lo-year
15-year
20-year
81 (7) 26
72 (8) 22
59 (9) 18
49 (9) 14
85 (6) 26
81 (7) 22
70 (8) 18
58 (9) 14
72 (8) 23
47 (9) 15
38 (9) 12
31 (8) 9
90 (5) 24
67 (9) 16
62 (10) 14
53 (10) 9
Breast-conserving therapy
223
Fig. 4
d,
4kI
!il3 Xme from treatment
Fig. 5
8
Survival
-I 192
240
d0
48
96 Time from treatment
(months)
(all patients).
Fig. 7
Disease-free
survival
I 144
192
240
(months)
(all patients).
I 0
49
9%
144
Time from treatment
Fig. 6
164
Disease-specific
survival
192
48
240
(months)
(all patients).
96 Time from treatment
Fig. 8
Local
control
(all patients).
144 (months)
192
240
224
The Breast Table 3 Survival for age at primary treatment Age < 40 years Age 2 40 years
5-year
lo-year
15-year
20-year
25-year
7/8 (88%) 19/24 (79%)
6/S (75%) 16/23 (70%)
4/8 (50%) 14123 (61%)
2/7 (29%) 12/23 (52%)
2/7 (29%) 8/23 (35%)
Survival The equal duration of follow-up for younger and older patients suggests a poorer age-corrected survival for younger patients, neutralizing the better life expectancy normally associated with younger age. Table 3 shows the survival at different intervals for patients aged under 40 years at primary treatment and those above that age. Thirteen patients died from breast cancer, 0.6-20.7 (median 11.3) years after diagnosis. This number includes 1 patient who developed a contralateral breast tumour 2 years after primary treatment. Of 8 patients who were under the age of 40 years at primary treatment, 5 died during follow-up, all of them from breast cancer. Of 19 patients treated under the age of 50, 13 died, 10 of them from breast cancer, 2 from causes unrelated to breast cancer, and 1 from an unknown cause. Of the 13 patients aged over 50 at primary treatment, 10 died during follow-up: only 3 of them from breast cancer; 4 died from confiied other causes; and 3 from unknown causes, at very old age. The numbers are too small to correlate factors other than age, such as clinical or pathological tumour size, axillary nodal status, histological grade or angio-invasion, with survival.
Local control No regional (axillary, supraclavicular or parastemal) recurrences occurred. Any evidence of further tumour in the remaining breast tissue was considered as a local treatment failure. Thirteen breast recurrences were observed, after an interval of 0.6-29.7 (median 8.6) years. All breast recurrences occurred without previous or simultaneous evidence of distant relapse. Of the 12 patients followed up after local recurrence, 7 eventually developed distant metastases, 0.9-20.5 (median 12.8) years after primary treatment and 0.3-10.5 (median 3.3) years after local relapse. In 11 of the 12 patients with non-diffuse breast recurrences, the tumour
was situated in the quadrant of the location of the primary tumour or in an immediately adjacent quadrant. One patient had an inflammatory relapse which was unsuitable for further surgery, and was treated systemically. Two of the other 12 patients declined mastectomy and were treated by segmental resection and tamoxifen. Eventually, both underwent a mastectomy for a second breast recurrence. One patient was lost to follow-up shortly after the detection of her breast recurrence. Eleven patients were followed up after intentionally curative treatment of a breast recurrence. Five years after breast recurrence, 7 of them (64%) were alive; at 10 years, 4 of 10 patients (40%) were alive. One patient was alive and well at the closure of the study, 8.3 years after a late breast recurrence (29.7 years after primary treatment). The small numbers do not allow correlation between the interval to local recurrence and subsequent survival. Overall and disease-specific survival from time of primary treatment for patients who developed a breast recurrence during follow-up and those who remained free of local recurrence is displayed in Table 4. Risk factors for local recurrence Owing to the small number of cases, a complete assessment of risk factors for local recurrence was not possible. Using x2 and/or Fisher’s exact test, a variety of possible prognostic factors was examined, including: age at diagnosis; tumour location, clinical and pathological tumour size, microscopically (in) complete excision; histological type; extensive intraductal component (EIC); histological grade; angioinvasion; axillary node involvement; and irradiation dose. The only factor with a relatively low P value (0.03, Fisher exact) was microscopic margin involvement (other data not shown). No notable difference was seen between patients treated with ‘high’ or ‘low’ radiation doses or even no irradiation, Breast recurrence was observed 5.3 years after partial mastectomy in 1 of the 3 patients who refused radio-
Table 4 Overall and disease-specific survival from diagnosis, patients without and with local recurrence 5-year
lo-year
15-year
20-year
25-year
No local recurrence Overall Disease-specific
14/19 (74%) 14/17 (82%)
KY19 (63%) 12/16 (75%)
1 l/19 (58%) 11/15 (73%)
9/19 (47%) 9/15 (60%)
7/18 (39%) 7/13 (54%)
Local recurrence Overall Disease-specific
lU13 (92%) 1213 (92%)
IO/12 (83%) lO/ll (91%)
7/12 (58%) 7/11 (64%)
6/12 (50%) 6/11 (55%)
302 (25%) 3/10 (30%)
Breast-conserving therapy therapy. In this patient, histological review revealed doubtful completeness of excision combined with EIC. The one patient with pure DCIS remained free of disease, despite the fact that histological review showed DCIS extending to all excision margins. This patient had not been irradiated.
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As expected in a series with such a long follow-up, a number of second primary malignancies occurred. Four nonmammary cancers were seen after 5, 9, 16 and 33 years, respectively; 2 of these patients were thought to have died from the second malignancy. Three patients developed a second primary malignancy in the contralateral breast following 2, 10 and 24 years. These were all treated with radical mastectomy.
in this treatment schedule. The dose of irradiation did not correlate with breast recurrence, but we are convinced that even the higher dose given to some patients was inadequate to provide local control. One may even consider that some of the late breast recurrences are related to the tumourigenic effect of the irradiation.‘g*20 Limited surgery for breast cancer requires adequate radiotherapy; more limited surgery may require even higher doses of irradiation. In this small series, no impact of breast recurrence on survival could be demonstrated. Remarkably, however, no local recurrences occurred after or simultaneously with distant metastasis, and some locally relapsing patients who eventually developed distant disease only did so after a very long interval, This does not support the hypothesis proposed by some, that local recurrence and distant relapse are two different expressions of the same, as yet unidentified, relapse-prone biological characteristic of some turnours.*’
DISCUSSION
References
Other malignancies
The small numbers in this series do not allow a thorough statistical analysis, but the similar duration of follow-up for ‘younger’ and ‘older’ (referring to age at diagnosis) patients is suggestive of a poorer disease-specific survival in younger patients. This is also reflected in the exclusiveness of breast cancer as cause of death for the young women and when comparing the overall survival of different age groups: younger patients had a better survival at 5 and 10 years, but a poorer survival at long-term follow-up, when normally one would expect the better life expectancy of the younger patients to become evident. Young age has been identified as a risk factor for disease-specific survival of breast cancer in many studies.14-‘8 Despite strict selection of patients and the technique of wide excision, a substantial number of breast recurrences was seen. In fact, only 2 recurrences had occurred when the treatment schedule was discontinued in 1961, but several more were observed in the following years, resulting in a local control rate of 90% at 5 and only 67% at 10 years. This prompted us to present a negative report at the Strasbourg conference.g The finding of several recurrences after very long intervals indicates the persisting risk of ipsilateral breast tumour recurrence. The fact that most recurrences were located near the excision site suggests that most of the breast recurrences originated from residual tumour or in a premalignant area. This is compatible with the fact that, in these small numbers, incomplete tumour excision was the only factor significantly correlated with local recurrence. The importance of a microscopically radical tumourectomy may not be so important when modem irradiation techniques and high doses are used, but it certainly appears to be a major factor
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