Download - Cancer: The consequences of cure

Clinical Radiology (1988) 39, 166-172

Cancer: The Consequences of Cure* J. S. MALPAS

Imperial Cancer Research Fund Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London EC1

Previous lectures have dealt with new developments either in imaging or therapy, so it seemed that the theme could be continued, and I could perhaps look at the consequences of the remarkable improvements in the care of patients with cancer. Some of the most notable improvements in out look have of course occurred in childhood cancer, and it is in the young people who are now surviving into early adulthood that many problems may arise.

Although 'late effects', as they are now called, affect many children and even some adults treated for cancer, and are undoubtedly important to study, I do not wish to confine myself to an exhaustive account. It would take too long a time to give a comprehensive view of all that we now know about late effects. Furthermore, it could not be complete, for I suspect that there may yet be delayed effects in children and young adults whom we are following that have not yet declared themselves. Although these late effects are important, I would like to look at some of the consequences of curing these young people in terms of their relation to society and society's responsibility to them.

DISCUSSION

The term 'cure' in the title is used with a certain amount of trepidation. I think we all know what we mean by cure, but as Arthur Jones (1980) showed, the term may have a number of definitions. Many of us would mean that the life expectancy of the treated cancer patient is the same as 'normal ' life expec- t a n c y - i n other words, that it is the same as a matched cohort of the general population. This is now beginning to happen with some cancers, and is the reason why one is privileged to be able to talk about late effects, but some caution is necessary. Taylor and Potish (1985) in reviewing the survival of 341 children treated from 1953 to 1975, who had lived at least 5 years from diagnosis, noted that the survival rate of these patients did not parallel the general population, even after many years following completion of therapy (Fig. 1). The greatest number of deaths occurred due to late relapse some 6 years after initial treatment. The majority of all deaths occurred before 10 years had passed. However, deaths were still occurring as late as 22 years after treatment (Fig. 2). These results are very similar to those pre- sented by Li et al. (1978). To put these results into perspective, the number of deaths related to either treatment or disease after 10 years is in fact very small. It would seem possible, therefore, that we can justifiably use the term 'cure' in the vast majority of patients who are going eventually to survive and to die, as far as we know, from causes unrelated to the original disease. We

*The Skinner Lecture of the Royal College of Radiologists delivered in London, 21 November 1986.

have to be cautious, for late effects have only relatively recently been identified, and our information on them is necessarily incomplete. Many have not been anticipated. Do we know, for example, what the results of treating the myocardium of a 7-year-old with a power- fully cardiotoxic anthracycline will be when this young person reaches the age of 55?

Long survival may, therefore, put the patient with cancer at risk for being 'cured' , at risk for a late relapse (which as we have seen is unusual after 10 years), and at risk for a second turnout. Some consideration of second malignant neoplasms must be in order, for of all the consequences of long-term survival, this must be the most dreaded.

Meadows et al. (1985) in an update of the survey conducted by the twelve paediatric oncology centres in the United States and Western Europe, provide details of 292 children who developed cancer more than once. The commonest primary turnouts were retinoblastoma, Hodgkin's disease, soft tissue sarcoma and Wilrns' turnout. The commonest second turnouts were bone sarcomas, and these were associated with radiation. The commonest second malignancy not associated with radiation was leukaemia. Second malignant turnouts in children who have received neither radiotherapy nor chemotherapy were seen in retinoblastoma, neurofibromatosis and xeroderma pigmentosum. The risk of developing a second neoplasm is about ten times that of a comparable age-matched population. It is estimated that between three and 12% of children will develop a second malignant turnout up to 20 years after diagnosis of their primary. The questions we now have to ask are what factors influence the development of these second tumours, and what weight can be given to them? For example, whilst it would seem that the aetiology of second neoplasms in retinoblastoma is very likely to be genetic, with less risk from treatment modalities, the reverse may be true with Hodgkin's disease, in which the modality of t reatment employed and possibly the nature of the drug combination used is of relatively greater importance than any genetic pre-disposition. It could be thought that perhaps Wilms' tumour and soft tissue sarcomas may fall between these two poles in relative importance of genetic and treatment factors.

Only carefully documented accumulation of sufficient numbers of cases over a long period will enable us to get anywhere near to answers to these questions. Draper , Sanders and Kingston (1986) have provided an analysis that will enable us to approach the answer to these problems in retinoblastoma in a very remarkable study of 822 children with this turnout, notified in Great Bri- tain from 1962 to 1977. Three hundred and eighty-four of these children had the genetic form of the disease (Table 1). Thirty, second primary lesions were iden- tifed, and 26 of these occurred in the genetic disease group. There is a striking difference in the incidence of second malignant neoplasms in the genetic and non-

THE SKINNER LECTURE 167

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Fig. 1 - Survival of 341 children treated with chemotherapy and radiotherapy compared with an age-adjusted general population.

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T a b l e 1 - S e c o n d m a l i g n a n t n e o p l a s m s ( S M N ) in r e t i n o b l a s t o m a

Type of Chemo- Radiotherapy All retinoblastoma therapy (no

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(no chemotherapy)

Genetic 1/3 2/67 3/70 (4.0%) Non genetic 0/8 2/390 2/398 (0.5%)

After Draper et al., 1986.

genetic types of tumour treated with radiotherapy. Only two tumours were found in 100 children treated with radiotherapy who had the non-genetic form of the disease, and one was a neoplasm of the brain 31 years following treatment. On the other hand, 23 out of 314 patients with the genetic form of the disease developed a second malignant neoplasm. There is a progressive diminution in incidence from genetic,forms of the disease treated with radiotherapy through to the non-genetic treated without the use of radiotherapy. There are too few patients treated with chemotherapy for an effect to be discerned but this may eventually be possible.

Fortunately, most late effects will not be as catastrophic. Turning to the long-term morbidity

following treatment, there is now enough experience to be able to put certain long-term effects into perspective, and on occasions strange paradoxes may be seen.

Starting first with the local effects on growth: scoliosis, kyphosis, spinal shortening, susceptibility to fractures, and facial asymmetry have all been recorded in a wide variety of childhood tumours. Examples of scoliosis can vary from quite mild to moderately severe. In reviewing the late effects seen in 26 children with Wilms' tumour followed up for a median of 12 years 9 months, Thomas and his colleagues (1983) noted scoliosis in 14, and the distribution with regard to age in months and dose, when plotted and subjected to regres- sion analysis (Fig. 3), did not suggest that age or radiation dose were significant factors. Despite more than half having definite scoliosis, only three had any symp- toms, and these only after marked exercise. Tissue wast- ing and scoliosis may be quite prominent, especially in some children treated at the end of the 1960s, but relatively little effect is seen on the patients' well-being.

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Fig. 3 - Scoliosis as a function of vertebral dose and age (after Thomas, 1983). Age of patient (months) is shown in boxes. [] No scoliosis detected; ~ scoliosis.

The reverse may, however, be seen in the case of children who survive following treatment of Ewing's sarcoma of a limb. Here one is only concerned with the end results in terms of function. It would be quite understandable if our perception of the best outcome for a patient with a tumour of the arm or leg was survival with preservation of the limb. In an assessment of the long- term morbidity of 55 patients with Ewing's sarcoma who survived 2 years or longer, Lewis et al. (1977) found that while radiation for sarcomas in the arms was much bet- ter than amputation, the same could not always be said for the treatment of tumours arising in non-dispensable bones in the legs. Of the 18 with femoral lesions, nine had moderate or severe complications with atrophy, severe shortening, fractures, or pain. Two went on to secondary amputation. In 12 with mostly tibial prim- aries, five had moderate or severe disabilities. Amputa- tion may, therefore, in the long-term be justifiable, particularly in the lower limbs of young children where there are extensive lesions, or where pathological fractures have occurred. Although we should certainly aim at offering limb salvage in children and young adults, it is

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evident that a replacement prosthesis should not be used if the patient's survival is jeopardised by a risk of local recurrence. In an analysis of the psychological outcome of extremity sarcoma survivors, Weddington et al. (1985) showed no significant difference in 14 amputees and 19 patients with salvage limbs in terms of their affect, mood, body image, physical function and general adjustment, and they considered (rather surprisingly) that the psychological outcome advantage of having limb salvage surgery compared with amputation had yet to be demonstrated.

If we need to keep a sense of perspective and con- tinually to monitor the true impact on the patient of a particular consequence of his or her cure, we also need to be aware that not infrequently multiple defects, some of them not anticipated, may arise as a result of treatment. As an example of this, experience at St Bartholomew's Hospital Paediatric Oncology Unit with orbital rhabdomyosarcoma may be mentioned. Rhab- domyosarcomas are a quite common tumour of childhood, and chiefly present in the head and neck and the genito-urinary tract. Orbital rhabdomyosarcomas form about 25% of the head and neck presentations, and are noteworthy for the excellent results now being achieved in terms of survival. In joint studies with the Royal Marsden Hospital, we have looked after a total of 16 cases during the past 10 years, all of whom survive. Examining the subsequent progress of the children treated at St Bartholomew's Hospital for their current position with regard to sight, complications in the treated eye, and general effects, in those that have been more than 4 years out from presentation, one can see a pattern very similar to that reported by Heyn et al. (1986), reporting on the late effects in the orbital rhabdomyosarcoma study in children in 1986. In their study, 50 children treated on the Intergroup Rhabdomyosar- coma protocols between 1972 and 1978 have had a variety of infective problems in the orbit; in addition, more than 90% of 37 children showed cataract formation; structural changes have been seen both in the cornea and retina, but what is most disturbing is the deceleration in growth seen in 27 out of the 44 children. This was unexpected, although they speculated that it was possible that radiation of the pituitary might be responsible. As far as I know, they have not documented any studies of pituitary function. In a review of 20 children treated for rhabdomyosarcoma of the head and neck at the Children's Hospital in Philadelphia, Fromm et al. (1986) noted that five out of their 15 pre- pubertal patients developed growth failure, and were

able to document growth hormone deficiency which they thought was related to pituitary irradiation. These complications may therefore be of significance, and under l ine the need for these children to be seen regularly in clinics where auxology is carried out. A summary of late complications in children with orbital rhabdomyosarcoma is given in Table 2.

For example, one of the boys in our series showed an increasing reduction in growth velocity. He had pre- sented with a small tumour at the inner margin of the

Fig. 4 Rhabdomyosarcoma arising at the inner canthus of the right eye of a child.

Table 2 - Late complications in children with orbital rhabdomyosarcoma

Infections Chronic sinusitis, otitis media, orbital infection

Functional Decreased or absent vision (common) Keratoconjunctivitis Photophobia Dryness of eye

Structural Changes in cornea and retina Cataract Facial asymmetry Hypoplasia of orbit

Failure to grow Second malignancies Fig. 5 - End result of treatment of the rhabdomyosarcoma shown in

Fig. 4.


right eye (Fig. 4). He was treated with radiotherapy using a wedge pair of mega-voltage photon fields to the whole orbit, to a dose of 5000 cGy in 30 fractions over 45 days. He continued with adjuvant chemotherapy. The end result was excellent in terms of appearance (Fig. 5). Visual acuity is currently 6/9ths in the eye, with no evidence of cataract formation. However, as the chart shows (Fig. 6), there was evidence of delayed development, and on testing he was shown to have a deficiency of growth hormone. Administration of growth hormone has led to an increase in his growth velocity from 2 cm a year to 7 cm a year. It can be seen from the iso-dose curves of his treatment plan (Fig. 7) that his pituitary will have received some 80% of the tumour dose, and, undot/btedly, his hypothalamus also.

More recently, work in the Depar tment of Endocrinology at St Bartholomew's Hospital in con- junction with the Depar tment of Paediatric Oncology has shown that failure to grow may not simply be due to failure of growth hormone production, but rather to growth hormone releasing hormone• Growth hormone releasing hormone is produced in the hypothalamus and can be shown to stimulate the production of growth hormone in children who have previously been shown to have little response to insulin-induced hypoglycaemia. A study in children who have had cranial irradiation has shown that growth hormone releasing hormone may be effective in stimulating growth (Blacklay et al . , 1986). I

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have spent some time considering the long-term effects of treatment of orbital rhabdomyosarcoma because I th inki t has some important lessons for us. There is no doubt that survival in these children is excellent. The retention o f satisfactory sight, however, and the com- plicatioias that may arise must give cause for concern. Furthermore, hitherto unsuspected problems such as impairment of growth should make us look at our treatment programmes again. It is apparent, from what I have said, that we should now be attempting to quantify the disabilities produced by a particular form of therapy, and we should be analysing the probability of the occur- rence of late effects. Bauer et al. (1987) have recently shown in a statistical analysis of late effects of combined modalities, that the statistical tools are available to us. For example Fig. 8 shows a Kaplan Meier estimate of a cumulative proportion of severe pulmonary complications experienced after 3 months f rom the start of treatment for non-small cell lung cancer patients, i n 208 patients, 18 experienced severe pulmonary toxicity before 2 years. If 208 is used as a denominator , the incidence of late toxicity could be given as 8.6%, whereas plotting this out as what would appear to be an inverted Kaplan Meier chart, the true estimate is some 13.7%, or more than 50% higher. The curve enables the period at which most toxicity was experienced to be seen. There can be no doubt that estimates of the grade

170 CLINICAL RADIOLOGY

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and frequency of late effects will have to be embodied in treatment protocols in the future.

So far, in this very selective discussion of long-term effects of treatment, I have considered problems which while in the short-term may affect patients' integration with society, will not produce a major problem throughout the duration of their lives. The long-term effects of treatment on the central nervous system are very different. The introduction by Pinkel and his colleagues of prophylactic cranial irradiation for children with acute lymphoblastic leukaemia must be an out- standing landmark in the history of treatment of the disease (Pinkel, 1971). Initially, I think, some of us were concerned that the effect on growth might be quite marked, and that we might be seeing the initiation of a generation of stunted children as a result of the 2400 cGy irradiation. However, as many have shown, in the study by Griffin and Wadsworth (1980), the actual loss of height is relatively minimal. Much more significant, and probably controversial, is the effect that central nervous system irradiation has on cerebral function. Initial reports (for example Soni et al., 1975) sug- gested that there were no adverse effects of central nervous system (CNS) preventive therapy, but gra- dually both intellectual impairment and objective changes on histology, computed tomography (CT) neuroendocrine and neuropsychological abnormalities have been described. The work of Eiser (1978) in this country and Meadows et al. (1981) in the United States has demonstrated that defects, particularly in the younger children irradiated, can occur. One of the most convincing of these case control studies was by Moss et al. (1981) who found a 13 point difference in the intelligence quotient using the Wechsler intelligence test in children in a group of age-matched siblings (Table 3). Brouwers et al. (1985) considered that these differences are sufficient to result, in the long-term, in a significant lowering of potential. Certainly his study in memory impairment linked to objective changes in the brain, such as cortical atrophy or calcification, suggests a deficit in delayed recall (Fig. 9).

This and similar reports have prompted a survey of the achievements of children treated in the Paediatric Oncology Unit at St Bartholomew's Hospital, and I would like to present briefly the results of a pilot study

Table 3 - Late effects--neuropsychological sequelae

Mean Mean Mean full verbal performance scale [Q scale IQ scale 1Q

CNS treated 98.6 99.9 97.8 patients

Siblings 112.5 112.2 110.0 IQ difference -13.9" -12.3" -12.2"

*P value<0.00l level of significance. After Moss et al., 1981.

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Fig. 9 - Immediate (D) and delayed (N) memory impairment related to brain CT appearances in normal patients, those showing atrophy and those showing calcification in long-term survivors of acute lymphoblastic leukaemia (Poplack and Brouwers, 1986).

we have carried out (Allen and Malpas, 1988). We enquired of 100 adolescents and young adults who were currently over the age of 16, who were well and had ceased all therapy, about their achievements in education and at work. Eighty replies were received (Table 4). Only eight had achieved no qualification, and the range of certificates of secondary education (CSEs) ordinary (O) and advanced (A) levels of general certificates of education was very comparable to the general population of the same age. Checking with the data on English school-leavers in London and the South-East, the average number obtaining qualifications in 1985 (the latest available figures) was 83%, whilst in our children some 90% in the survey had been successful. Now I am sure these figures are not statistically significant, but it does indicate that in this group, at least, the educational achievements were not worse. Did those children who had received cranial irradiation for either teukaemia or lymphoma feature prominently in the poor achievers?

The achievements of the children in this study, who either had or did not have cranial irradiation, have been

Table 4 - Academic achievement of patients off treatment aged 16 or over

No. of questionnaires sent 100 Replies received 80 (80%) Without qualification 8 (10%) CSEs 26 (32.5%) GCE 'O' level 35 (43.75%) GCE 'A' level 8 (10%) Degrees 3 (3.75%)

After Allen and Malpas, 1988.


examined, and it has been found that 23 out of 26 (or 88%) of children who have had radiotherapy were successful in CSE, O and A levels, or in achieving a degree. Some 49 out of 53 children who did not have radiotherapy to the cranium had a similar spectrum of examination results, so that in this instance, 92% were successful (Table 5). This difference is not statistically significant. Currently a more comprehensive case control study is in progress. It does seem clear that the answer to the question seems to be that the group having radiotherapy did not appear to have a greater number of poor achievers, and that the end result, despite the undoubted demonstrat ion of some effect on intelligence quotient, is in practical terms highly encouraging. There should be no room for a pessimistic attitude, either by pupils, parents, teachers or society about the ability of these children to achieve.

Table 5 - Achievement in children who have had prophylactic cranial irradiation

Total No. Achieved % no. evaluable CSE 'O ' / 'A ' success

level, degree

Children who had 27 26 23 88 radiotherapy

Children who had 53 53 49 92 no radiotherapy


Educational achievement is not the only factor in a young person 's successful integration into society. Pro- blems relating to marriage, fertility, job-finding and insurance form a recurrent theme in our discussions with these young people in the adolescent clinic we have run for the last 4 years. I am quite convinced of the value of the adolescent follow-up clinic. It is absolutely vital if we are to know more about the effects of our t reatment , but it is also a great source of support to these young people, who are on the threshold of adult life.

The first question which may be asked in the clinic is about fertility. The effect of chemotherapy and particularly alkylating agents has been well documented. In boys, both pre-puberta l and pubertal , who have under- gone t rea tment with either MOPP or MVPP for Hodgkin 's disease, there is a high incidence of infer- tility. Donaldson and Kaplan (1982) repor ted that boys treated with the MOPP combination showed complete azoospermia when five boys were tested some 4 to 11 years after chemotherapy. In girls, on the other hand, 88% retained their menstrual periods, and 12 of these have had 13 pregnancies.

In our series of 80 children treated for Hodgkin ' s disease (Robinson et a l . , 1984), of the 80 who have been followed up for a median of nearly 5 years, four boys have been tested. Three were azoospermic, one after only three courses of chlorambucil VPP, and one is oligospermic. In girls with Hodgkin ' s disease, the outlook is less gloomy. Two girls in the series of Robin- son et a l . , each of whom had 10 courses of chlorambucil VPP, have subsequently had two normal offspring. Although our advice is for them to have their children early, we feel that we can encourage these young women that they will not only be able to have a baby, but that there is no significant increase in abortion, malforma-

tion or malignant disease in these babies. Apar t f rom families with ret inoblastoma and neurofibromatosis , there does not appear to be a higher risk for malignant disease in the progeny.

Although it was shown in a study by Holmes et al. (1986) that those who had been t reated for and who survived cancer were less likely to marry, nevertheless many do. American studies on their ability to obtain insurance are of interest. In Holmes ' s study, 100 patients were compared with 100 controls, and in most features were ident ical--age, education and annual income were comparable . It was understandable that the patients had lost a greater amount of t ime off work. When the patients are compared with controls, it can be seen that they have more difficulty in getting insurance, fewer were successful, and when they did get it, it was for less cover (Table 6). This does, of course, have a very significant bearing on the standard of living enjoyed by these patients.

I know of no comparable British study, and since most of our young adults over 16 years of age would not yet be involved in obtaining insurance, I decided to ask in a pilot study how well they were doing with regard to employment . Get t ing a job these days, for a school- leaver, is not easy. Care has to be taken to compare rates of employment with those obtained at the same time in the same area because of seasonal and regional variations.

Of the 76 of whom we have details, 42 were in full- time education, 29 were in full-time employment , and I certainly include the three mothers with babies in this latter group! (Table 7). Only two of our patients over 16 years of age were unemployed. Comparison with t h e national and regional norms looks encouraging, and we are particularly pleased that none of our 21 to 25-year- olds is currently unemployed (Table 8).

Table 6 - Availability of insurance for patients compared with controls

Patients Controls

Number having difficulty 44/98 2/98* obtaining insurance

Number obtaining 70/100 87/1007 insurance

Range of insurance 0-$250 000 0-$500 000 Mean sum assured $30 337 $48 815

*P=0.001; i-P=0.004. After Holmes et al., 1986.

Table 7 - Employment and education of patients off therapy aged 16 or over.

Full-time education 42 (55%) Full-time employment 29 (38%) Mothers with babies 3 (4%) Unemployed 2 (2%)

After Allen and Matpas, 1988.

Table 8 - Employment and education of patients off therapy aged 16 or over.

National average March and April 1986

London and South East March and April 1986

16+ off therapy, mostly London and South East

Follow-up at 21+ to 25+

School leavers unemployed 14% School leavers unemployed 9.8% Unemployed 3.9%

Unemployed 0%


172 CLINICAL RADIOLOGY

C O N C L U S I O N

There are some impor t an t lessons which I th ink should be drawn. However serious the in t e r rup t ion of their schooling, these chi ldren achieve norma l educat ional s tandards , and, despite the adverse reports on central nervous system funct ion , appear in practice to do as well as their peers. They do, therefore , deserve to be encouraged to succeed at school and later, an at t i tude that is not always shown by their teachers , who regard them with a mixture of fearfulness and indulgence. Fu r the rmore , for wha tever reason, earl ier matur i ty , earl ier close contact with the adult world, these young people achieve well in work and at universi ty. I believe they deserve be t te r of the publ ic services, various pro- fessions, and even the a rmed services, who f requent ly reject them out of hand. Now that there are large numbers of these youngsters en te r ing adu l thood (it has been es t imated, for example , that by 1990 one in every two thousand individuals aged 20 will be a cured chi ldhood cancer pa t ien t ) , it is a great responsibi l i ty to see that these young people in tegra te satisfactorily with society and that cure produces no adverse consequences .

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Allen, A & Malpas, JS (1988) Achievement in children surviving cancer. (In preparation).

Bauer, M, Diener-West, M & Cox, JD (1987). Sample size and duration of follow-up for estimating long-term complications in phase II clinical trials. Controlled Clinical Trials, in press.

Blacklay, A, Grossman, A, Ross, RJM, Savage, MO, Davies, PSW, Plowman, PN et al. (1986). Cranial irradiation for cerebral and nasopharyngeal tumours in children: evidence for the production of a hypothalamic defect in growth hormone release. Journal of Endocrinology, 108, 25-29.

Brouwers, P, Riccardi, R, Fedio, P & Poplack, DG (1985). Long-term neuropsychological sequelae of childhood leukaemia---correlation with CT brain scan abnormalities. Journal of Pediatrics, 106, 723- 730.

Donaldson, SS & Kaplan, HS (1982). Complications of treatment of Hodgkin's Disease in children. Cancer Treatment Reports', 66, 977- 989.

Draper, GJ, Sanders, BM & Kingston, JE (1986). Second primary neoplasms in patients with retinoblastoma. British Journal of Cancer, 53, 661-671.

Eiser, C (1978). Intellectual abilities among survivors of childhood

leukaemia as a function of CNS irradiation. Archive of Diseases in Childhood, 53, 391-395.

Fromm, M, Littman, P, Raney, RB, Nelson, L, Handler, S, Diamond, Get al. (1986). Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck. Cancer, 57, 2070-2076.

Griffin, NK & Wadsworth, J (1980). Effect of treatment of malignant disease on growth in children. Archive of Diseases in Childhood. 55, 600-603.

Heyn, R, Ragab, A, Raney, RB, Ruymann, F, Tefft, M, Lawrence, W et al. (1986). Late effects of therapy in orbital rhabdomyosarcoma in children. A report from the Intergroup Rhabd0myosarcoma Study. Cancer, 57, 1738-1743.

Holmes, GE, Baker, A, Hassanein, RS, Bovee, EC, Mulvihill, J J, Myers, MH et al. (1986). The availability of insurance to long-time survivors of childhood cancer. Cancer, 57, 190-193.

Jones, AE (1980). End-points in cancer therapy. Clinical Radiology, 31, 121-135.

Lewis, RJ, Marlove, RC & Rosen, G. (1977). Ewing's sarcoma: functional effects of radiation therapy. Journal of Bone and Joint Surgery, 59A, 325-331.

Li, FP, Myers, MH, Heise, HW & Jaffe, N (1978). The course of five year survivors of cancer in childhood. Journal of Pediatrics, 93, 185-187.

Meadows, A, Massari, D & Fergusson, J. (1981). Decline in IQ scores and cognitive dysfunctions in children with acute lymphocytic leukaemia treated with cranial irradiation. Lancet, i, 1015-1018.

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