DETECTION OF BREAST CARCINOMA METASTASES IN BONE: RELATIVE MERITS OF X-RAYS AND SKELETAL SCINTIGRAPHY

613

Occasional

Survey

DETECTION OF BREAST CARCINOMA METASTASES IN BONE: RELATIVE MERITS OF X-RAYS AND SKELETAL SCINTIGRAPHY DAVID J. PEREZ JONATHAN MILAN H. T. FORD JAMES S. MACDONALD

TREVOR J. POWLES J. C. GAZET V. RALPH MCCREADY R. CHARLES COOMBES

Medical Breast Unit, Department of Medicine, Institute of Cancer Research and Royal Marsden Hospital, Sutton, Surrey SM2 5PT; Departments of Nuclear Medicine and Diagnostic Radiology, Royal Marsden Hospital; Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital; Combined Breast Clinic, St. George’s Hospital, London

Of 1116 patients receiving primary treatfor breast carcinoma at the Royal Marsden Hospital since 1976, 651 had an abnormal bone scintigram either at primary diagnosis (378) or on subsequent follow-up (273) and 167 developed radiographically detectable bone metastases (21 at the time of primary diagnosis). Comparison of bone scintigrams and X-rays showed that scintigraphy was an inaccurate localiser of existing radiographic metastases and an inaccurate predictor of future radiographically detectable metastases. If X-rays alone are used to detect bone metastases a limited examination with five plates will detect metastases with 92% accuracy. After primary surgery, routine X-ray screening for bone metastases is not necessary since it is possible to identify patients at risk on the basis of clinical examination, chest X-ray, and serum alkaline phosphatase and &ggr;-glutamyl transpeptidase levels.

Summary

ment

INTRODUCTION

and bone scintigraphy are the most reliable of the biochemical and imaging techniques for the detection many of breast carcinoma metastases in bone. Bone scintigraphy is sensitive but relatively non-specific, whereas X-ray is specific but insensitive.2 Because of its sensitivity, bone scintigraphy has been used increasingly for the detection of early skeletal metastases3 and radiographic skeletal surveys are now used infrequently. It has been proposed that screening for early bone metastases can be achieved by bone scintigraphy, chest X-ray, and X-rays of the scintigraphically abnormal areas.4 The assumption underlying this approach is that scintigraphically normal bones do not contain metastases and therefore X-rays should only be used to

X-rays

34 Wilson JD, Sutherland DC, Thomas AC. Has the change to beta agonists combined with oral theophyllines increased cases of fatal asthma? Lancet 1981; i: 1235-37. 35. Napp Pharmaceuticals. Advertisement. Hospital Update 1980; 6: 1017. 36 Leitch AG, Morgan A, Ellis DA, Bell G, Haslett C, McHardy GJR. Effect of oral salbutamol and slow release aminophylline on exercise tolerance in chronic bronchitis. Thorax 1981; 36: 787 37 Eaton ML, Green BA, Church TR, McGowan T, Niewoehner DE. Efficacy of theophylline in "irreversible" airflow obstruction. Ann Intern Med 1980; 92: 758-61. 38 Eaton ML, McDonald FM, Church TR, Niewoehner DE. Effects of theophylline on breathlessness and exercise tolerance in patients with chronic airflow obstruction. Chest 1982; 82: 538-42. 39 Aubier M, De Troyer A, Sampson M, Macklem PT, Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981; 305: 249-52. 40. Moxham J, Miller J, Wiles CM, Newham D, Edwards RHT, Green M. Effects of aminophylline on human diaphragm and limb muscle contractility Thorax 1983; 38 232

exclude benign pathology or confirm metastases at the sites of increased uptake of isotope. To study this further we have reviewed the patterns of relapse in our patients with primary breast cancer. In particular we have analysed the scintigraphic and radiographic changes which occur in these patients in whom bone metastases develop to define better the advantages and limitations of these techniques.

METHODS 1116 women with primary breast cancer have been followed up by the Medical Breast Unit at the Royal Marsden Hospital between 1976 and 1982. Every 6 months or so after primary surgery patients underwent detailed physical examination, measurement of serum alkaline phosphatase and y-glutamyl transpeptidase, radiographic skeletal survey, and Tc-99m methylene diphosphonate bone 5 scintigraphy as previously described by Coombes et awl. skeletal lateral views of the skull, Radiographic surveys comprised cervical, thoracic and lumbar spines; anterior-posterior (A-P) views of the thoracic and lumbar spines, pelvis, humerii and femurs and a P-A view of the chest. Bone scintigram abnormalities were defined as any localised area of enhanced isotopic uptake and radiographic skeletal metastases were defined as areas of bone sclerosis or lysis which were not attributable to a benign cause. The diagnosis of bone relapse was strictly limited to radiographic evidence of metastases. X-ray and bone scintigram data were derived from routine reports provided by several observers. X-rays and scintigrams were reported separately to avoid bias. After primary surgery and before the appearance of overt metastases some of the patients studied received adjuvant drug therapy including aspirin, aminoglutethimide, and, in a few cases, combination cytotoxic

therapy. RESULTS

.

Of 1116 patients studied 651 had an abnormal scintigram at primary diagnosis or later in the follow-up period and 167 had radiographically confirmed bone metastases (table 1). 497 patients with abnormal scintigrams had skeletal surveys performed when the scintigram first became abnormal (table H) and 62 (12%) of these had concurrent radiographically detectable metastases. Where the scintigrams showed more than two hot spots the scintigram/X-ray correlation was 30%, but where the scintigram showed only one or two hot spots concurrent metastases were detected radiographically in only 3% and 10% of cases, respectively. 70% of patients in whom radiographic bone metastases had just developed (table Hi) TABLE 1-PRESENCE OR

SUBSEQUENT DEVELOPMENT OF METASTASES

AND/OR LOCAL RELAPSE FROM PRIMARY BREAST CANCER

*Only 165 had a skeletal survey and 148 had a bone scintigram at the time of radiological evidence of bone metastases. tOf these 651 patients only 497 had a modified radiographic skeletal survey at first the

time

the

scan was

first abnormal.

614 TABLE II-PRESENCE OF RADIOGRAPHIC BONE METASTASES WHEN BONE SCINTIGRAM WAS FIRST ABNORMAL

had more than two hot spots but 24% had only one or two hot spots and 6% had normal bone scintigrams. The accuracy of the scintigram in localising concurrent radiographic metastases is shown in table IV. 148 patients with metastases detected by radiography had concurrent bone scintigrams on TABLE III-NUMBER OF BONE SCINTIGRAM HOT SPOTS AT TIME OF RADIOGRAPHIC RELAPSE IN BONE

U

I

L

j

Years since primary diagnosis

Fig 1-Actuarial analysis of probability of remaining free of radiographic metastases in relation to bone scintigram findings at primary diagnosis. TABLE IV-COMPARISON* OF X-RAYS AND SCINTIGRAMS BY SITE IN

148 PATIENTS WITH I

*Total number

RADIOGRAPHIC BONE METASTASES I

of X-ray/scintigram comparisons

388.

or more occasions allowing 388 X-ray/scintigram comparisons. Although 84% of patients with thoracic spine metastases detectable on X-ray had concurrent thoracic spine hot spots, the correlation at other sites was not as good particularly in the skull (60%), pelvis (60%), and femurs (35%). Concordance of X-ray and bone scintigram was regarded as the presence of concurrent lesions anywhere within the bone in question rather than lesions at identical

one

anatomic sites. A bone scintigram is frequently used to detect bone metastases that are not yet evident on X-ray and this is particularly useful at primary diagnosis. Figs 1 and 2 present actuarial analyses of the probabilities of developing radiographic metastases after a positive scintigram at primary diagnosis or during follow-up. Because patient numbers after 3 years were limited we will confine our comments to the probability of radiographic metastases developing within 3 years of the scintigram becoming positive. Of 1116 patients screened at primary diagnosis 21 had radiological evidence of bone metastases. Of the remaining 1095 patients 378 had abnormal scintigrams but at 3 years only those patients with more than two hot spots had an increased incidence of radiographic metastases (fig 1). Thus the presence of one or two hot spots at primary diagnosis is of little prognostic importance. The appearance of more than two hot spots on the first abnormal scintigram occuring during follow-up is associated with an increased probability of radiographic metastases (fig 2). Even so, between 60% and 70% of patients with more than two hot spots on first abnormal scintigram will remain free of radiographic metastases for at least 3 years.

Years since positive bone-scintigram Fig 2-Actuarial analysis of probability of remaining free of radiographic metastases after an abnormal bone scintigram at any stage from primary diagnosis onwards. The limitations of bone scintigraphy in the diagnosis of early bone metastases prompted us to examine the usefulness of X-ray evidence of metastases. The pelvis and thoracic and lumbar spines are the major sites, of radiographically detectable bone relapse and, for the last two sites, lateral X-rays alone will detect 80% of metastases (table v). Similarly 80% of femoral metastases occur in the femoral head and neck regions and therefore will be detected on the pelvic X-ray. Several X-ray combinations and the reliability with which they detect radiographic relapse at any site are given in table VI. Compared with a 100% detection rate with a full skeletal survey (12 X-ray plates) the combination of pelvis, lateral thoracic spine, lumbar spine, skull and chest X-rays (5 plates) will detect 92% of all radiographically detectable metastases. Furthermore, it is unnecessary to perform skeletal X-rays on patients who are symptom free, who are normal on clinical examination, and who have a normal chest X-ray, alkaline phosphatase, and y-glutamyl transpeptidase level (table VII). All of the abnormalities listed in table vll are easily measured in out-patients and 95% of patients with radiographic metastases will demonstrate one or more of these

615 TABLE

V-FREQUENCY OF BONE RELAPSE BY X-RAY ANATOMIC SITE IN 99 PATIENTS

PLATE AND

TABLE VI-DETECTION OF INITIAL RADIOGRAPHIC RELAPSE IN BONE AT ANY SITE BY VARIOUS X-RAY COMBINATIONS IN

165 PATIENTS

167 PATIENTS AT 567 PATIENTS FREE OF METASTASES FOR AT LEAST 1 YEAR

TABLE VII-ABNORMALITIES PRESENT IN RADIOGRAPHIC RELAPSE IN BONE AND IN

*Not

histologically confirmed.

abnormalities. Conversely 33% of patients who are free of metastases for at least twelve months will exhibit one or more of these abnormalities during that period. Thus if these criteria are used to select patients for skeletal X-rays there will be a very low false-negative rate, and 67% of patients without radiographic metastases will be spared unnecessary X-rays. DISCUSSION

Bone metastases at distant sites are a major problem in patients wih breast carcinoma. More than 50% of these patients have bone metastases and 1007o have their metastases exclusively in bone. Bone scintigraphy is well recognised as a sensitive but non-specific detector of bone metastases. In this study 94% of patients with radiographic evidence of bone metastases had abnormal scintigrams. Conversely only 12% of patients with abnormal scintigrams had concurrent radiographically detected metastases and only 30% of the remaining patients developed radiographically detectable metastases in the following three years. The scintigram/X-ray

correlation will probably improve if scanning of bone by computerised tomography (CT) is more extensively used. CT scans detect metastases with far greater sensitivity than do orthodox X-rays.6 Another important aspect of bone scintigram interpretation when X-rays are normal is the relation between hot spots and the likelihood of future radiographic metastases. Galasko’ reported that all of 36 patients with advanced breast cancer and scintigraphic "metastases" but normal X-rays had radiographic or necropsy evidence of bone metastases within 18 months. This has not been confirmed in this study. At primary diagnosis patients with one or two hot spots have the same chance of skeletal metastases developing within 3 years as those with a normal scintigram. Those with more than two hot spots have an increased risk of 15-20%, but 70% of patients still remain free of radiographically detectable metastases after 3 years. A similar pattern is present for patients in whom an abnormal scintigram develops at any stage during follow-up. These results suggest that bone scintigraphy is a poor predictor of subsequent radiographically detectable relapse, but analysis beyond 3 years is needed to clarify this point. The predictive ability of bone scintigraphy might be improved if "benign" hot spots are excluded by concurrent X-rays but this information was deliberately excluded from the analysis so that bone scintigraphy could be assessed in its own right. However, a recent study of bone scintigraphy performed within 30 days of mastectomy used additional information from X-rays to classify patients as normal/probable benign bone disease or probable bone metastases and after a 30-month follow-up period the incidence of radiographic bone metastases in the two groups was not significantly different.8 Similarly the 5-year follow-up of the British Breast Group’s Study9 revealed a 50% incidence of radiographically detectable metastases at 5 years in patients whose bone scintigrams were regarded as "metastatic" at primary presentation and whose X-rays were normal. Because X-rays are less sensitive than scintigraphy in detecting bone metastases, X-rays are often restricted to those areas which are normal on the scintigram.4 The comparison of scintigraphy and X-rays by site in this study shows that scintigraphy is a poor localiser of metastases demonstrated on X-ray, particularly in the skull, pelvis, and femurs. Although bone scintigraphy has an established role in the detection of early bone metastases, particularly before primary surgery, it could be argued that the high falsepositive rate necessitating confirmatory X-rays and the imperfect localisation of bone metastases makes radiographic screening more appropriate for the assessment after surgery of most symptom-free patients. Generally the detection of very early bone metastases in the symptom-free patient is not of great therapeutic importance since drug therapy and radiotherapy are usually reserved for specific situations such as bone pain, progressive metastases, or hypercalcaemia. However, it is important to detect radiographically apparent metastases to assess the development of the disease and, if possible, prevent complications from spontaneous fractures.Most radiographically detectable metastases (92%) can be demonstrated with only five X-rays (chest, pelvis, lateral skull, and lateral thoracic and lumbar spines). Although the ideal screen for breast carcinoma bone metastases includes a full skeletal survey and bone scintigram, the cost of both tests is difficult to justify. The costs of bone scintigraphy and full skeletal survey are similar (within and outside the National Health Service) and the use

616 Grebbell FS. The radiologic demonstration of osseous Clin Radiol 1967; 18: 158-62. 3. Bone scanning in breast cancer. Preliminary statement by British Breast Group on bone scanning Br Med J 1978; ii: 180-81. 4. Roberts JG, Gravelle IH, Baum M, Bligh AS, Leach KG, Hughes LE. Evaluation of radiography and isotopic scintigraphy for detecting skeletal metastases in breast cancer. Lancet 1976; i: 237-39. 5. Coombes RC, Abbott M, Ford HT, et al. Physical tests for distant metastases in patients with breast cancer. J Roy Soc Med 1980; 73: 617-23 6. Muindi J, Coombes RC, Powles TJ, Golding S, Husband J. The role of computed tomography in the detection of bone metastases in breast cancer patients. Br J Radiol 1983; 56: 233-36. 7. Galasko CSB. Skeletal metastases and mammary cancer. Ann Rov Coll Surg Eng 1972, 50: 3-28. 8. Rossing N, Munck O, Nielsen SP, Andersen KW. What do early bone scans tell about breast cancer patients? Eur J Cancer Clin Oncol 1982; 18: 629-36. 9. Roberts MM, Hayward JL. Bone scanning and early breast cancer: Five year follow-up. Lancet 1983; i: 997-98. 10 Coombes RC, Powles TJ, Gazet J-C, et al. Assessment of biochemical tests to screen for metastases in patients with breast cancer. Lancet 1980; i: 296-97. 11. Winchester PD, Sener SF, Khandekar JD, et al. Symptomatology as an indicator of recurrent or metastatic breast cancer. Cancer 1979; 43: 956-60. 12. Scanlon EF, Oviedo MA, Cunningham MP, et al. Preoperative and follow up procedures on patients with breast cancer. Cancer 1980; 46: 977-79. 13. Valagussa P, Tesoro Tess JD, Rossi A, Taneini G, Banfi A, Bonadonna G. Adjuvant CMF effect on site of first recurrence, and appropriate follow-up intervals, in operable breast cancer with positive axillary nodes. Breast Cancer Res Treat 1981, 1: 349-56.

of a limited skeletal survey is considerably cheaper than a bone scintigram plus confirmatory X-rays, when required. In addition the number of patients X-rayed can be reduced substantially if patients at risk are selected on the basis of the clinical criteria listed in table VII. The observation that simple clinical tests (history, physical examination, chest X-ray, alkaline phosphatase, and y-glutamyl transpeptidase) can identify patients with a high risk of metastases confirms previous reports from this unit.5,1O Reports that historytaking and physical examination alone will identify 78-96% of patients who have breast carcinoma metastases at any sitel-13 confirm the conclusion that extensive screening for breast carcinoma metastases is unnecessary. We acknowledge and thank our surgical and radiological colleagues at the Royal Marsden Hospital, Sutton who have collaborated with us on this project. Correspondence should be addressed to T. J. P., Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT.

2.

Edelstyn GA, Gillespie PJ, metastases

REFERENCES

Doyle FH. The detection of skeletal metastases from mammary carcinoma. A regional comparison between radiology and scintigraphy. Clin Radiol

I.Galasko CSB,

1972; 23: 295-97.

From

our

Correspondents

Cuba THE CUBAN EXPERIENCE

A remarkable conference in Havana at the beginning of July celebrated Cuba’s development of a national health service and offered other countries an example of what could be achieved. The conference was supported by WHO and attended by some 1500 participants from more than a hundred countries. The International Conference Centre provided simultaneous translation in four languages for plenary and working-group sessions; and at one of the social occasions the host was President Fidel Castro, who talked with those guests whose Spanish was adequate. The British HealthCare Export Council mounted an exhibition by 25 British

companies. The conference heard of the development and organisation of health services, the training of doctors and other personnel, and the trends in morbidity and mortality over the twenty-five years since the health system was established. The model for the Cuban service is basically that of the socialist countries of eastern Europe, but with emphasis on primary prevention by environmental control and personal protection. In particular the populace has been drawn into health education and environmental hygiene by means of an extensive network of public bodies established since the revolution. Important among them have been the committees for the Defence of the Revolution, which exist in each village and city block, the National Association of Small Farmers, the Cuban Women’s Organisation, and the trade unions. These bodies provide a large force of voluntary workers, who collect data for the health information system, ensure a high level of cover for immunisation and screening services, and support the health personnel in

encouraging public participation. The population of Cuba is just under 10 million. It has increased by some 10% in the past decade and by about a quarter since the revolution. The number of children under 14 years has fallen from 36% to 23% in that time and those over 65 have increased from 4 -3% to 7 - 4%. Thus the population rise is mainly attributable to declining mortality. The total number of practising physicians, which fell shortly after the revolution when some 1700 doctors left the country, has now nearly tripled to just under 17 000, giving a ratio of 1 doctor to just under 600 of population-a remarkable figure for the Third World. Health care is based on a system of polyclinics and hospitals. An early priority was a more even distribution of resources throughout the country and most of the population now has a hospital nearby, while polyclinic coverage is comprehensive. Polyclinics provide

and specialist medical and dental care, plus nursing and environmental health services. The achievements have been remarkable. Malaria has been eliminated, deaths from tuberculosis have declined from well over 1000 a year to 100, diphtheria has been eliminated, and sexually transmitted disease is now rare. Infant mortality has declined from unknown levels of over 100 per 1000 live births to l7’3per 1000 in 1982, perinatal mortality is down to 21’8per 1000 births, and expectation of life at birth is 73’5 years. These figures compare favourably with those in the industrialised countries and indeed the residual Cuban health problems resemble those of Britain. For schoolchildren the leading causes of death are now accidents and malignant disease and for adults over 50 they are ischaemic heart disease and cancer. Thus, although this presentation of the Cuban experience was intended as an example to the Third World, the present problems of Cuba and the organisation of its services are of much interest to the developed countries. The Cubans have eschewed the medical auxiliary in favour of a service based on fully trained doctors and nurses whose training emphasises the importance of prevention and primary care, without prejudice to the need for referral to technologically specialised care for a minority of cases. An interesting development is the inclusion of pharmaceutical production within the health service and the limitation of pharmaceutical substances to about 700 preparations. Cancer and heart disease are being attacked by a programme of primary prevention, early detection, technologically advanced treatment, and services for occupational rehabilitation. Conversation with Cuban doctors gives the impression that they are proud of what they have achieved and also concious of the difficulties to be overcome if advance is to be maintained. They seem happy with their circumstances and give every impression of living a comfortable and rewarding life. They regret the isolation from US and British doctors imposed by the international political situation, but they have good relationships with doctors from eastern Europe and increasingly with those from the African countries with whom Cuba has close associations: Cuba now trains many doctors from African countries, a process facilitated by the accessibility of the Spanish language. An outstanding impression for a British visitor to Havana is the prime importance accorded to health in the system of Government priorities, as further demonstrated by the close involvement of President Castro in the conference proceedings and by the Government’s public commitment to diversification away from economic dependence on the production of sugar and tobacco.

primary

Round the World

.

Department of Epidemiology and Social Research, University of Manchester and University Hospital of South Manchester, Kinnaird Road, Manchester M20 9QL

ALWYN SMITH