In, J Rrrdruron Onwlojy &,I/ t’hJ’.\ Vol. 24. pp. 253-260 Printed I” the II S.A. All rights reserved.

Copyright

0360.3016192 $5.00 t .OO 0 1992 Pergamon Press Ltd.

??Clinical Original Contribution

BREAST JOHN BOYAGES, FRCR

(LoND.),

CONSERVATION:

LONG-TERM

MBBS (Hors.), FRACR,’ FRACR,

FRCS

BRUCE BARRACLOUGH,

CARLA

BOSCH,’ ALLAN

(ED),’ A. MICHAEL

MBBS,

FRACS,

AUSTRALIAN

DDU3

BILOUS, M.A.,

0.

DATA

LANGLANDS,

M.B.,

CHB.,

B.Sc., FRCPA,2

AND VAL J. GEBSKI, M. STAT.~

‘Division of Radiation Oncology, ‘Institute of Clinical Pathology and Medical Research, ‘Department of Surgery, Westmead Hospital, Westmead, NSW, 2 145; and 4Statistical Laboratory, Macquarie University, Ryde, NSW, 2 109 and NHMRC Clinical Trials Centre, Sydney University, NSW, 2006, Australia Long-term data on the management of early breast cancer in Australia by conservative surgery and radiation therapy is limited. To examine this issue we reviewed our experience of 131 patients with Stage I or II breast cancer treated between November 1979 and December 1985. Ninety patients had a Tl tumor and 41 a T2 tumor. The extent of surgery varied from a local excision (LE), a wide local excision, to a quadrantectomy or partial mastectomy. Sixty-two per cent of patients also had an axillary dissection. One hundred and nineteen patients were treated using 6Mev photons to the whole breast (Median dose; 50 Gy) + regional nodes followed by a single plane Iridium-192 boost to the primary tumor site (median dose; 30 Gy). Ten patients did not receive a boost and two elderly patients were treated with an implant only. The median follow-up of surviving patients was 83 months (range, 51-133 months). Six other patients were lost to follow-up at a median of 48 months (range, 4-62). The pattern of first relapse is: breast alone, 7.0%; breast + distant, 0.75%; breast + nodes, 0.75%; regional nodes only, 0.75%; and distant disease, 18%. The extent of surgery did not influence the probability of a recurrence in the primary tumor region. The time to a breast recurrence ranged from 12 to 127 months (median, 61 months). The 5-year actuarial rate of a breast recurrence was 4.5%. The 5-year freedom from distant relapse was 80%. The complications of treatment were acceptable. These included rib fracture (5%), symptomatic pneumonitis (4%), fat necrosis or fibrosis requiring surgery (4.5%), severe arm edema (4.5%). The treatment of the axilla by both surgery plus radiation therapy was associated with a moderate or severe arm edema rate of 29% compared to 8% for surgery alone and 6% for radiation therapy alone. Our long-term data indicate that conservative surgery plus radiation therapy is associated with low rates of breast cancer recurrence which are independent of the extent of surgical resection. Complications were acceptably low provided that the axilla was treated by surgery or radiation therapy but not by both modalities.

Lumpectomy, Radiation, Local recurrence. INTRODUCTION

have been identified in which radiation therapy can be

avoided” (3). Comprehensive data on the pattern of care for patients with operable breast cancer are not available in Australia. Breast conserving treatment is uncommon and is used for less than 25% of all eligible patients (11, 19). Many patients are not referred for RT after conservative surgery (CS) ( 11, 19). Long-term data on the use of CS + RT in Australia is also limited. In order to provide long-term data, we have updated our results of a series of patients treated at Westmead Hospital, N.S.W., Australia, between 1980 and 1985 (5). Our results continue to indicate that a high level of breast tumor control is achieved using this approach with minimal long-term complications.

In June 1990, the National Cancer Institute, USA, sponsored a consensus development conference on the treatment of early breast cancer. The conference concluded: “Breast conservation is an appropriate method of primary therapy for the majority of women with Stage I and II breast cancer, and is preferable, because it provides survival equivalent to mastectomy and axillary dissection while preserving the breast (3)” Breast conservation was defined as excision of the primary tumor and adjacent breast tissue, followed by radiotherapy (RT). The panel also noted that “although local control can be obtained in some patients with local excision alone, no subgroups

Presented in part at the 42nd Annual General and Scientific Meeting of the Royal Australasian College of Radiologists, Adelaide, September 199 1.

Reprint requests to: Dr. John Boyages. Accepted for publication 17 March 1992. 253

254

I. J. Radiation Oncology 0 Biology 0 Physics

METHODS

AND MATERIALS

One hundred thirty-one women with clinical Stage I or II invasive breast cancer were treated at Westmead Hospital between November, 1979 and December, 1985 (1). A Stage I tumor was a lesion 2 cm or less in diameter without clinical evidence of significant lymph node involvement (TINO&. A Stage II tumor included lesions greater than 2 cm and up to 5 cm or any tumor up to 5 cm with clinically involved axillary lymph nodes (T2N0, Ti-*NIB). Patients with non-invasive ductal carcinoma in situ or patients who presented with simultaneous bilateral tumors or with a significant previous malignancy were excluded from this study. As of June 199 1, median follow-up was 83 months for 96 surviving patients (range, 5 1-133 months). In addition, 6 patients who were lost to follow-up (LTFU) without evidence of disease were censored at intervals of between 4 and 62 months (median, 48 months). Median followup for all patients (dead, alive, and LTFU) was 73 months (range, 4-133 months). Ninety-four of the 96 surviving patients (98%) had follow-up of at least 5 years. The median age at diagnosis was 5 1 years (range, 27-8 1). During the study time period, preoperative mammograms were performed in 44% of patients. Fifty-six per cent of patients were referred from outside Westmead Hospital. The amount of tissue removed at surgery was therefore variable and ranged from an excision biopsy (that is, removal of the tumor surrounded by a small margin of normal tissue), to wide local excisions, quadrantectomy, or in some cases, a partial mastectomy. Eight per cent of patients who underwent surgery outside the hospital were referred for an opinion pre-operatively compared to 47% of patients from Westmead Hospital. Eighty-one patients (62%) underwent axillary nodal dissections, usually a complete axillary dissection. In general, axillary dissections were not recommended for premenopausal patients who indicated in advance, that, irrespective of the findings they would not accept advice to receive adjuvant chemotherapy, or postmenopausal patients with a clinically negative axilla which could be irradiated, in whom adjuvant chemotherapy was not indicated. One hundred twenty-nine patients received whole breast irradiation to a median dose of 50 Gy (range 45 to 50 Gy) usually over 5 weeks. Ten patients were treated to the whole breast without a boost because of poor general condition or because of the large amount of normal tissue removed at initial surgery. A boost dose to the primary tumor site after whole breast irradiation was given to 119 patients. The boost was delivered by an Iridium-192 implant in 118 cases and photon beam in one case. The median boost dose was 30 Gy (range, 8-30 Gy). Two other patients were treated by a definitive local implant (total dose 50 Gy and 60 Gy) because of poor general condition. A single-plane implant was used for all except 1 patient. The median area of all implants was 20 cm2 (range, 7-67 cm2). The area recorded was the ‘actual’ area

Volume 24, Number 2, 1992

of the implant as calculated by a physicist for each implant. The implant generally encompassed the entire surgical scar. Implants were performed using plastic coated platinum-filtered continuous Iridium- 192 wire. The target volume minimum dose was usually specified as at a plane 0.5 cm from the plane of the implant. The dose rate was generally determined by Iridium-192 wire strength but was usually 40-50 cGy per hr. The area of the implant was known for 114 patients. The effect of area of implant on the probability of breast cancer recurrence was determined by sorting the areas approximately into thirds. The total dose to the region of the primary tumor ranged from 45 to 80 Gy (median, 80 Gy). Of the 129 patients who received external beam treatment, 13 patients ( 10%) received radiation to the breast only, 9 (7%) to the breast and supraclavicular fossa (SCF) and 3 patients (2%) to the breast and internal mammary chain (IMC). Ninetyone patients (7 1%) were treated with a four-field technique to the breast, SCF and axilla and 13 patients ( 10%) were treated with a five-field technique which included the IMC. Chemotherapy was given to 10 node-positive patients (8%). The regimens prescribed were: (a) Oral cyclophosphamide (C), 100 mg/m’ (Days (D) l-14) intravenous (iv) methotrexate (M), 40 mg/m2 (D1,8) and iv lluorouracil (F), 600 mg/m2 (D 1,8), given every 28 days (“Oral CMF”) six cycles (3 patients); (b) iv C, 600 mg/m2, iv M 40 mg/m* and iv F 600 mg/m2 (“IV CMF”), given every 2 1 days for six cycles (6 patients). One patient also received three cycles of Novantrone (N) and C (750 mg/m2) in addition to IV CMF because of extensive nodal involvement (7). Patients usually received adjuvant prednisone, 7.5 mg daily. Four postmenopausal node-positive patients in whom tumor estrogen receptor was positive received adjuvant Tamoxifen 20 mg daily for 2 years. Dose modifications or treatment delays occurred on the basis of haematologic toxicity. World Health Organ&ion (WHO) (37) toxicity grades were recorded. Toxicity was reported as the worst toxicity grade for a given side effect as recorded throughout the entire course of chemotherapy. Patients received their chemotherapy either sequentially, with chemotherapy commencing after completion of radiation (6 patients); concurrently, with chemotherapy commencing at the same time as radiation (2 patients); or in a “sandwich” fashion, with at least one cycle of chemotherapy administered prior to radiation and further chemotherapy at the completion of radiation (2 patients). Initial biopsy material was reviewed by one of the authors (M.B.) for 119 of the 13 1 breast tumors (9 1%). The impact of pathologic factors on the probability of breast cancer recurrence or distant relapse will be assessed elsewhere (6). The volume of excised tissue was also recorded. An excision co-efficient was calculated for 97 patients with available data on the dimension of excised tissue and pathologic tumor size. The volume of excised tissue and pathologic tumor size was calculated using the largest diameter. Volume was calculated from the diameter using the relation, V = 7rD3/6 as described elsewhere (20). The

Breast conservation 0 J. BOYAGESet al.

volume of excised tissue was divided by the pathologic volume of the tumor to obtain the excision co-efficient. The larger the co-efficient the larger the extent of excision of normal tissue compared to tumor. The excision coefficient was sorted by area and for comparison divided into a lower third (1 .O-9.0 cm’, 33 patients), middle third (9.1-32.0 cm3, 33 patients) and upper third (> 32 cm’, 32 patients). A similar analysis using area of excised tissue (length X breadth) divided by the pathologic area of the tumor (a?) did not alter the results. The effect of the extent of initial surgery was examined by assessing the rate of breast cancer recurrence in the primary tumor region. We assumed that the rate of recurrence in other quadrants of the breast would not be influenced by the extent of excision of the involved quadrant. Patients were followed in a dedicated breast conservation follow-up clinic alternating appointments with the surgeon and radiation oncologist. Patients were planned to be followed up at 3-monthly intervals for years l-3; 6monthly for years 4-10 and 12-monthly intervals after ten years. Apart from a physical examination at each visit, bilateral film-screen mammograms were to be performed at yearly intervals. Long-term complications from treatment were collected from information from the radiotherapy record, referring doctor, or from direct communication with the patient. Data collected included; the presence of breast tenderness, symptomatic pneumonitis, rib fracture, surgery for fat necrosis or fibrosis, or arm edema. Arbitrarily, minimal, moderate, or severe arm edema was set at a difference of between 0.5 to 2 cm, 2.1 to 4.0 cm, and more than 4.0 cm in girth between the treated and untreated side usually measured 10 cm above the olecranon. Breast recurrence was defined as the detection of cancer in the treated breast or overlying skin occurring before or simultaneously with the diagnosis of distant metastases. (Two patients developed breast recurrences after the diagnosis of distant metastases). Breast recurrences were classified by location in the breast relative to the primary tumor site and boost volume as true recurrences (TR, within the area of the boost), marginal misses (MM, up to 2 cm adjacent to the boost area), recurrences elsewhere (E, in other quadrants of the breast) and skin recurrences (S) as defined by other groups (32). Data was entered into a commercially available data base.* Quality control procedures included manual crosschecking with the patients’ data forms and extensive computerized range and consistency checks. Results were analyzed using two computerized statistical packages.+ Factors examined as to their influence on breast cancer recurrence were age at diagnosis (using a comparison of I 34 years versus 2 35 years as used elsewhere); T-stage;

* Clinical Reporting System (CRS), Sydney, Australia. + SPIDA (Statistical Computing Laboratory) Sydney, tralia, RSl (BBN Enterprises) Cambridge, MA, USA.

Aus-

255

Table 1. Study population-clinical

No. evaluable

Factor Menopausal status Premenopausal Prior Hx or Ox when Premenopausal Postmenopausal Age at diagnosis 5 34 2 35 Laterality Left Right T-stage TI T2 N-stage NO/IA NIB UICC stage 1 11 Eostrogen receptor status Positive Negative Not known Hx = Hysterectomy;

characteristics %I

55

42

20 56

15 43

9 122

7 93

56 75

43 57

90 41

69 31

126 4

97 3

87 44

66 34

27 18 86

21 I4 65

Ox = Oophorectomy.

N-stage; UICC stage; pathologic nodal status; excision coefficient; delay in RT commencement; radiation dose and volume; and the use of adjuvant chemotherapy. The risk of breast recurrence was evaluated by the use of actuarial calculations and by crude incidence. Actuarial curves of breast recurrence were calculated by the method of Kaplan and Meier and comparisons between curves were made using the two-tailed log-rank test. Patients were censored from the calculation of breast recurrence at the time of last disease-free follow-up, the discovery of metastatic disease (25 patients), the discovery of regional nodal disease without a breast recurrence (one patient), or death from intercurrent illness (4 patients). Patients were censored from the calculation of distant failure at the time of last follow-up, scoring failure at the time of first discovery of me&static disease (regional nodal failures: axilla, one patient, IMC, 2 patients) and opposite breast cancers ( 1 patient) were included as an event). All distant relapses were analysed as failures irrespective of the status of the treated breast. Actuarial overall survival times were calculated using death from any cause as an event (29 patients). Actuarial disease-related survival times were also calculated scoring death only when caused by breast cancer (23 patients). Differences between proportions were tested by the Fisher exact test. p-values of 0.05 or less were considered statistically significant.

I. J. Radiation Oncology 0 Biology 0 Physics

256

Volume 24, Number 2, 1992

RESULTS

100

Table 1 shows the patient and tumor characteristics of the study group. Eighty-six patients had a T 1,NO/ 1A tumor, 3 patients (Tl,NlB), 40 patients (T2,NO/lA), and 1 patient (T2NlB). For 1 patient with a Tl tumor the clinical nodal status was not recorded. The median clinical tumor size was 2 cm (range, O-4 cm). Estrogen receptor studies were not routine during the study time period and were known in only 45 patients (35%). The pattern of first relapse is shown in Table 2. With a median follow-up of 83 months, 11 of 131 patients (8.5%) have developed a breast cancer recurrence. One of the 11 patients also had a simultaneous distant relapse. The corresponding 5- and IO-year actuarial rates of breast recurrence were 4% and 13% (Fig. 1). An “Elsewhere” (E) recurrence was the most common pattern of breast recurrence. Seven patients developed an E recurrence and 4 patients a TR. No patient developed a MM. The median time to diagnosis was 22 months for a TR and 73 months for failures outside the primary tumor region. Seventyfive per cent of true recurrences occurred within 5 years compared to only 29% of E failures. Six of the breast recurrences were detected by clinical examination alone, three by mammography alone, and two by both techniques. We examined the relationship between various patient, tumor and treatment characteristics and the incidence of breast cancer recurrence. We found that very young patients (I 34 years) had a higher incidence of recurrence than older patients. Two of 9 very young patients (22%) developed a breast recurrence compared with 9 of 122 older patients (7%) (p = NS). The corresponding 5-year actuarial breast recurrence rates were 22% for very young patients and 4% for older patients (p = N.S.). We also assessed the incidence of distant recurrence for the two age cohorts and found no significant difference. The 5year actuarial incidence of distant recurrence was 20% for patients aged 35 or older and 33% for younger patients (Log-rank, p = N.S.). The crude incidence of a breast recurrence in relation to clinical characteristics of the tumor is shown in Table 3. Clinical TN stage had no association with the incidence of breast recurrence. Pathologic nodal status also did not influence the probability of a breast cancer recurrence. We also examined the influence of various treatment parameters on the risk of a breast recurrence. The effect of the extent of excision of the primary tumor was deterTable 2.

Pattern of first failure

Status

No.

%

Disease-free Breast alone Breast + distant Nodes Distant

95 10 1

72 8 1 1 18

I 24

90 1

8Oi 70 %

60 50 40 30 -

10 0 0

2

4

Y&S

8

10

Fig. I. Breast cancer recurrence: The number and 10 years is shown in parentheses.

12

of patients

at 5

mined by examining the incidence of a TR or MM by a calculated excision coefficient (see above). A high excision coefficient (that is, excision of a higher portion of normal tissue with the primary tumor) did not result in a significantly lower rate of recurrence in the region of the primary tumor. Evaluation of a radiation dose effect was limited because only 2 1 patients received less than 70 Gy to the primary tumor region. Total dose to the primary site and implant volume were not associated with the incidence of a breast recurrence (Table 4). We did not find a significantly higher crude rate of breast recurrence for patients in whom the interval between excision of the primary tumor and the commencement of radiation was less than 7 weeks, compared to those patients in whom the delay was 7 weeks or greater (9% vs. 5% respectively, p = NS). We examined the influence of adjuvant chemotherapy on the risk of a breast recurrence (Table 4). The crude incidence of a breast recurrence was 11% for patients who received chemotherapy compared with 10% for patients who did not receive chemotherapy (p = NS). The use of chemotherapy was not associated with a lower breast recurrence rate among patients aged 49 years or younger or patients who were noted to be premenopausal. Table 3. Crude breast recurrence:

influence

of clinical factors

Breast recurrence Factor Age I 34 2 35 T-stage Tl T2 N-stage NO/IA NIB

No. evaluable

No. (W)

p-value

9 122

2 (22) 9 (7)

0.17

90 41

8 (9) 3 (7)

N.S.

126 4

10 (8) 0

N.S.

NS = Not significant.

Breast conservation 0 J. BOYAGES et al. Table 4. Crude breast recurrence: influence of treatment factors Total number

Factor Excision coefficient Low+ Medium High Treatment delay I 7 weeks > 7 weeks Total dose to primary site 70Gy Implant volume (area, CM’) < 17 18-23 > 23 Chemotherapy-all pts. Yes No

% breast recurrence

p-value

33 33 32

3* 3* 3*

109 22

9 5

12 17 102

0 17 6

35 39 40

11 5 8

NS

10 121

10 8

NS

NS

NS

NS

* E failures excluded. + See text for definitions.

Of the 11 patients with an isolated breast cancer recurrence, 6 were treated with a total mastectomy, 1 a total mastectomy and axillary dissection. Of the 7 patients treated with a mastectomy, 1 patient developed a subsequent inoperable axillary node recurrence and 3 other patients developed metastatic disease. Two patients who refused a mastectomy and treated with a further wide excision recurred again at the same site. Two patients who had a diffuse inoperable recurrence (including a mass at the primary tumor region) treated with chemotherapy died without local control of disease (Table 5). At the time of last follow-up or death, 127 of the 13 1 patients (97%) had loco-regional control of disease.

Table 5. Outcome Initial mammogram

Detection of recurrence

of patients

Time to breast recurrence

The complications of treatment were acceptable. Radiation induced rib fracture occurred in 5% of patients, symptomatic pneumonitis (4%) fat necrosis or fibrosis leading to surgery (4.5%), severe arm edema (4.5%). Symptomatic pneumonitis occurred in 5 patients at intervals ranging between 3 and 10 months (median, 5 months). The use of chemotherapy did not influence the probability of side-effects. Rib fracture occurred in seven patients at a median interval of 27 months (range, 14 to 58 months). The median time interval to surgery for fat necrosis or fibrosis was 26.5 months (range, 7 to 43 months). Temporary paraesthesia, possibly due to radiation induced brachial plexopathy, occurred in 1 patient. One patient who was initially thought to have brachial plexopathy was subsequently noted to have tumor recurrence in the axilla on a Magnetic Resonance Imaging (MRI) scan. Breast tenderness was not uncommon particularly around the primary tumor region and occurred at some time in 44% of patients. The treatment of the axilla by both S + RT was associated with a moderate or severe arm edema rate of 29% compared to 8% for S alone and 6% for RT alone. The long-term prognosis for the study group is good. The 5- and IO-year actuarial freedom from a distant relapse for all patients was 79% (97 patients at risk) and 7 1% (5 patients at risk), respectively. The corresponding rates of overall survival were 83% and 77% (Fig. 2). Disease-related survival rates at 5 and 10 years were 8 5% and 80%, respectively. DISCUSSION Our results in this updated series of patients treated at least 5 years ago continue to show a high level of breast tumor control achieved with minimal long-term complications. Factors such as tumor size or pathologic nodal status do not predict for breast cancer recurrence. We also found that larger resections were not associated with a

who developed

an isolated breast recurrence

Site

Treatment

E E TR E E E E TR TR TR E

TM TM + AXD TM TM TM TM LE CT CT TM LE

Status (mths)

Disease status

Alive Alive Dead (6 1) Alive Alive Alive Alive Dead (35) Dead ( 14) Alive Alive

NED Mets Mets NED Mets Regional Chest wall* Local and mets Local and mets NED NED+

E = Elsewhere recurrence; TR = “True recurrence;” TM = Total mastectomy; AXD = Axillary dissection; CT = Chemotherapy; NED = No evidence of disease; Mets = metastatic disease. * Second local recurrence at 2 l/l2 treated by TM with subsequent chest wall recurrence. ’ 2nd recurrence treated by re-excision.

LE = Local excision;

Not done Not done Not done Not done Negative Positive Positive Not done Negative Negative Not done

Mammogram Both Clinical Mammogram Clinical Clinical Clinical Clinical Clinical Both Mammogram

127 82 19 65 91 73 57 26 12 66 50

251

I. J. Radiation Oncology 0 Biology 0 Physics

258

100 90 80 70

%

60 SO40-

(-"-

3020lo07 0

Fig. 2. Freedom

I 2

0. 4

8

0 8

r 10

" 12

from distant failure (FDF) and overall survival

(OS).

lower probability of failure in the region of the primary tumor. Treatment of the axilla by both surgery and RT is not recommended because of its associated high rate of significant arm edema. The rate of CS + RT in Australia is difficult to determine. The frequency of breast conserving surgery from Western Australia in 1984 for patients with Stage I and II disease was 14% (11). In a similar study from Victoria, 22% of patients with operable breast cancer were treated with breast conserving surgery in 1986 ( 19). In both these series 62% and 47%, respectively, of patients treated by CS were not referred for post-operative RT. These rates of breast conservation are lower than that of major centers in the United States and Europe and the use of CS alone, an experimental approach, is being utilized as standard therapy by some surgeons (8). Our experience has also revealed a misconception amongst many clinicians (surgeons and radiation oncologists) in Australia that CS + RT is not appropriate for patients with tumors greater than two or three centimeters or for patients with lymph node involvement because of a perceived greater risk of a breast cancer recurrence. Previous reports from other centers have shown no increase in breast cancer recurrence for patients with larger tumors (2, 10, 13, 18,28,29,34). In a series from the Joint Center for Radiation Therapy (JCRT), the risk of a breast cancer recurrence was 10% at five years for Tl or T2 tumors (9). Similarly, in the NSABP B-06 trial, local recurrence rates were 7% for patients with T 1 tumors and 10% for patients with T2 tumors (p = NS). In a series of patients from the Radiation Therapy Oncology Group (RTOG), the rate of local recurrence for patients who underwent an excisional biopsy was 2% for Tl patients and 10% for T2 patients (p = 0.01). In our study clinical tumor size (Tl vs T2) or nodal status (NO/lA vs NlB) did not influence the risk of breast cancer recurrence. Patients with larger tumors or with positive axillary lymph nodes have a higher risk of metastatic failure and therefore would be more appropriate candidates for less aggressive surgical approaches and possibly initial chemotherapy (4).

Volume 24, Number 2, 1992

Prognostic factors predicting for a breast recurrence following treatment with CS + RT vary from institution to institution. Commonly reported risk factors include, young age at diagnosis, the presence of an extensive intraductal component (EIC), and a high tumor grade. Investigators from the JCRT have found that 26% of patients with infiltrating duct carcinoma with an EIC developed a breast cancer recurrence compared to 7% without an EIC (p = 0.0001) in a series of patients treated with a simple gross excision prior to radiation therapy (9). The presence of an EIC is not a risk factor for breast cancer recurrence when wider excisions or a quadrantectomy is performed. Investigators from the Institut Curie and the Netherlands Cancer Institute have also found by univariate analysis, that the presence of an EIC+ tumor predicts for a significantly increased rate of breast cancer recurrence but this finding is not universal (12, 14, 34). The influence of pathologic factors on breast recurrence and distant relapse in our series will be examined elsewhere (6). Our data also suggested that very young age at diagnosis may be associated with an increased rate of breast cancer recurrence. The definition of young age was arbitrarily chosen as 34 years or less at the diagnosis of breast cancer as used by other centers (30). The very young age group was a small component (7%) of our study sample. Young age has also been found to be associated with an increased risk of breast recurrence by some investigators ( 10, 14, 15, 21, 26, 27, 30, 34, 36). Others, however, have found no increased risk of breast recurrence with young age (33). The reasons for this association between very young age and breast recurrence are unknown and a similar higher incidence of local recurrence amongst younger patients has been found in a series of patients treated with a mastectomy from the M.D. Anderson Hospital and from a series from the John Hopkins Hospital treated between 1889 and 193 1 (23, 25). We found that seven of the 11 recurrences (64%) in the breast occurred in quadrants outside the primary tumor region. This contrasts with a predominance of failures in the vicinity of the primary tumor (TR or MM) in other reported series (12, 16, 22, 24, 27). A recent study from the JCRT examined the time course and patterns of breast recurrence as a first sign of failure in 607 clinical Stage I or II invasive breast cancers treated between 1968 and 198 1 (31). Forty-eight of the 67 failures (72%) were at or near the primary tumor’s site (33 true recurrences and 15 marginal misses). Recurrences at or near the primary site occurred earlier (median, 38.5 months) than recurrences at distant sites in the breast (median, 64.5 months). In our series, the median time to a TR was also shorter than the median time to a recurrence elsewhere in the breast (22 vs 73 months). The lower proportion of recurrences in the vicinity of the primary tumor most likely reflects our deliberate high dose policy to the primary tumor site during the study time period. A previous study from our institution found that larger tumor resections led to significantly larger area of implant

Breast conservation 0 J. BOYAGESet ul.

and a reduced cosmetic result (5). In this study we have found that larger resections (expressed as an excision coefficient) do not reduce the likelihood of a failure in the primary tumor region. Further, patients who received a larger area of implant boost to the primary tumor site or a higher dose did not have a reduced rate of breast cancer recurrence. Other investigators have retrospectively compared patients treated with an excisional biopsy or a quadrantectomy followed by RT with no consistent benefit being shown for larger resections (12, 27, 34). The only published randomized trial compared ‘TART’ (tumorectomy followed by external RT and an Ir- 192 boost) to “QUART” (quadrantectomy followed by external RT) for patients with tumors measuring up to 2.5 cm. Both groups of patients also underwent a complete axillary dissection. Patients treated with tumorectomy had a higher rate of breast cancer recurrence than patients treated with a quadrantectomy (7% vs. 2.2%). The mastectomy-free survival was 98% for QUART compared to 96% for TART (X2, p = 0.06). There was no difference in overall survival between the two groups, but patients treated with TART had a superior cosmetic result than patients treated with QUART. In our opinion, the optimal balance of the two modalities can be achieved with an excision biopsy followed by moderate dose RT for the majority of patients. Larger resections are recommended for patients with an EIC or with extensively involved margins (35).

259

Similarly, management of the axilla by both surgery and RT is associated with a high risk of arm edema. In a report from the JCRT, the risk of arm edema after a complete axillary dissection and axillary irradiation was 36% at 6 years compared to 7% for patients who underwent a limited dissection and axillary irradiation. In our study, the risk of moderate or severe arm edema was 29% for patients who underwent surgery and axillary irradiation compared to 8% for S alone and 6% for RT alone. We currently recommend an excision biopsy and for most patients an axillary dissection of at least levels I and II. If the margins of excision are extensively involved or there is an associated EIC, a re-excision and in some cases a mastectomy is recommended. The dose of radiation delivered to the breast is approximately 45 Gy over 5 weeks followed by an electron beam boost to the primary site of 16 Gy in eight fractions. The reduction in dose was prompted by our previous study which revealed a poor cosmetic result for many patients because of high dose radiation effects such as breast retraction and telangiectasia and from other evidence from the literature (17). Patients who are referred following an inappropriately large resection (usually with an inferior cosmetic result) do not receive a boost dose of radiation. Our long-term data from this study indicate that CS + RT is an acceptable option for patients with operable breast cancer.

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3. 4.

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American Joint Committee on Cancer. Manual for staging of cancer, 2nd edition. Philadelphia: JB Lippincott; 1983. Amahic, R.; Santamaria, F.; Robert, F.; Seigle, J.; Altschuler, C.; Kurtz, J. M.; Spitalier, J. M.; Brandone, H.; Ayme, Y.; Pollet, J. F.; Burmeister, R.; Abed, R. Radiation therapy with or without primary limited surgery for operable breast cancer: a 20-year experience at the Marseilles Cancer Institute. Cancer 49:30-34;1982. Anonymous. National Institutes of Health (NIH) consensus development conference statement: treatment of early stage breast cancer. JAMA 265:391-395;1991. Bonadonna, G.; Veronesi, U.; Brambilla, C.; Ferrari, L.; Luini, A.; Greco, M.; Bartoli, C.; de Yoldi, G. C.; Zucali, R.; Rilke, F.; Andreola, S.; Silvestrini, R.; Di Fronzo, G.; Valagussa, P. Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. JNCI 82: 1539- 1545; 1990. Boyages, J.; Barraclough, B.; Middledorp, J.; Gorman, D.; Langlands, A. 0. Early breast cancer: Cosmetic and functional results after treatment by conservative techniques. Aust. NZ J. Surg. 58:111-121;1988. Boyages, J.; Bilous, M.; Bosch, C.; Barraclough, B.; Langlands, A. 0. Pathologic predictors of failure after breast conservation. Breast 1992 (in press). Boyages, J.; Langlands, A. 0. The efficacy of combined chemotherapy and radiotherapy in advanced non-metastatic breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:7178;1988. Boyages, J.; Langlands, A. 0. Breast cancer: The role of radiation therapy after treatment by conservative surgery. Aust. NZ J. Surg. (in press). Boyages, J.; Recht, A.; Connolly, J. L.; Schnitt, S. J.; Gelman, R.; Kooy, H.; Love, S.; Osteen, R. T.; Cady, B.; Silver, B.;

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