- Email: [email protected]
SURVIVAL AND CAUSES OF DEATH IN THALASSAEMIA MAJOR
27
probably the case in about half the patients in whom EIC + is suspected after a limited resection (around 15% of all patients with infiltrating ductal carcinomas). On the other
SURVIVAL AND CAUSES OF DEATH IN THALASSAEMIA MAJOR
hand, an initial wide excision would mean overtreatment for
MARIA GRAZIA ZURLO PIERO DE STEFANO CATERINA BORGNA-PIGNATTI ANNUNZIATA DI PALMA ANTONIO PIGA CATERINA MELEVENDI FELICIA DI GREGORIO MARIA GABRIELLA BURATTINI SEVERINA TERZOLI
about 85 % of the patients not having a substantial amount of DCIS outside the invasive tumour. Extensive breast surgery can have an adverse effect on the cosmetic outcome. If we know the EIC status of a tumour, therefore, we may be able to limit the extent of breast resection. For EICtumours, limited breast resection plus radiotherapy offers good cosmetic results with low risk of local recurrence. By contrast, EIC + tumours must be widely excised to achieve negative margins of resection before radiotherapy. Another unresolved question concerns the management of a patient with an EIC + tumour after re-excision has shown that the margins are still involved. Some clinicians advocate mastectomy while others argue for high-dose radiotherapy (particularly if the patient is old or has positive nodes). The interrelation between age and EIC needs to be explored further. There are hints from the Paris data that EIC + tumours carry a better long-term prognosis than EIC- tumours. This suggestion needs to be examined by multivariate analysis and in data from other series. CONCLUSIONS
Epidemiological, clinicopathological,
and cell
biology
studies indicate that in-situ breast cancers represent a wide spectrum of diseases ranging from the indolent to the rapidly progressing. We need a uniform classification of these lesions whereby we can identify lesions with a high risk of progression. Such a classification would be helpful in the evaluation of prospective randomised trials of breast conserving treatment in patients with DCIS, by allowing results to be compared and also combined in overview analyses. The principal risk factor for breast relapse after breast conserving treatment is large residual burden, and the main source of this burden is an EIC, which is found adjacent to 10-15% of all invasive breast carcinomas. These EIC + tumours are difficult to identify. We still have much to learn about the merits of different surgical and radiotherapeutic techniques in terms of accurate information on cosmetic results and recurrence free survival. We also need to know the outcome in patients who have undergone salvage mastectomy after breast relapse. Correspondence and requests for copies of the abstract book of the meeting should be addressed to J. A. van Dongen, Department of Surgery, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. REFERENCES
SJ, Sadowsky NL, Conolly JL, Harris JR. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 1988; 318: 898-903. 2. Schnitt SJ, Conolly JL, Recht A, Silver B Harris JR. Breast relapse following radiation therapy for early breast cancer. II Detection, pathologic features and prognostic significance. Int J Rad Onc Biol Phys 1985; 11: 1277-84. 3. Carpenter R, Gibbs M, Matthews J, Cooke T. Importance of cellular DNA content in pre-malignant breast disease and pre-invasive carcinoma of the female breast. Br J Surg 1987; 74: 905-06. 4 Van de Vijver MJ, Peterse JL, Mooi WJ, Wiseman P, Lomans J, Dalesio O, Nusse R. Neu-protein overexpression in breast cancer: association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 1988, 319: 1239-45. 5. Nielsen M, Thomsen JL, Primdahl S, Dyreborg V, Andersen JA. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br J Cancer 1987, 56: 814-19 6 Ronay G, Tulusan AH. Bilaterality of invasive breast cancer. In: Bassler R, ed. Pathology of neoplastic and endocrine induced disease of the breast. Stuttgart: 1 Schnitt
Silen W,
Gustav Fisher, 1986 7 Fisher ER, Sass
R, Fisher B, Wickenham L, Paik SM. Pathologic findings from the National Surgical Adjuvant Breast Project. I Intraductal carcinoma Cancer 1986; 57: 197-208. 8 Bartelink H, Borger JH, Van Dongen JA, Peterse JL. The impact of tumor size and histology on local control after breast conserving treatment. Rad Oncol 1988; 11: 297-305
IRCCS "San Matteo", Pavia, Italy; Departments of Paediatrics of the Universities of Milan, Verona, Torino, Catania, and Bari; and Divisions of Paediatrics of Ospedale Galliera, Genova, and Ospedale Sant’ Anna, Ferrara
Survival and causes of death were studied in 1087 Italian patients with thalassaemia major who were born on or after Jan 1, 1960. At the age of 15 years, the Kaplan-Meier estimate of survival after the first decade of life was 80·6% for subjects born in 1960-64, 84·2% for those born in 1965-69, and 96·9% for those born in 1970-74. At the age of 20 years, survival from the age of 10 was 59·1% for patients born in 1960-64, and 70·2% for those born in 1965-69; at 25 years, survival from the age of 10 was 40·7% in the 1960-64 cohort. Overall survival from birth for patients born in 1970-74 was 97·4% at 10 years, and 94·4% at 15 years. The most common cause of death was heart disease, followed by infection, liver disease, and
Summary
malignancy. INTRODUCTION
THE reported survival of patients with thalassaemia major has been disappointing. In 1982, Economidou’ found that the mortality of 441 Greek patients with thalassaemia major and intermedia was similar to that of the general population up to the age of 6 years, but increased gradually thereafter so that only 24% were alive at 28 years. Modell et al2 reported 25% survival at the age of 25 years for 92 patients with thalassaemia major born in or before 1963. However, the management of patients with thalassaemia major has changed during the last fifteen years. In Italy, treatment with intramuscular desferrioxamine has been available for most patients since 1975, and regular subcutaneous desferrioxamine infusion was started between 1979 and 1981. Over the same period, transfusion policy for these patients has been changed from correction of anaemia only when it was severe enough to cause symptoms, to "hypertransfusion" and "supertransfusion" regimens intended to maintain haemoglobin levels at or above 9-10 g/dl and 12 g/dl, respectively. Have these changes in management been associated with improved survival? PATIENTS AND METHODS
Details of patients with thalassaemia major who were born on or after Jan 1, 1960, were obtained from seven Italian teaching hospitals. All patients were eligible for inclusion in the study if they were alive at the time when, at each centre, clinical records were complete and reliable. Full data were available since 1965 for two centres (290 patients), 1967 for one centre (125), 1969 for one centre (255), and 1970 for the others (417). For patients born before 1970, therefore, mortality during the first decade of life could not be calculated, and survival after the first decade of life was used for comparison with later birth cohorts. For patients born in or after 1970, overall survival at all ages could be calculated (retrospectively before 1983 and prospectively thereafter) up to the last follow-up on
June 30,1988.
28 TABLE I-STATUS OF POPULATION BY YEAR OF BIRTH
Number (% of cohort). BMT = underwent bone marrow
transplant.
Fig 1-Survival after first decade of life by cohort of birth. 1087 patients (588 M, 499 F) were included in the study (table I). 21 patients were lost to follow-up by the centres, but data on 15 could be updated through the Italian Registry of Thalassaemia Patients. 21 patients underwent bone marrow transplantation (2 in 1985,2in 1986, and 17 subsequently) and are included up to the day of operation. Median duration of follow-up was 178 months (range 7-342). The Kaplan-Meier method3 and log-rank test4were used to estimate and to compare survival, respectively. The age and sex standardised cancer mortality ratios was calculated from cancer mortality rates observed in Italy in 19756 RESULTS
On June 30,1988,901 (82-9%) of 1087 patients were alive conventional therapy, 21 (1-9%) had undergone bone marrow transplantation, 6 (0-6%) had been lost to observation, and 159 (14-6%) had died (table I). Crude death rates ranged from 60-6% for patients born before 1965 to 0-6% for those born after 1979; median age at death was 14 years 7 months (range 6 months-26 years). Survival from birth for patients born before 1970 could not be calculated because of incomplete data; instead, survival after the first decade of life was calculated (table II) and compared with later cohorts (fig 1). For patients born in or after 1970, survival from birth is shown in table III. There was no difference in survival between sexes, and the results were not significantly affected if the 6 patients lost to observation were considered to have died on the day after their last follow-up visit. Information on the primary cause of death was available for 151 (95%) of the 159 patients who died (table IV). Of the other 8 patients 4 were known to have severe heart disease, one of whom had endocrine and renal complications and another had liver disease, but they were not included in the analysis. After exclusion of 4 deaths due to trauma, a single cause of death was reported for 81 patients (55-1%); of the other 66 patients who died, 56 had heart disease, which was associated with endocrine disease in 19 patients, liver disease in 18, or both complications in 8. Heart disease was the most common cause of death (63-6%), and was present in 76-8% of patients who died. Acute myocardial infarction caused death in 6 patients aged
on
- = 1960-64 cohort.
cohort; ----=1965-69 cohort; and ..... = 1970-74
13-21 years, one of whom had diabetes mellitus and another had hypothyroidism. After the age of 10 years, the Kaplan-Meier estimates for the probability of death from heart disease at the age of 15 were 12-3%, 10%, and 2-4%, respectively, for the 1960-64, 1965-69, and 1970-74 birth cohorts. At 20 years of age, the estimates were 29-4% and 21-4%, respectively, for the 1960-64 and 1965-69 cohorts, and 44-8% at 25 years for the 1960-64 cohort (p 0-0002 for trend of curves; fig 2). 13% of deaths were caused by infections, mostly before the age of 15 years. After that age, liver disease was the second most common cause of death, and was a subsidiary complication in 16 other deaths. 8 patients died from malignant disease: 2 had acute lymphoblastic leukaemia, 2 had non-Hodgkin lymphoma, and 1 each had acute myeloid leukaemia, meningeal sarcoma, hepatic cell carcinoma, and neuroblastoma (6 of these patients have been reported elsewhere7-tO). Endocrine disease was considered the cause of death in 4 patients and was present in a further 27 who =
TABLE III-SURVIVAL FROM BIRTH FOR PATIENTS BORN IN
1970-79
Results shown as % survivors
(95% confidence limits); p
=
0-28 for trend of
curves.
TABLE IV-PRIMARY CAUSE OF DEATH BY AGE AT DEATH
TABLE II-SURVIVAL AFTER FIRST DECADE FOR PATIENTS BORN IN
1960-74
Results shown as % survivors (95% confidence limits); p < 00001 for trend of curves.
*Other causes of death were thrombocytopenia (1), unspecified shock (1), and sudden death in a drug addict (1). tTotal deaths in this age group (number of patients under observation at the start of each evaluable age group).
29 years. In patients with cirrhosis, iron deposition in other organs increases,17 and is associated with an increased risk of diabetes mellitus.111 Death from liver disease may not have
Fig 2-Probability of death due to heart disease after first decade of life. =1960--64 cohort; -—-=1965-69 cohort; and —=1970-74 cohort.
died. Only 2 patients died of anaemia (at 6 and 42 months), both before transfusion treatment was started. DISCUSSION
Patients were only eligible for inclusion in the study if they were alive at the time full data were available from the hospital where they were followed up. Before 1970, therefore, it is likely that patients with and deaths from thalassaemia were under-reported, and the improvement in survival noted in later birth cohorts may be an underestimate. Nevertheless, survival curves before 1970 are similar to those reported by Economidoul and Modell .2 Since 1980, recruitment of patients with thalassaemia major has fallen (133 in 1980-84 vs 294 in 1975-79): this observation may be partly attributable to the 30% fall in the birth rate observed in Italy over the past 10 years, to the increased availability of prenatal diagnosis and genetic counselling, and to patients as yet undiagnosed. Our data indicate a striking improvement in life expectancy over the past 15 years; this fmding is mainly due to a decrease in mortality from cardiac disease, although it remains the most common cause of death in patients with thalassaemia major. Deaths from other causes have not decreased, but the numbers in recent years are too small for individual analysis. Have the changes in the management of thalassaemia major improved survival? Several reports"’" indicate that iron chelation improves organ function, and can prevent or delay cardiac disease.14 Modell et aP have found that desferrioxamine chelation significantly improves survival in thalassaemia major, and our results indicate that survival has improved since such treatment began. Most patients alive today have been treated with subcutaneous desferrioxamine for the last 8 years, and for 10 years before that intramuscular desferrioxamine was started shortly after the start of transfusion therapy. As 11 of our patients born after 1970, and therefore chelated at least from 5 years of age, died from heart disease by the age of 15, the amount of treatment may have been insufficient to maintain a negative iron balance-although compliance with subcutaneous desferrioxamine may be a problem, especially in adolescents. is Liver disease was the second most common cause of death after the age of 15 years; in our patient population, blood-borne viral hepatitis was probably an important factor in these deaths. Jean et all’, found histological features of hepatitis in 75 of 86 biopsy specimens taken at splenectomy: 11 showed chronic active hepatitis, and most patients with thalassaemia had cirrhosis by the age of 16
been caused by defective chelation; comparison with idiopathic haemochromatosis indicates that effective iron depletion can afford a survival similar to that of the general population, provided that the iron load or liver disease is not too severe at diagnosis.19 In contrast, if hepatic cirrhosis is already present, patients may fare poorly-especially if they also have diabetes mellitus. The second most common cause of death overall was infection, especially before the age of 10 years. Between 1960 and 1978 in the UK, Modell and Berdoukas2O found that the main cause of death was infection or anaemia in all but one of the children in this age group who died (the exception had a cerebral haemorrhage). Of our patients born after 1970, 14 died before the age of 10: 6 because of infection, 2 from anaemia, 3 from heart disease, and 3 from malignancy. The frequent occurrence of infection as a cause of death in this age-group is consistent with other reports.120 Only 2 of our patients died of anaemia: as the study was hospital-based, some patients may have died at home without diagnosis or treatment, but such an event would be unusual. No patient had uncontrollable haemolysis or refused transfusions. 6 patients died of myocardial infarction and 4 from thromboembolism. Data about antibiotic prophylaxis, anticoagulant treatment, and previous splenectomy are not complete for patients who died of infection or coagulation abnormalities. The prevalence of insulin dependent diabetes in live patients over the age of 10 years is 29 (5-9%) of 448 in our study population. In contrast, of 137 patients who have died after the age of 10, 24 (17-5%) had diabetes.18 8 patients died of malignant disease, 5 of whom had leukaemia or lymphoma. The expected number of cancer deaths in this population was 1-24, with an age and sex standardised cancer mortality ratio of 6-45 (95 % confidence limits 28-127).6 This excess could be due to chance alone, but an association between haematological malignancies and haemoglobinopathies has been suggested,7,21,22 possibly induced by long-standing haemopoietic stress. Expression of oncogenes has been observed during stimulated erythropoiesis in rats.23 Other possibilities include of blood-borne transmission oncogenic viruses, caused by multiple transfusions,24 a immunosuppression two link between separate diseases, and a genetic of iron25 or desferrioxamine. effect carcinogenic Since 1960, we have observed an improved life expectancy for patients with thalassaemia major, considered as 5-year birth cohorts. It is not yet possible to say whether this favourable trend will continue as patients get older, but thalassaemia major is no longer a rapidly fatal disease when patients are promptly treated with transfusion and iron chelation: most will now reach the age of employment or marriage. Evaluation of alternative treatments will need to take into account this improved survival. In particular, the improved quality of life after bone marrow transplantation (a procedure at present associated with a 15% mortality26) must be assessed against a 95% survival to the age of 15 years with conventional treatment. Correspondence should be addressed to C. B.-P., Clinica Pediatrica, Universita di Verona, Policlinico Borgo Roma, 37134 Verona, Italy.
30
Peptide Regulatory Factors This article concludes the series, which will be published later in book
form.
PEPTIDE REGULATORY FACTORS AND
MALIGNANCY C. M. STEEL MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU
To the cell biologist, cancer is a disorder of the social behaviour of cells in a multicellular organism. This, of course, simply begs the question "what regulates the social behaviour of cells?" Intuitively we might reply that regulation must depend on external signals mediated by both soluble factors and contact events. After all, excess or deficiency of certain well-characterised hormones-
oestrogens, androgens, erythropoietin, corticotropinresults in growth or involution of target tissues, and breaking a bone or breaching the skin surface triggers coordinated cellular responses. Conversely, the social behaviour of cells must also depend to some extent on properties intrinsic to individual members of the cell population-a nerve cell, a lymphocyte, and an osteoblast will each have its own distinctive pattern of behaviour, this being the essence of differentiation. In principle, disruption of social behaviour could therefore come about either through errors in external signals delivered to the cells or through lesions in their internal control mechanisms. Most modem theories of carcinogenesis have emphasised the latter route, a view that seems to be endorsed by a whole series of clinical and experimental observations: recognition that many carcinogens, viruses, and chemicals and ionising radiation damage DNA; association of chromosomal aberrations with malignancy; clear heritability of certain cancers; and, perhaps most persuasively, discoveries of cellular oncogenes (proto-oncogenes) and tumour-suppressor genes.12 Alternative hypotheses, invoking alterations in the
production of or response to regulatory signals, are not new3 but have found little favour, especially as regards specific factors that promote or inhibit cell proliferation.’ Remarkably, these two superficially opposed views of carcinogenesis are not difficult to reconcile, although such harmony has taken many decades to achieve. The basis of the current consensus is the realisation that many if not all of the lesions in the genome of malignant cells disrupt the recognition of, and response to, interactive signals that should regulate growth and differentiation. Put at its simplest, proto-oncogenes encode growth factors, their receptors, or components of the signal-transduction sequences that lead to implementation of the instruction "grow", whereas the function of anti-oncogenes or tumour suppressor genes is to inhibit the issue, receipt, or implementation of that instruction. S-7 This conceptual framework, within which we can examine the role of growth factors and growth inhibitory factors in malignancy, is straightforward and consistent with all known facts of cellular and molecular oncology. Nevertheless, there is no tumour of man or animals in which the disordered social behaviour of the malignant cells is fully understood at the molecular level. Such understanding will undoubtedly come in due course and studies on the interactions of cells and peptide regulatory factors (PRFs) will contribute to the process of illumination. However, as other contributions in this series have made clear, there are levels of complexity in these interactions that promise to keep cancer research laboratories busy for some little time.
MECHANISMS
of the above outline, there are at least four mechanisms whereby cell growth might become principal disordered. (a) Abnormalities of growth factor production (b) Abnormalities of growth factor receptors (c) Disturbance of post-receptor signal transmission (d) Reduced production of, or sensitivity to, growth inhibitory factors. In
terms
M. G. ZURLO AND OTHERS REFERENCES 1. Economidou J. Problems related
to treatment of
beta-thalassemia major Paediatrician
1982; 11: 157-77 2. Modell B, Letsky EA, Flynn DM, Peto R, Weatherall DJ. Survival and desferrioxamine in thalassaemia major Br Med J 1982; 284: 1081-84. 3. Kaplan EL, Meier P Nonparametric estimations from incomplete observations. J Am Stat Assoc 1958, 53: 457-81. 4. Peto R, Pike MC, Armitage P, et al Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II Analysis and examples Br J Cancer 1977; 35: 1-39 5 Breslow NE, Day NE. Statistical methods in cancer research. II. the design and analysis of cohort studies. Lyon, France. International Agency for Research on Cancer, 1987: 65-72 6 De Carli A, La Vecchia C. Cancer mortality in Italy, 1955-1978. Tumori 1984; 70 (suppl): 581-742. 7. Miniero R, Pastore G, Saracco P, Terracini B. Homozygous &bgr;-thalassaemia and cancer Haematologica 1985, 70: 78-79. 8. Russo A, Schiliro G. Thalassemia major and malignancies. Am J Hematol 1987, 24: 111
R, Saracco P. Cancer in thalassemia and other hemoglobinopathies. Am J Hematol 1987; 27: 74. 10 Borgna-Pignatti C, DeStefano P, Cammaren V, Magrini U. Hepatocellular carcinoma in thalassemia major. Med Pediatr Oncol 1986; 15: 32-34 9. Miniero
A, Martin M, Schwartz E. Depletion of excessive liver iron desferrioxamine. Br J Haematol 1984; 58: 369-73.
11. Cohen
stores
with
Kaye SB, Owen M. Cardiac arrhythmias in thalassaemia major: evaluation of chelation treatment using ambulatory monitoring. Br Med J 1978, i: 342. 13 Davies SC, Marcus RE, Hungerford JL, Miller MH, Arden GB, Huehns ER. Ocular toxicity of high-dose intravenous desferrioxamine. Lancet 1983; ii: 181-84. 14. Wolfe L, Olivien N, Sallan D, et al. Prevenuon of cardiac disease by subcutaneous 12
deferoxamine in patients with thalassemia major. N Engl J Med 1985; 312: 1600-03. 15. Di Palma A, Barrai I, Candini G, Vullo C. Compliance alla terapia chelante dei soggetti affetti da anemia di Cooley Riv Ital Ped 1982, 8: 183-87. 16. Jean G, Terzoli S, Mauri R, et al Cirrhosis associated with multiple transfusions in thalassaemia Arch Dis Child 1984, 59: 67-70. 17. Brissot P, Wright TL, Ma WL, Weisiger RA. Efficient clearance of non-transferrinbound iron by rat liver Implications for hepatic iron loading in iron overload states. J Clin Invest 1985; 76: 1463-70. 18. De Sanctis V, Zurlo MG, Senesi E, et al. Insulin dependent diabetes in thalassaemia. Arch Dis Child 1988, 63: 58-62 19. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985, 313: 1256-62 20 Modell B, Berdoukas VA. The clinical approach to thalassemia New York: Grune and Stratton, 1984 151-74. 21 Stricker RB, Linker CA, Crowley TJ, Embury SH. Hematologic malignancy in sickle cell disease report of four cases and review of the literature. Am J Hematol 1986, 21: 223-30 22 Das Gupta A, Nair L, Shah A, Barbhaya SA. Association of hematologic malignancies with hemoglobinopathies. Am J Hematol 1988; 28: 130.
23. 24
Bering HA, Duttagupta S, Lebowitz P Proto-oncogene expression during erythroid proliferation Clin Res 1984, 32: 304A (abstr) Kaplan J, Sarnaik S, Gitlin J, Lusher J Diminished helper-suppressor lymphocyte ratio and natural killer activity in recipients of repeated blood transfusions. Blood
1984, 64: 308-10 25 Stevens RG, Jones DY, Micozzi MS, Taylor PR Body iron stores and the nsk of cancer N Engl J Med 1988; 319: 1047-52. 26. Lucarelli G. Bone marrow transplantation for thalassemia N Engl J Med 1987; 317: 964.
probably the case in about half the patients in whom EIC + is suspected after a limited resection (around 15% of all patients with infiltrating ductal carcinomas). On the other
SURVIVAL AND CAUSES OF DEATH IN THALASSAEMIA MAJOR
hand, an initial wide excision would mean overtreatment for
MARIA GRAZIA ZURLO PIERO DE STEFANO CATERINA BORGNA-PIGNATTI ANNUNZIATA DI PALMA ANTONIO PIGA CATERINA MELEVENDI FELICIA DI GREGORIO MARIA GABRIELLA BURATTINI SEVERINA TERZOLI
about 85 % of the patients not having a substantial amount of DCIS outside the invasive tumour. Extensive breast surgery can have an adverse effect on the cosmetic outcome. If we know the EIC status of a tumour, therefore, we may be able to limit the extent of breast resection. For EICtumours, limited breast resection plus radiotherapy offers good cosmetic results with low risk of local recurrence. By contrast, EIC + tumours must be widely excised to achieve negative margins of resection before radiotherapy. Another unresolved question concerns the management of a patient with an EIC + tumour after re-excision has shown that the margins are still involved. Some clinicians advocate mastectomy while others argue for high-dose radiotherapy (particularly if the patient is old or has positive nodes). The interrelation between age and EIC needs to be explored further. There are hints from the Paris data that EIC + tumours carry a better long-term prognosis than EIC- tumours. This suggestion needs to be examined by multivariate analysis and in data from other series. CONCLUSIONS
Epidemiological, clinicopathological,
and cell
biology
studies indicate that in-situ breast cancers represent a wide spectrum of diseases ranging from the indolent to the rapidly progressing. We need a uniform classification of these lesions whereby we can identify lesions with a high risk of progression. Such a classification would be helpful in the evaluation of prospective randomised trials of breast conserving treatment in patients with DCIS, by allowing results to be compared and also combined in overview analyses. The principal risk factor for breast relapse after breast conserving treatment is large residual burden, and the main source of this burden is an EIC, which is found adjacent to 10-15% of all invasive breast carcinomas. These EIC + tumours are difficult to identify. We still have much to learn about the merits of different surgical and radiotherapeutic techniques in terms of accurate information on cosmetic results and recurrence free survival. We also need to know the outcome in patients who have undergone salvage mastectomy after breast relapse. Correspondence and requests for copies of the abstract book of the meeting should be addressed to J. A. van Dongen, Department of Surgery, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. REFERENCES
SJ, Sadowsky NL, Conolly JL, Harris JR. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 1988; 318: 898-903. 2. Schnitt SJ, Conolly JL, Recht A, Silver B Harris JR. Breast relapse following radiation therapy for early breast cancer. II Detection, pathologic features and prognostic significance. Int J Rad Onc Biol Phys 1985; 11: 1277-84. 3. Carpenter R, Gibbs M, Matthews J, Cooke T. Importance of cellular DNA content in pre-malignant breast disease and pre-invasive carcinoma of the female breast. Br J Surg 1987; 74: 905-06. 4 Van de Vijver MJ, Peterse JL, Mooi WJ, Wiseman P, Lomans J, Dalesio O, Nusse R. Neu-protein overexpression in breast cancer: association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 1988, 319: 1239-45. 5. Nielsen M, Thomsen JL, Primdahl S, Dyreborg V, Andersen JA. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br J Cancer 1987, 56: 814-19 6 Ronay G, Tulusan AH. Bilaterality of invasive breast cancer. In: Bassler R, ed. Pathology of neoplastic and endocrine induced disease of the breast. Stuttgart: 1 Schnitt
Silen W,
Gustav Fisher, 1986 7 Fisher ER, Sass
R, Fisher B, Wickenham L, Paik SM. Pathologic findings from the National Surgical Adjuvant Breast Project. I Intraductal carcinoma Cancer 1986; 57: 197-208. 8 Bartelink H, Borger JH, Van Dongen JA, Peterse JL. The impact of tumor size and histology on local control after breast conserving treatment. Rad Oncol 1988; 11: 297-305
IRCCS "San Matteo", Pavia, Italy; Departments of Paediatrics of the Universities of Milan, Verona, Torino, Catania, and Bari; and Divisions of Paediatrics of Ospedale Galliera, Genova, and Ospedale Sant’ Anna, Ferrara
Survival and causes of death were studied in 1087 Italian patients with thalassaemia major who were born on or after Jan 1, 1960. At the age of 15 years, the Kaplan-Meier estimate of survival after the first decade of life was 80·6% for subjects born in 1960-64, 84·2% for those born in 1965-69, and 96·9% for those born in 1970-74. At the age of 20 years, survival from the age of 10 was 59·1% for patients born in 1960-64, and 70·2% for those born in 1965-69; at 25 years, survival from the age of 10 was 40·7% in the 1960-64 cohort. Overall survival from birth for patients born in 1970-74 was 97·4% at 10 years, and 94·4% at 15 years. The most common cause of death was heart disease, followed by infection, liver disease, and
Summary
malignancy. INTRODUCTION
THE reported survival of patients with thalassaemia major has been disappointing. In 1982, Economidou’ found that the mortality of 441 Greek patients with thalassaemia major and intermedia was similar to that of the general population up to the age of 6 years, but increased gradually thereafter so that only 24% were alive at 28 years. Modell et al2 reported 25% survival at the age of 25 years for 92 patients with thalassaemia major born in or before 1963. However, the management of patients with thalassaemia major has changed during the last fifteen years. In Italy, treatment with intramuscular desferrioxamine has been available for most patients since 1975, and regular subcutaneous desferrioxamine infusion was started between 1979 and 1981. Over the same period, transfusion policy for these patients has been changed from correction of anaemia only when it was severe enough to cause symptoms, to "hypertransfusion" and "supertransfusion" regimens intended to maintain haemoglobin levels at or above 9-10 g/dl and 12 g/dl, respectively. Have these changes in management been associated with improved survival? PATIENTS AND METHODS
Details of patients with thalassaemia major who were born on or after Jan 1, 1960, were obtained from seven Italian teaching hospitals. All patients were eligible for inclusion in the study if they were alive at the time when, at each centre, clinical records were complete and reliable. Full data were available since 1965 for two centres (290 patients), 1967 for one centre (125), 1969 for one centre (255), and 1970 for the others (417). For patients born before 1970, therefore, mortality during the first decade of life could not be calculated, and survival after the first decade of life was used for comparison with later birth cohorts. For patients born in or after 1970, overall survival at all ages could be calculated (retrospectively before 1983 and prospectively thereafter) up to the last follow-up on
June 30,1988.
28 TABLE I-STATUS OF POPULATION BY YEAR OF BIRTH
Number (% of cohort). BMT = underwent bone marrow
transplant.
Fig 1-Survival after first decade of life by cohort of birth. 1087 patients (588 M, 499 F) were included in the study (table I). 21 patients were lost to follow-up by the centres, but data on 15 could be updated through the Italian Registry of Thalassaemia Patients. 21 patients underwent bone marrow transplantation (2 in 1985,2in 1986, and 17 subsequently) and are included up to the day of operation. Median duration of follow-up was 178 months (range 7-342). The Kaplan-Meier method3 and log-rank test4were used to estimate and to compare survival, respectively. The age and sex standardised cancer mortality ratios was calculated from cancer mortality rates observed in Italy in 19756 RESULTS
On June 30,1988,901 (82-9%) of 1087 patients were alive conventional therapy, 21 (1-9%) had undergone bone marrow transplantation, 6 (0-6%) had been lost to observation, and 159 (14-6%) had died (table I). Crude death rates ranged from 60-6% for patients born before 1965 to 0-6% for those born after 1979; median age at death was 14 years 7 months (range 6 months-26 years). Survival from birth for patients born before 1970 could not be calculated because of incomplete data; instead, survival after the first decade of life was calculated (table II) and compared with later cohorts (fig 1). For patients born in or after 1970, survival from birth is shown in table III. There was no difference in survival between sexes, and the results were not significantly affected if the 6 patients lost to observation were considered to have died on the day after their last follow-up visit. Information on the primary cause of death was available for 151 (95%) of the 159 patients who died (table IV). Of the other 8 patients 4 were known to have severe heart disease, one of whom had endocrine and renal complications and another had liver disease, but they were not included in the analysis. After exclusion of 4 deaths due to trauma, a single cause of death was reported for 81 patients (55-1%); of the other 66 patients who died, 56 had heart disease, which was associated with endocrine disease in 19 patients, liver disease in 18, or both complications in 8. Heart disease was the most common cause of death (63-6%), and was present in 76-8% of patients who died. Acute myocardial infarction caused death in 6 patients aged
on
- = 1960-64 cohort.
cohort; ----=1965-69 cohort; and ..... = 1970-74
13-21 years, one of whom had diabetes mellitus and another had hypothyroidism. After the age of 10 years, the Kaplan-Meier estimates for the probability of death from heart disease at the age of 15 were 12-3%, 10%, and 2-4%, respectively, for the 1960-64, 1965-69, and 1970-74 birth cohorts. At 20 years of age, the estimates were 29-4% and 21-4%, respectively, for the 1960-64 and 1965-69 cohorts, and 44-8% at 25 years for the 1960-64 cohort (p 0-0002 for trend of curves; fig 2). 13% of deaths were caused by infections, mostly before the age of 15 years. After that age, liver disease was the second most common cause of death, and was a subsidiary complication in 16 other deaths. 8 patients died from malignant disease: 2 had acute lymphoblastic leukaemia, 2 had non-Hodgkin lymphoma, and 1 each had acute myeloid leukaemia, meningeal sarcoma, hepatic cell carcinoma, and neuroblastoma (6 of these patients have been reported elsewhere7-tO). Endocrine disease was considered the cause of death in 4 patients and was present in a further 27 who =
TABLE III-SURVIVAL FROM BIRTH FOR PATIENTS BORN IN
1970-79
Results shown as % survivors
(95% confidence limits); p
=
0-28 for trend of
curves.
TABLE IV-PRIMARY CAUSE OF DEATH BY AGE AT DEATH
TABLE II-SURVIVAL AFTER FIRST DECADE FOR PATIENTS BORN IN
1960-74
Results shown as % survivors (95% confidence limits); p < 00001 for trend of curves.
*Other causes of death were thrombocytopenia (1), unspecified shock (1), and sudden death in a drug addict (1). tTotal deaths in this age group (number of patients under observation at the start of each evaluable age group).
29 years. In patients with cirrhosis, iron deposition in other organs increases,17 and is associated with an increased risk of diabetes mellitus.111 Death from liver disease may not have
Fig 2-Probability of death due to heart disease after first decade of life. =1960--64 cohort; -—-=1965-69 cohort; and —=1970-74 cohort.
died. Only 2 patients died of anaemia (at 6 and 42 months), both before transfusion treatment was started. DISCUSSION
Patients were only eligible for inclusion in the study if they were alive at the time full data were available from the hospital where they were followed up. Before 1970, therefore, it is likely that patients with and deaths from thalassaemia were under-reported, and the improvement in survival noted in later birth cohorts may be an underestimate. Nevertheless, survival curves before 1970 are similar to those reported by Economidoul and Modell .2 Since 1980, recruitment of patients with thalassaemia major has fallen (133 in 1980-84 vs 294 in 1975-79): this observation may be partly attributable to the 30% fall in the birth rate observed in Italy over the past 10 years, to the increased availability of prenatal diagnosis and genetic counselling, and to patients as yet undiagnosed. Our data indicate a striking improvement in life expectancy over the past 15 years; this fmding is mainly due to a decrease in mortality from cardiac disease, although it remains the most common cause of death in patients with thalassaemia major. Deaths from other causes have not decreased, but the numbers in recent years are too small for individual analysis. Have the changes in the management of thalassaemia major improved survival? Several reports"’" indicate that iron chelation improves organ function, and can prevent or delay cardiac disease.14 Modell et aP have found that desferrioxamine chelation significantly improves survival in thalassaemia major, and our results indicate that survival has improved since such treatment began. Most patients alive today have been treated with subcutaneous desferrioxamine for the last 8 years, and for 10 years before that intramuscular desferrioxamine was started shortly after the start of transfusion therapy. As 11 of our patients born after 1970, and therefore chelated at least from 5 years of age, died from heart disease by the age of 15, the amount of treatment may have been insufficient to maintain a negative iron balance-although compliance with subcutaneous desferrioxamine may be a problem, especially in adolescents. is Liver disease was the second most common cause of death after the age of 15 years; in our patient population, blood-borne viral hepatitis was probably an important factor in these deaths. Jean et all’, found histological features of hepatitis in 75 of 86 biopsy specimens taken at splenectomy: 11 showed chronic active hepatitis, and most patients with thalassaemia had cirrhosis by the age of 16
been caused by defective chelation; comparison with idiopathic haemochromatosis indicates that effective iron depletion can afford a survival similar to that of the general population, provided that the iron load or liver disease is not too severe at diagnosis.19 In contrast, if hepatic cirrhosis is already present, patients may fare poorly-especially if they also have diabetes mellitus. The second most common cause of death overall was infection, especially before the age of 10 years. Between 1960 and 1978 in the UK, Modell and Berdoukas2O found that the main cause of death was infection or anaemia in all but one of the children in this age group who died (the exception had a cerebral haemorrhage). Of our patients born after 1970, 14 died before the age of 10: 6 because of infection, 2 from anaemia, 3 from heart disease, and 3 from malignancy. The frequent occurrence of infection as a cause of death in this age-group is consistent with other reports.120 Only 2 of our patients died of anaemia: as the study was hospital-based, some patients may have died at home without diagnosis or treatment, but such an event would be unusual. No patient had uncontrollable haemolysis or refused transfusions. 6 patients died of myocardial infarction and 4 from thromboembolism. Data about antibiotic prophylaxis, anticoagulant treatment, and previous splenectomy are not complete for patients who died of infection or coagulation abnormalities. The prevalence of insulin dependent diabetes in live patients over the age of 10 years is 29 (5-9%) of 448 in our study population. In contrast, of 137 patients who have died after the age of 10, 24 (17-5%) had diabetes.18 8 patients died of malignant disease, 5 of whom had leukaemia or lymphoma. The expected number of cancer deaths in this population was 1-24, with an age and sex standardised cancer mortality ratio of 6-45 (95 % confidence limits 28-127).6 This excess could be due to chance alone, but an association between haematological malignancies and haemoglobinopathies has been suggested,7,21,22 possibly induced by long-standing haemopoietic stress. Expression of oncogenes has been observed during stimulated erythropoiesis in rats.23 Other possibilities include of blood-borne transmission oncogenic viruses, caused by multiple transfusions,24 a immunosuppression two link between separate diseases, and a genetic of iron25 or desferrioxamine. effect carcinogenic Since 1960, we have observed an improved life expectancy for patients with thalassaemia major, considered as 5-year birth cohorts. It is not yet possible to say whether this favourable trend will continue as patients get older, but thalassaemia major is no longer a rapidly fatal disease when patients are promptly treated with transfusion and iron chelation: most will now reach the age of employment or marriage. Evaluation of alternative treatments will need to take into account this improved survival. In particular, the improved quality of life after bone marrow transplantation (a procedure at present associated with a 15% mortality26) must be assessed against a 95% survival to the age of 15 years with conventional treatment. Correspondence should be addressed to C. B.-P., Clinica Pediatrica, Universita di Verona, Policlinico Borgo Roma, 37134 Verona, Italy.
30
Peptide Regulatory Factors This article concludes the series, which will be published later in book
form.
PEPTIDE REGULATORY FACTORS AND
MALIGNANCY C. M. STEEL MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU
To the cell biologist, cancer is a disorder of the social behaviour of cells in a multicellular organism. This, of course, simply begs the question "what regulates the social behaviour of cells?" Intuitively we might reply that regulation must depend on external signals mediated by both soluble factors and contact events. After all, excess or deficiency of certain well-characterised hormones-
oestrogens, androgens, erythropoietin, corticotropinresults in growth or involution of target tissues, and breaking a bone or breaching the skin surface triggers coordinated cellular responses. Conversely, the social behaviour of cells must also depend to some extent on properties intrinsic to individual members of the cell population-a nerve cell, a lymphocyte, and an osteoblast will each have its own distinctive pattern of behaviour, this being the essence of differentiation. In principle, disruption of social behaviour could therefore come about either through errors in external signals delivered to the cells or through lesions in their internal control mechanisms. Most modem theories of carcinogenesis have emphasised the latter route, a view that seems to be endorsed by a whole series of clinical and experimental observations: recognition that many carcinogens, viruses, and chemicals and ionising radiation damage DNA; association of chromosomal aberrations with malignancy; clear heritability of certain cancers; and, perhaps most persuasively, discoveries of cellular oncogenes (proto-oncogenes) and tumour-suppressor genes.12 Alternative hypotheses, invoking alterations in the
production of or response to regulatory signals, are not new3 but have found little favour, especially as regards specific factors that promote or inhibit cell proliferation.’ Remarkably, these two superficially opposed views of carcinogenesis are not difficult to reconcile, although such harmony has taken many decades to achieve. The basis of the current consensus is the realisation that many if not all of the lesions in the genome of malignant cells disrupt the recognition of, and response to, interactive signals that should regulate growth and differentiation. Put at its simplest, proto-oncogenes encode growth factors, their receptors, or components of the signal-transduction sequences that lead to implementation of the instruction "grow", whereas the function of anti-oncogenes or tumour suppressor genes is to inhibit the issue, receipt, or implementation of that instruction. S-7 This conceptual framework, within which we can examine the role of growth factors and growth inhibitory factors in malignancy, is straightforward and consistent with all known facts of cellular and molecular oncology. Nevertheless, there is no tumour of man or animals in which the disordered social behaviour of the malignant cells is fully understood at the molecular level. Such understanding will undoubtedly come in due course and studies on the interactions of cells and peptide regulatory factors (PRFs) will contribute to the process of illumination. However, as other contributions in this series have made clear, there are levels of complexity in these interactions that promise to keep cancer research laboratories busy for some little time.
MECHANISMS
of the above outline, there are at least four mechanisms whereby cell growth might become principal disordered. (a) Abnormalities of growth factor production (b) Abnormalities of growth factor receptors (c) Disturbance of post-receptor signal transmission (d) Reduced production of, or sensitivity to, growth inhibitory factors. In
terms
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deferoxamine in patients with thalassemia major. N Engl J Med 1985; 312: 1600-03. 15. Di Palma A, Barrai I, Candini G, Vullo C. Compliance alla terapia chelante dei soggetti affetti da anemia di Cooley Riv Ital Ped 1982, 8: 183-87. 16. Jean G, Terzoli S, Mauri R, et al Cirrhosis associated with multiple transfusions in thalassaemia Arch Dis Child 1984, 59: 67-70. 17. Brissot P, Wright TL, Ma WL, Weisiger RA. Efficient clearance of non-transferrinbound iron by rat liver Implications for hepatic iron loading in iron overload states. J Clin Invest 1985; 76: 1463-70. 18. De Sanctis V, Zurlo MG, Senesi E, et al. Insulin dependent diabetes in thalassaemia. Arch Dis Child 1988, 63: 58-62 19. Niederau C, Fischer R, Sonnenberg A, et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985, 313: 1256-62 20 Modell B, Berdoukas VA. The clinical approach to thalassemia New York: Grune and Stratton, 1984 151-74. 21 Stricker RB, Linker CA, Crowley TJ, Embury SH. Hematologic malignancy in sickle cell disease report of four cases and review of the literature. Am J Hematol 1986, 21: 223-30 22 Das Gupta A, Nair L, Shah A, Barbhaya SA. Association of hematologic malignancies with hemoglobinopathies. Am J Hematol 1988; 28: 130.
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