Clinical Oncology (1990) 2:27-34 © 1990 The Royal College of Radiologists

Clinical Oncology

Original Article Conservation of the Breast Using Two Different Radiotherapy Techniques: Interim Report of a Clinical Trial G. G. Ribeiro 1, Gillian Dunn 2, R. Swindell2, M. Harris 3 and S. S. Banerjee 3 Departments of 1Radiotherapy, 2Medical Statistics and 3Histopathology, The Christie Hospital, Manchester, UK

Abstract. Patients with a clinically palpable breast carcinoma, 4 cm or less in diameter, and with no palpable nodes in the axilla were prospectively entered into a randomized clinical trial. A total of 713 patients were registered between November 1982 and December 1987, of whom 708 are evaluable at a median follow-up of 37 months. Following excision of the primary tumour, patients were randomly allocated either to have radiotherapy to the affected quadrant only (LF group) or to the whole breast and regional lymph node areas (WF group). No adjuvant hormone or chemotherapy was prescribed. The primary tumour was reported as completely excised histologically in 80% of cases, incompletely excised in 10%, and no estimate was possible in 10%. At six years from first randomization, 96% of the WF group and 92% of the LF group have remained free of breast recurrence (94% and 87% actuarial breast recurrence-free survival at 5 years). Part of the difference may be explained by the 20% recurrence rate in the breast for lobular carcinomas treated within the LF group. Of the WF group 14 patients (4%)-developed recurrent disease in the axilla, compared to 50 patients (14%) in the LF group (95% and 86% actuarial axillary recurrent-free survival at 5 years). Patients with primary tumours histologically 1 cm or less in diameter had a 98% actuarial 5-year survival compared with 74% for those with tumours measuring 2 cm or more in diameter (P=0.003). Continued follow-up of these patients will provide further information on the factors governing local/regional recurrence.

Keywords: Breast; Conservation; Radiation therapy; Recurrence

Correspondence and of]print requests to: G. G. Ribeiro, The Christie Hospital, Wilmslow Road, Withington, Manchester, M20 9BX, UK.

INTRODUC~ON

In 1972, 40 women were referred to The Christie Hospital and Holt Radium Institute, Manchester, for elective radiotherapy, having had a local excision of a Stage I carcinoma of the breast. By 1980 the number had increased to 95, rising to 280 in 1982, with the latest figures for 1987 showing that 750 women had a Stage I carcinoma of the breast treated by local excision followed by radiotherapy. Anticipating this steep increase in the use of radiotherapy treatment through the 1980s, it became an urgent necessity to assess what was the optimum size of tumour suitable for this type of treatment and how best to use scarce resources and available treatment time on the therapy machines without detriment to the survival of patients. Reports (Hellman et al., 1980; Clark et al., 1982; Kurtz et al., 1983; Fisher et al., 1986) over a period of time had suggested that most patients who developed recurrent disease in the breast following excision and radiotherapy, tended to relapse in the primary site. Some long-term results from published clinical trials (CRC Working Party, 1976; Fisher et al., 1985b) also showed that the recurrence rate in the untreated ipsilateral axilla was much lower than anticipated. It seemed perfectly reasonable to question whether the whole breast and ipsilateral axilla needed to be treated in all cases, and what surgical and pathological factors influenced the site and rate of local recurrence. A clinical trial was, therefore, initiated in which patients with breast carcinoma, 4 cm or less in diameter would have the tumour excised. The patients would then be randomized to have wide field radiotherapy treatment to the whole breast and regional lymph nodes over 3 weeks or localized high-dose electron therapy to the tumour bed only over 10 days. As the patients entered into the trial were not to be given adjuvant therapy, there was no reason to

28

G . G . Ribeiro et al.

know the axillary status for that purpose. The advantages of not dissecting and/or irradiating the axilla are the elimination of potential morbidity and irreversible damage to the axillary structures. These advantages have to be balanced against uncontrollable malignant disease at the site, and the effects on the patient of experiencing an axillary recurrence. Similarly, by using low-energy electron therapy to treat the breast, damage to the deeper structures such as the heart and lungs could be avoided. Electron therapy was chosen because there was most machine-time available for this modality. Furthermore we wished to know what was the shortest possible overall time in which to treat these patients. It had been indicated previously, by patients, that they would be more likely to attend as out-patients if the shorter overall time was used in their treatment because of difficulty with transport to the hospital. The primary information sought from this trial would be the following:

Preoperative investigations were kept to a minimum and included a chest radiograph, full blood count and biochemical profile, including liver fuction tests. At The Withington Hospital, which entered 25% of the patients, bilateral mammograms were routinely done on all patients preoperatively. No adjuvant hormone or chemotherapy was to be administered. Criteria for the exclusion of patients from the trial are as follows.

1. The local control rate of breast carcinoma in the two groups 2. The factors governing the likelihood of recurrence in the breast 3. The incidence of axillary recurrence in the treated and untreated axilla 4. The survival of the two groups 5. The sequelae of radiation therapy in the two groups

Follow-Up

In this interim report, information on the first four parameters will be provided and discussed. The last parameter will be discussed in greater detail in a later report.

1. Primary tumours greater than 4 cm clinically 2. Fixed primary tumours or diffuse malignancy in the breast 3. Metastatic disease 4. Bilateral carcinomas 5. Inflammatory carcinoma or Paget's disease 6. Previous carcinoma of the breast 7. Sarcoma of the breast 8. Concurrent pregnancy

After treatment, both groups of patients were followed-up at similar intervals, at 3 monthly intervals for the first two years and thereafter at 6 monthly intervals. The examinations were purely clinical. Mammography was only done if symptoms or signs suggested possible recurrence. At each visit side-effects of treatment were noted and at yearly intervals an assessment of cosmesis was made. Factors noted were the degree of any fibrosis, the extent of any telangiectasia and the presence of oedema, fat necrosis, and the junction effect. No patients have been lost to follow-up.

Statistics MATERIALS AND METHODS Eligible patients were those with a single, mobile, palpable lump in the breast, 4 cm or less in two perpendicular diameters and with no palpable nodes in the ipsilateral axiUa. The women had to be less than 70 years of age. The primary tumour was excised with no recommendation as to the margin of clearance to be taken, the ipsilateral axilla was not dissected. Having established a histological diagnosis of carcinoma, the patient was then entered in the trial, and randomized to one of two groups. The first involved limited field irradiation to the tumour bed only in eight fractions over ten days (LF Group) and the second, wide field irradiation of the whole breast and regionial lymph node areas in 15 fractions over 21 days (WF Group). Surgeons were specifically requested to limit the surgical scar to a maximum of 8 cm in length.

Patients were entered into the trial by means of a direct telephone call to the statistics department. They were then allocated to one of the two groups, which had been randomized using a balanced block design, where each block size in sequence was chosen at random from a given range of 6 to 16. Follow-up and survival times were calculated from the date of randomization. Survival curves and freedom from relapse curves were calculated by the Kaplan-Meier method. The number of patients at risk for each year of follow-up are shown. Curves were compared using the log-rank test (Peto et al., 1977).

Radiotherapy In the LF group, the quadrant in which the tumour lay was irradiated by means of a single field directly

Carcinoma of the Breast

placed. The average field size was 8 cm x 6 cm. The means of irradiation in the majority of patients was an electron beam of 10 MeV energy. This beam would deliver a tumour dose of 85%-90% at a depth of 2.5 cm, thereafter falling off very steeply to 10% of the dose at a depth of 5 cm. In patients with large breasts, a beam energy of 14 MeV electrons was used. The given dose was 4250 cGy in eight treatments over 10 days. During the trial the International Code of Practice relating to the calibration of electron beams was revised (The Hospital Physicist's Association Code of Practice, 1985). This meant that the factors used in converting instrument readings into absorbed dose were changed and led to an increase in the dose actually given per unit dose prescribed. To maintain consistency in the dose given to patients, the prescribed dose was reduced from 4250 cGy to 4000 cGy. In the WF group, the whole breast was treated using a tangent pair of parallel opposed fields on the 4 Mv linear accelerator. A tumour dose of 4000 cGy was delivered in 15 fractions over 21 days to the posterior and centre of the breast. Wedge filters were not used, so that the dose rose to about 10% higher than that at the deeper portion of the breast. A thin strip of bolus material was placed over the surgical scar, but no other means of boosting the dose were used. The ipsilateral axilla, supra- and infraclavicular fossae were treated by means of a single direct field matched on to the breast fields. The given dose on this field was 4000 cGy in 15 fractions over 21 days. The internal mammary nodes were not treated intentionally.

29

lined by recognizable endothelial cells. However, no specific stains (e.g. Factor VIII related antigen or Ulex europaeus lectin 1) were done for identification of endothelial cells. Measurement of the histopathological size of the primary turnout and assessment of the completeness of excision was accepted from the report of the various pathologists in the referring hospitals and was not reviewed at the Christie Hospital.

RESULTS

Between November 1982 and the close of the trial in December 1987, a total of 713 patients were entered and randomized at the Christie Hospital and Holt Radium Institute, Manchester. Patients were referred by surgical colleagues for the North-West of England (see Appendix). Five patients were excluded immediately following randomization. Two had palpable nodes at randomization, one had angiosarcoma, and two had leuco-erythroblastic anaemia due to bone metastases, later confirmed by bone scans. A total of 708 patients were therefore available for analysis, of whom 353 were randomized to the LF group and 355 to the WF group. Four patients randomized to the LF group did not get their allocated treatment, but for the purposes of the analysis they remain in the LF group. Seven patients were given adjuvant tamoxifen but are not excluded. The main characteristics of the 708 patients are shown in Table 1. Table 1. Characteristics of 708 patients

Pathology Blocks or unstained sections of the cases included in the study were obtained from various hospitals in the North West of England. All sections were stained with haematoxylin and eosin. In selected cases, histochemical stains (PAS with or without diastase, PAS-alcian blue, Grimelius and Toluidine blue) and immunocytochemical studies (for cytokeratin, EMA, vimentin, desmin, and SIOO protein) were performed. The following features were recorded in every case: (a) type of tumour; (b) grade of tumour for infiltrating ductal carcinomas and (c) evidence of any lymphatic or vascular invasion. The grade of infiltrating duct tumours was assessed on a scale of 1 (well differentiated) to 3 (poorly differentiated) taking into account tubular differentiation, nuclear pleomorphism and mitotic activity according to the method recommended by Bloom and Richardson (1957). Lymphatic or vascular invasion was reported when tumour cells were seen within spaces

Age - Mean Site UOQ LOQ UI LI Midline Clinical Size 2 cm Pathological Size 2 era Not known Complete excision Yes No Not known

LF

WF

(353)

(355)

Total (%)

53

52

198 43 52 16 44

211 38 47 14 45

409 (58) 81 (11) 99 (14) 30 (4) 89 (13)

225 128

231 124

456 (64) 252 (36)

156 48 149

156 49 150

312 (44) 97 (14) 299 (42)

286 29 38

280 40 35

566 (80) 69 (10) 73 (10)

The median follow-up for the whole series at the time of analysis in January 1989 is 37 months (1-72 months). Measurements of the primary tumour size after removal are available in 58% of cases. Where it was known, comparing the clinical estimation of

30

G . G . Ribeiro et al.

size with the pathological estimate showed that the clinical size was invariably an overestimate by approximately 1 cm. The distribution of the cases by histology, following review at the Christie Hospital (by MH and SSB) is shown in Table 2. Approximately 5% of cases previously labelled as being infiltrating duct carcinomas were changed to infiltrating lobular carcinomas on review. An unusual finding was a higher than expected proportion of Grade 3 infiltrating duct carcinomas compared to a previous study (Howat et al., 1983) in which the bulk of the tumours were Grade 2 and the remainder equally divided between Grades 1 and 3. Table 2. Distribution by histopathology

Table 3. First treatment failure Site

Metastases

LF (353) No. (%)

WF (355) No. (%)

Breast only

Absent Present Absent Present Absent Present Absent Present Absent Present

17 (4.8) 1 (0.3) 32 (9.0) 3 (0.8) 10 (2.8) 0 1 1 7 (2.0) 22 (6.2)

10 (2.8) 1 (0.3) 10 (2.8) 0 2 1 1 1 1 36 (10.1)

Axilla only

Type Infiltrating duct cancer Grade 1 - 88 Grade 2 - 208 Grade 3 - 213 Unknown- 12 Infiltrating lobular cancer Mixed ductal + lobular Duct cancer (microinvasive) with extensive intraduct component Mucoid cancer Medullary Tubular Lobular in-situ Adenoid cystic cancer Squamous cell cancer Apocrine cancer Total

Table 3 shows the site of first relapse, in each group, and whether the patients had simultaneous distant metastases. The majority of patients had local recurrence only without evidence of distant metastases. A total of 58 patients (8%) developed distant metastases only without any evidence of local recurrence. There was no significant difference in the distant disease-free survival between the WF and LF groups.

No.

%

521

74

67 28

9 4

45

6

Breast + Axilla

] Supraelavicular

21 9 14 0 1 1 1 708

Multiple regionaP Distant only

a(LF: Breast 3, Axilla 5, Supraclavicular 7) (WF: Breast 1, Axilla 1, Supraclavicular 1)

3 } 4

In 45 cases diagnosed as infiltrating duct carcinoma there was an extensive intraduct component, a definition used when the microinvasive portion involved less than 25% of the tumour area. Included in the 45 cases were three cases of pure intraductal carcinoma but for convenience they have not been separated. Lymphatic invasion (as defined in this paper), was noted in 81 of the 708 (11%) and vascular invasion in only 24 (3%) of cases.

C U R R E N T STATUS Of the 708 patients, 633 (89%) are alive at January 1989, six years after the first randomization, with 62 (9%) having died of breast carcinoma and 13 (2%) dying from other causes.

Local/Regional Control First relapse at a site was counted if it was the first event prior to distant metastases or occurred simultaneously with distant metastases.

In the LF group, a total of 30 patients (8.0%) developed recurrent disease in the breast (including simultaneous recurrences in the axilla or supraclavicular fossa, but without distant metastases). One patient had breast recurrence with simultaneous distant metastases. Of the 30 patients that recurred without metastases, 20 were ductal carcinomas, of whom 15 (75%) recurred within the treated quadrant. Nine of the 30 patients had 'lobular' carcinomas, and of these three recurred only within the treated area, three outside the treated area and three had recurrent disease both within and outside the treated area. Thirteen patients (4.0%) in the WF group had breast recurrences only and a further two patients had a breast recurrence with simultaneous distant metastases. With regard to the ipsilateral axilla, in the LF group, 50 patients (14%) ultimately developed axiUary recurrence with or without distant metastases, compared to 14 patients (4%) in the WF group. Fig. 1 shows the actuarial curves for breast recurrent-free survival projected out to 5 years. From these curves, the WF group would have a 94% breast recurrence-free survival compared with 87% in the LF group. These curves do not allow for the differences in the lobular and ductal groups outlined above. Fig. 2 similarly shows the actuarial curves for axillary recurrence-free survival. The projected figures for 5 years are 95% for the WF group versus 86% for the LF group.

Carcinoma of the Breast

31

40 ~

recurrences are looked at from the histopathological point of view, than it will be seen from Table 4 that 20% of the primary tumours with a 'lobular' component treated within the LF group recurred. On the other hand, lobular carcinomas treated in the WF group (whole breast) had a 7% recurrence rate which was significantly less. The lobular carcinomas were responsible for approximately half the significant difference in breast recurrences between the two groups.

20.

Table 4. 46 Breast recurrences: histopathology

I00

• i---

7 .....................

~_~

L_ LF

80ffl £. 0

60-

> > c_ CO

Type

p=O.O05 i

i

i

i

t2

24

36 Months

48

60

LF 304 33t

2t8 245

148 156

82 7g

33 30

WF

~ g . 1. Actuarial survival freeofbreastrecurrence.

100"

~......... ~IF -

-

I

u LF 80, O3 o

Infilt. Duct Ca. Infilt. Lobular Ca. Infilt, Duct + Lobular Mucoid Extensive Duct Ca, in situ

LF Group

WF Group

No. Total % Rec. Treated

% No. Total Rec. Treated

17 8 3 1

258 38 15 10

8 2 1 0

263 29 13 11

3 5 8 0

2

24

8.0 3

21

14

6.5 21.0 20.0 10.0

Of the 26 infiltrating duct carcinomas that recurred, only three cases were classified as Grade 1 tumours, the remainder being Grade 2 or 3. Lymphatic and vascular invasion were so rare in this series, that it was not possible to correlate these factors with local recurrence.

60-

> > c O~

Treatment for Recurrent Disease

40

20-

p=o.oool --

L

1

1

L

12

24

36 Months

A8

6O

LF ~04 WF 331

218 245

148 ~56

82 7g

33 30

Fig. 2. Actuarial survival free of axillary recurrence.

Factors Affecting Local/Regional Recurrence The majority of breast recurrences (56%) occurred in patients less than 50 years of age. Of the 46 patients who developed recurrent disease in the breast, the primary tumour had been reported as being totally excised histologically in 34 (74%) cases, incompletely excised in seven cases and no data were available for five cases. On the present data, there was no evidence to suggest that the larger primary tumours were more likely to recur than the smaller tumours. If the 46 cases that ultimately developed breast

Of the 31 patients in the LF group who developed recurrent disease in the breast, 20 were able to have a mastectomy, and six a further wide excision, the remainder being treated by systemic therapy only. Of the 20 patients subjected to mastectomy 13 are alive with no clinical evidence of disease, but the remainder have developed metastases. Of the six patients who had a wide excision, two had lobular carcinomas and developed a second recurrence but are now well following mastectomy. In the WF group, nine of the 15 patients recurrent in the breast had a mastectomy and one a further excision. The remainder were treated by systemic therapy. In the LF group 28 patients had an axillary dissection only, without further surgery on the breast. The node histology was positive in all cases, and 22 of the 28 patients had radical radiotherapy to the axillary area, without any overlap into the previous treated area in the breast. The majority of these patients were also prescribed tamoxifen or cytotoxic drugs as indicated. As yet none of these patients has subsequently developed arm oedema or further disease in the axilla.

32

G.G. Ribeiro et al.

Survival The actuarial survival for the whole series of 708 patients in 83% at six years from the inception of the trial. Fig. 3 shows the survival of patients with respect to the clinical size of the primary tumour. The actuarial survival at 5 years for patients with primary tumours equal to or less than 1 cm in diameter is 92%, versus 76% for those with primary tumours greater than 2 cm in diameter. This difference is statistically significant (P=0.003). Similarly Fig. 4 shows the actuarial survival of tOO ~r~.......h ,

L__

80-

A

k

f._ 0

>

60-

> [_ U)

40-

A

20-

2 c m

p=O.003 i

A o a

i

i

12

24

36 Months

99 337 235

77 253 i73

55 169 120

I

i

48

60

29 97 62

~4 38 22

Fig. 3. Survivalby clinical size of primary carcinoma.

t00

I___

L__E_

-

' .......

~

0

I. . . . . . .

> > f._

I I

zx < = C c m o I. C-2cm [] > 2 c ~

p=O.O03 t

~.2

I

i

24

36

i

i

48

60

25 64 22

B 32 ~

Months

67 234 89

It was exceptional for any patient to develop moist desquamation but the patients in the WF group had a marked reaction around the nipple and areolar region, causing considerable discomfort. By the use of wedged fields this problem has been alleviated completely. Again in the WF group the scar area developed telangiectasia due to the addition of bolus material. The use of bolus material has now been stopped. Ten patients developed breast oedema (three in the LF group and seven in the WF group). The oedema usually settled within 6 months and in all cases within 12 months. Nine patients were found to have spontaneous rib fractures (four in the LF group and five in the WF group). Three patients developed symptomatic pneumonitis (all in the WF group). These cases occurred early in the study and no further cases have been reported. Twelve cases of fat necrosis have been noted (10 in the LF group and 2 in the WF group). Of the twelve cases, five have been proven by biopsy and the remainder clinically diagnosed; the latter have been watched carefully and the lesions have shown no progression.

52 175 62

36 1t6 43

DISCUSSION

[]

60

40

Side-Effects

L ........

BO03 [.0

patients compared to the pathological measurement of the primary tumour which was available in 409 of the patients. At 5 years, 98% of the patients with tumours 1 cm or less in diameter are alive compared to 74% of those with tumours greater than 2 cm in diameter (P=0.003). There was no significant difference in survival when groups were compared by age, menopausal status, site of primary tumour and radiotherapy tumour dose.

Fig. 4. Survivalby pathological size of primary carcinoma.

This trial has shown that it is possible to achieve adequate control of small carcinomas of the breast (4 cm or less clinically) providing the primary tumour is totally excised histologically and radiotherapy is administered subsequently. The recurrence rate of 4.0% (6.0% actuarial at 5 years) for those patients that had wide field irradiation at 37 months median follow-up compares favourably with the 7.7% recurrence rate reported by Fisher et al. (1985a). While the NSABP (B-06) trial used the same eligibility of tumours 4 cm or less in diameter, all patients had a full axillary dissection and those with positive nodes received adjuvant chemotherapy. The median follow-up was 39 months. Gerard et al. (1985) reported a 4% breast relapse

Carcinoma of the Breast

in patients with tumours less than 3 cm; their patients also had a full axillary dissection, adjuvant chemotherapy for the node positive patients and an iridium implant boost to the primary site. Calle (1985) has described his experience in treating patients with tumours equal to or less than 3 cm, without axillary dissection. The patients had a lumpectomy and 5 weeks of radiotherapy with a further boost. The breast and/or axillary recurrence rate at 5 years was 8% and 14% at 10 years. Clark et al., (1982) have retrospectively analysed a series of 680 patients treated at the Princess Margaret Hospital in Toronto between 1958 and 1978, by means of excision without axillary dissection. The radiotherapy dose was 4000 cGy in 3 weeks with a boost to the primary site. The majority of the tumours were pathologically staged as T1 and T2. When the breast only was irradiated, the recurrence rate was 8.7% at 5 years. Only five patients developed a relapse remote from the primary site. With regard to the limited irradiation (LF) group, the breast recurrence was higher at 8.0% (13% actuarial at 5 years), approximately half of the increase being accounted for by the 20% recurrence rate for lobular carcinomas treated in this manner. The pattern of recurrence suggests that there may have been a 'geographical miss' in treating these multifocal tumours with limited field irradiation. This would explain the second recurrences which occurred after wide excision for recurrent turnout. Furthermore, the recurrence rate for lobular carcinomas treated by whole breast irradiation was 7%, which was significantly less than the 20% for limited field irradiation. Kurtz et al. (1989) have recently reported a series in which the recurrence rate of lobular carcinomas was higher than that of ductal carcinomas treated by whole breast irradiation (13.5% versus 8.8%), suggesting a degree of radioresistance in these tumours. As far as the invasive ductal carcinomas treated by limited field irradiation are concerned, 75% of the recurrences occurred within the treated quadrant of the breast. This suggests that all disease may not be adequately treated with the limited penetration of electron therapy. Holland et al. (1985) studying mastectomy specimens, found that 43% of specimens contained tumour loci more than 2 cm from the primary tumour and that 27% of these foci were histologically invasive. The relapse rate in the ipsilateral axilla at 6 years from the initial randomization is 14% for the LF group and 4% for the WF group (14% and 5% actuarial at 5 years). The patients in the LF group were able to have further treatment without significant morbidity. At present there is no statistically significant difference in distant recurrence-free or overall survival between the LF and WF groups.

33

The low relapse rate of 14% for the untreated axilla is of interest. In the NSABP (B-04) trial, Fisher et al. (1985b) reported that of 365 patients with clinical Stage I tumours who underwent total mastectomy without axillary dissection, 17.8% had positive nodes removed subsequently over a period of ten years with the majority (78.5%) occurring in the first 24 months. In the series of Gerard et al. (1985), axillary dissection at the time of primary surgery yielded positive nodes in 19% of cases, thus routine axillary dissection in patients with smaller carcinomas will be 'negative' in at least 80% of cases. It is not wise to make recommendations about techniques at this early stage. Very few problems have been encountered with the wide field technique. However, lobular carcinomas are probably best not treated by the limited field technique. The high rate of fat necrosis encountered in the LF group could probably be lessened by a reduction in the size of the fractions and longer overall treatment time; a three week schedule is currently being assessed.

APPENDIX Surgeons Participating in the Trial D. Allan, W. Allan, W. Bell, M. Brennan (retd), K. Buckler, J. Bancewicz, J. Curt, D. Cade, D. Cowley, M. Crumplin, G. Carr (retd), J. Done, K. Dickinson, M. Davies, J. Duthie, M. Duari, P. England, L. Forrest, E. N. Gleave, E. Hoare, B. Hancock, C. S. Humphreys, Professor M. Irving, G. Ingram, J. Kelly, R. Kingston, M. Lambert, W. Lawson, W. Lonsdale (retd), J. Lythgoe, H. Leighton-Davies, J. Laine, N. Maybury, I. McLennan, S. Meehan, B. Newmann, R. Nicholson, T. O'Brien, Professor R.Sellwood, A. Swithinbank (retd), W. Samarji, L. Turner (retd), R. Todd, R. Wilson, R. J. Williams, A. Watson, J. Yule (retd).

Radiotherapists Participating E. Allan, M. Duthie, D. Deakin, R. Gattameneni, N. Gupta, R. Hunter, B. Hancock, R. James, R. Pointon, D. Pearson (retd), G. Read, M. Sutton, R. Stout, A. Stewart, I. Todd (retd).

Medical Oncologist A. Howell.

34

References Bloom HJG, Richardson WW (1957). Histological grading and prognosis in breast carcinoma. British Journal of Cancer, 11, 359. CaUe R (1985). Experience with breast conserving approaches at the Curie Institute. In Primary Management of Breast Cancer: Alternatives to Mastectomy, eds. Tobias JS, Peckham MJ, p. 59. Edward Arnold, London. Cancer Research Campaign Working Party (1976). Management of 'early' cancer of the breast. Report on an international multicentre trial supported by the CRC. British Medical Journal, i, 1035. Clark RM, Wilkinson RH, Mohoney LJ, Reid JG, MacDonald WD et al. (1982). Breast Cancer: A 21-year experience with conservative surgery and radiation. International Journal of Radiation Oncology, Biology, Physics, 8, 967. Fisher B, Bauer M, Margolese R, Poisson R, Pilch Y, Redmond C et al. (1985a). Five-year results of a randomised clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. New England Journal of Medicine, 312, 665. Fisher B, Redmond C, Fisher E, Bauer M, Wolmark N, Wickerham DL, et al. (1985b) Ten-year results of a randornised clinical trial comparing radical mastectomy and total mastectomy with or without radiation. New England Journal of Medicine, 312, 674. Fisher ER, Sass R, Fisher B, Gregorio R, Brown R, Wickerham Let al. (1986). Pathologic findings from the National Surgical

G . G . Ribeiro et al. Adjuvant Breast Project (protocol 6): 11. Relation of local breast recurrence to multicentricity. Cancer, 57, 1717. Gerard JP, Montbarbon JF, Chassard JL, Romestaing P, Ardiet JM, Delaroche G e t al. (1985). Conservative treatment of early carcinoma of the breast: significance of axillary dissection and iridium implant implant. Radiotherapy and Oncolog),, 3, 17. HeUman S, Harris JR, Levene MB (1980). Radiation therapy of early cancer of the breast without mastectomy. Cancer, 46,988. Holland R, Veiling SH_J, Mravunac M, Hendriks JHCL (1985). Histologic multifocality of T1S, T1-T2 Breast carcinomasimplications for clinical trials of breast conserving surgery. Cancer, 56, 979. Hospital Physicists' Association (1985). Code of practice for electron beam dosimetry in radiotherapy. Physics and Medicine in Biology, 30, 1169. Howat JMT, Barnes DM, Harris M, Swindell R (1983). The association of cytosol oestrogen and progesterone receptors with histologicalfeatures of breast cancer and early recurrence of disease. British Journal of Cancer, 47, 629. Kurtz JM, Spitalier JM, Arnalric R (1983). Late breast recurrence after himpectomy and irradiation. International Journal of Radiation Oncology, Biology, Physics, 9, 1191. Kurtz JM, Jacqumier J, Torhorst J, Spitalier JM, Amalric R, Hunig R et al. (1989). Conservation therapy for breast cancers other than infiltrating duct carcinomas. Cancer, 63, 1630. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. (1977). Design and analysis of randomised clinical trials requiring prolonged observation of each patient. 11 Analysis and examples. British Journal of Cancer, 35, 1. Received for publication 25.7.89 Accepted 17.8.89