MANCHESTER REGIONAL BREAST STUDY
Preliminary Results J. P. LYTHGOE Department of Surgery, Sharoe Green Hospital, Preston IAN LECK
Regional Cancer Epidemiology Unit, Christie Hospital and Holt Radium Institute, Manchester
with early breast cancer treated between March, 1970, and
October, 1975, according to a prospective clinical trial. The results have been recorded after a follow-up of two to seven
of clinical stage-I
randomly allocated to treatment by simple mastectomy and postoperative radiotherapy, or simple mastectomy alone. There was no statistically significant difference in overall survival or in survival without distant metastases between the two groups. There was a significant reduction in the incidence of local recurrence in those who had received early postoperative radiotherapy compared with those who had not. 307 cases of clinical stage-II cancer were randomly allocated to treatment by simple mastectomy and postoperative radiotherapy or radical mastectomy alone. There was no statistically significant difference in survival or in the incidence of local recurrence or distant metastases between the two groups.
by simple mastectomy and early postoperative radiotherapy to the chest wall and regional lymphnodes. However, in many of these, mastectomy alone
might have been adequate; there has also been evidence suggesting that radiotherapy to non-invaded lymphnodes might adversely affect the prognosis by interfering with immunological defence mechanisms.1.2 In order to find out whether routine postoperative radiotherapy to beneficial, useless,
harmful, we and compared simple mastectomy early postoperative radiotherapy versus simple mastectomy only (but further treatment was given for recurrence or when metastases became apparent). is
Most surgeons believe that some treatment should be directed at palpable axillary nodes (clinical stage u). We have compared the two most commonly employed treatments, namely simple mastectomy plus early postoperative radiotherapy and radical mastectomy alone.
Patients and Methods of breast carcinoma in clinical stagei (T,_2, No, Mo) stage n (Tl-2, N,, Mo) as defined in the original TNM classification3 were accepted for the trial except for paAll
with severe intercurrent disease. Apart from a chest X-ray to exclude pulmonary metastases, staging was by clinical examination alone. Patients were randomly allocated, with stratification by surgeon, to one or other of the treatment groups under comparison. Simple mastectomy was defined as removal of the whole breast including the pectoral fascia but without intentional removal of any axillary node; thin skin flaps were to be avoided and transverse incisions preferred. Radical mastectomy consisted of removal of the whole breast with dissection of the axillary nodes; removal of the pectoral muscles was left to the discretion of the individual surgeon. Postoperative radiotherapy was given by one of two tech-
niques : 1. Quadrate Technique This includes 3 fields
tangent to the chest
wall, which irradiate the chest wall, parasternal region and axilla; there is also a field to the supraclavicular fossa and a posterior field to the apex of the axilla mated dose 3700 rads in three weeks).
2. Peripheral and Tangent Pair Technique (a) Single megavoltage (4 MV) field consists of irradiating the parasternal, supraclavicular, and axillary regions from the front (given dose 4000 rads in three weeks). (b) Parallel pair of fields to the chest wall, 300 kV (middose 3000 rads in three weeks; maximum dose to skin 3800-4500 rads). All patients who were premenopausal or less than three years postmenopausal were offered induction of an artificial menopause by X-ray or surgical castration. The former was carried out by low-dose irradiation to the ovaries by a parallel pair of fields (megavoltage therapy, mid-pelvic dose 500 rads,
THE management of early breast cancer is a controversial subject and the relative merits of different methods of treatment can be assessed only by large prospective clinical trials. In 1969, the Manchester Regional Association of Surgeons, which includes the general surgeons and radiotherapists working in hospitals of the former Manchester Regional Hospital Board and United Manchester Hospitals, initiated such a trial. Patients with clinical stage-i tumours are commonly
aged over 70 years, those pregnant or lactating, males, patients who would not be available for follow-up, those who had previously had cancer of the opposite breast, and those tients
Patients were followed up at intervals of not more than three months for the first two years, and at intervals of not more than six months for the next three years. Thereafter follow-up was at annual intervals. Patients who had evidence of recurrence or metastases were treated according to their individual problem. Surgeons supplied initial information about all patients and the data forms were sent to the Regional Cancer Epidemiology Unit, Christie Hospital, where annual follow-up reports were assembled. Data were analysed by the computer to produce time-based curves of total survival, survival without distant metastases, and survival with no local recurrence or metastases, computed by actuarial methods for various groups of patients and examined by the log-rank test4 for significant differences in outcome between groups. 1020 cases (713 stage i and 307 stage n) were admitted to the trial between March, 1970, and October, 1975.
Results 354 stage-i patients had simple mastectomy with radiotherapy, and 359 simple mastectomy only. 159 stage-n patients had simple mastectomy with radiotherapy and 148 radical mastectomy only. Table i shows that stage-ii patients were on average about 1 Zyears older than those in stage i, but within each stage the agedifference between treatment groups was negligible. In the groups not given postoperative radiotherapy, fewer women who were premenopausal or less than three years postmenopausal were sterilised; but these groups included fewer cases in which the stage specified on entry to the study differed from that indicated by the clinical findings, or in which either an error or a decision by the clinician or patient had led to a departure from the treatment plan allocated. The proportion of cases in-
volving discrepancies between notified
and actual clinibetween allocated and actual treatment, was 12% for each treatment group in the stage-i trial and 11 % for each in the stage-n trial. Follow-up data for one or more years were available for 688 of the 713 entries in the stage-i trial, and for 300 of the 307 in the stage-n trial. Table n shows the standard life-table probabilities for three kinds of favourable outcome (total survival, survival with no metastases outside the axillary and supraclavicular lymph nodes and chest wall, and survival without any recognised metastasis or recurrence) at one, three and five years. The lower half of table ii gives the probabilities after exclusion of the cases in which there was known to have been a departure from the study protocol. cal stage,
The survival for all cases (classified by stage reported and treatment allocated at entry) and the survival for only those in whom the protocol was strictly adhered to are in general very similar. In the rest of this paper we refer to the results obtained for the entire group as they were staged and allocated treatment at entry-these results are perhaps a better guide to what is likely to be achieved in ordinary practice (where aberrations of staging and treatment are also bound to occur). There were no significant differences in outcome between groups in the trial involving stage-it patients. The two groups with stage-i disease did equally well in terms of total survival and survival with no distant metastases, but those who received radiotherapy did significantly better in terms of survival without recurrence
TABLE I-GROUPS OF PATIENTS IN TRIAL
TABLE II-SURVIVAL RATES
*Estimated by actuarial methods. tSignificance of overall difference in frequency of death/recurrence, assessed by log-rank method with continuity correction.
(see also figs 1 and 2), indicating that recurrence in the chest wall or axillary or supraclavicular nodes during the first few years after treatment was less common in those given prophylactic radiotherapy. or metastases
LENGTH OF FOLLOW-UP
TABLE III--SURVIVAL WITHOUT RECURRENCE IN CASES ENTERED
RELATED TO CLINICAL CONDITION ON ENTRY AND TREATMENT ALLOCATED
Fig. I-Survival curves for all cases entered as stage I. Continuous line--simple mastectomy without radiotherapy. Broken line--simple mastectomy with radiotherapy.
(table in). Stage-i cases with neoplasms in the midline of the breast did no better with radiotherapy than without. The protection given by radiotherapy was greater and significant when neoplasms were more than 2 cm in diameter and when patients were premenopausal. The striking differences in the five-year survival between radiated or non-irradiated patients among those seen within three years after the menopause and those with midline tumours (table n) are probably due to chance since the results are based on very small numbers. recurrence
LENGTH OF FOLLOW- UP
Fig. 2-Survival curves for all cases entered as stage II. Continuous line-radical mastectomy without radiotherapy Broken line--simple mastectomy with radiotherapy. We explored the possibility of using clinical criteria such as site and size of neoplasm or menopausal status of patient to identify those stage-i patients whom radiotherapy is particularly likely to protect against local
preliminary results are based on a maximum follow-up period of less than seven years-the mean duration of follow-up is around three years and the number of patients followed for more than five years is small. The trends revealed in this study may be reversed when more patients have been followed-up for a longer period; firm conclusions cannot be drawn until the five and ten year survival figures for the entire series are These
available. Nevertheless, there is nothing in our study to support the contention of Bondl and Stjernswardzthat
early postoperative radiotherapy may be harmful. The only statistically significant difference revealed in either trial is the reduced incidence of local recurrence in those stage-i cases who received early postoperative radiotherapy. Similar findings were obtained in the Cancer Research Campaign Trials an international multicentre trial which took place concurrently with the present study. There is no evidence so far that patients whose radiotherapy is delayed until local recurrence is detected will fare worse in terms of survival than those whose recurrence has been prevented by early radiotherapy. Occult residual tumour in the operation field or regional nodes may be a source of metastases during the
interval between surgery and delayed radiotherapy. If this is so it should be reflected in the long-term survival figures. Radiotherapy was better able to prevent local recurrence of the laterally and medially placed tumours than that of those in the midline of the breast. This is
partly because laterally placed tumours are more likely to give rise to axillary node metastases which can be detected at follow-up. Also, the possibility of incomplete removal is greater with peripheral tumours since they are likely to be excised with a smaller margin of surrounding normal tissue than central ones. Similarly, radiotherapy had a larger influence in preventing recurrence of larger tumours probably because the more advanced carcinomas would be more likely to have spread to lymph-nodes and less likely to have been adequately removed by local mastectomy. The induction of an artificial menopause was offered to patients who were premenopausal or less than three years postmenopausal because a previous trial had indicated that it produced a slight improvement in the reduction in the incidence of was unjustifiable to withhold this possible benefit from all patients although we appreciated that sterilisation would not be acceptable or considered appropriate in every case. We admit that the non-random way in which some patients did not have artificial induction of the menopause might introduce a slight bias to the results. However, it is now believed that the benefit of an artificial menopause is temporary -it delays but does not prevent recurrence or death in those who are destined to die.7 The long-term survival figures are thus unlikely to be influenced by induced menopause. Table n indicates that our results have not been significantly affected by the small number of patients who did not have an artificial menopause. Our study supports the now widely held view that there is little to choose between different methods of conventional treatment by surgery and/or radiotherapy. Postoperative radiotherapy for patients presenting in stage I can safely be delayed until they have evidence of local recurrence or lymph-node metastases. Simple mastectomy with postoperative radiotherapy or radical mastectomy alone are equally effective for treating stage-ii patients-the former is more time-consuming and expensive and the patient may have the unpleasant immediate sequelae of radiotherapy, but the latter produces greater disfigurement. The choice would depend on individual circumstances and preferences of the patient and surgeon. Surgery and/or radiotherapy may control the local survival
recurrence.6 We felt that it
manifestation of breast cancer but the survival rate depends on the presence or absence of distant metastases and on host resistance. Any improvement on the present results can only be expected from adjuvant systemic therapy of which numerous regimens are being studied. The members of the committee which organised the trial were: Prof. M. R. Alderson (until 1970), Mr A. R. Anscombe, Dr R. Gibb, Mr A. W. Hargreaves (since 1975), Mr N. F. Kirkman, Dr 1. Leck (since 1970), Mr. M. Lentin, Mr J. P. Lythgoe, Dr I. D. H. Todd. Surgeons taking part in the trial were: Mr A. R. Anscombe, Mr M. A. Brennan, Mr A. S. Bullough, Mr H. J. Done, Mr H. M. Goldberg, Mr A. W. Hargreaves, Mr H. Hassall, Mr E. Henderson, Mr G. Ingram, Mr N. C. Keddie, Mr J. H. Kilshaw, Mr N. F. Kirkman, Mr D. K. Lennox, Mr M. Lentin, Mr W. H. Lonsdale, Mr J. P. Lythgoe, Mr J. Magell, Mr J. W. Main, Mr N. Macdonald, Mr A. F. Robinson, Mr J. Y. W. Russell, Mr 1. G. Schraibman, Mr H. F. Smith, Mr W. A. B. Strachan, Mr J. Wilks, Mr A. F. Williams. Radiotherapists taking part in the trial were: Dr J. R. Brown, Dr M. P. Cole, Dr D. P. Deakin, Dr M. B. Duthie, Prof. E. C. Easson, Dr R. Gibb, Dr N. K. Gupta, Dr A. W. Jackson, Dr D. M. Jackson, Dr I. J. Kerby, Dr D. Pearson, Dr R. S. Pointon, Dr G. G. Ribeiro, Dr E. Sherrah-Davis, Dr J. G. Stewart (who has since died), Dr M. L. Sutton, Dr I. D. H. Todd. The study was supported by a grant from the Manchester Regional Hospital Board.
Bond, W. H. in The Treatment of Carcinoma of the Breast (edited by A. S. Jarrett); p. 24. Amsterdam, 1968. 2. Stjernsward, J. Lancet, 1974, ii, 1285. 3. T.N.M. Classification of Malignant Tumours. U.I.C.C., Geneva, 1968. 4. Peto, R., Pike, M. C., Armitage, P., et al. Br. J. Cancer, 1977, 35, 1. 5. Working Party of the Cancer Research Campaign. Br. med. J. 1976, i, 1035. 6. Paterson, R., Russell, M. H. J. Fac. Radiol. 1959, 10, 130. 7. Cole, M. P. in The Clinical Management of Advanced Breast Cancer— Second Tenovus Workshop (edited by C. A. F. Joslin and E. N. Gleave); p. 2. Cardiff, 1970. 1.
PROTRUDING AURICLE: A NEUROMUSCULAR SIGN DAVID W. SMITH
Department of Pediatrics, University of Washington, Seattle, U.S.A. HIROTADA TAKASHIMA
Department of Pediatrics, University of Washington, and Nihon University, Japan A protruding auricle is usually associated with a defect in development or function of the posterior auricular muscle, which normally draws the pinna towards the calvarium. Hence, a protruding auricle may be a sign of a neuromuscular disorder, as is ptosis.
Introduction MUSCLE function can influence the shape of cartilage and bone’-for example, ear muscles may affect the shape of the external auricle.2 Man has three extrinsic ear muscles extending from the calvarium to the cartilaginous pinna and six intrinsic pinna muscles.3 The role of these muscles is evident from the hearing-related movements of the external ear in animals such as the dog or cat. Though such movements are seldom noticeable in man, Seiler3 demonstrated by electromyographic techniques that the human ear muscles are responsive to sound stimuli. We have studied the impact of ear mus-