Inl J Radrarwn Omio~,’ Bml. Phr.\ Vol. Pnntcd I” the US 4. All nghts reserved
19. pp.
I303-
0360.3016190
I308
Copynght 0 I990
$3.00 + 00 Perganml Press plc
0 Oncology Intelligence
CANCER OCCURRING AFTER RADIOTHERAPY LARS-ERIK Department
of Cancer Prevention,
HOLM,
Radiumhemmet,
M.D.,
AND CHEMOTHERAPY
PH.D.
Karolinska Hospital, S- 104 0 1 Stockholm, Sweden
Radiotherapy and chemotherapy can effectively control cancer but can also cause new cancers to develop as longterm complications. Almost all types of cancer have been associated with radiotherapy. The breast, thyroid, and bone marrow are the organs most susceptible to radiation carcinogenesis. The bone marrow is also most frequently involved by chemotherapy and the leukemia risk is much higher than after radiotherapy. The combination of intensive radiotherapy and chemotherapy is particularly leukemogenic. The latent period between radiotherapy/ chemotherapy and the appearance of a second primary cancer ranges from a few years to several decades. The risk for a second primary cancer following radiotherapy or chemotherapy emphasizes the need for life long follow-up of patients receiving such treatments. This is particularly the case in individuals with long life expectancy, for example, patients treated for childhood neoplasms. The benefits of radiotherapy and chemotherapy in oncology exceed the risks for second primary cancers. Efforts should be directed towards identifying those patients who will benefit from the treatments so that only they are exposed to the risk. Radiotherapy,
Chemotherapy,
Second cancers, Radiation-induced.
ment. Thus, for purpose of risk evaluation, the data for any given type of malignant tumor have been considered applicable, within certain limits, to other populations. The effects of exposure to radiation at low doses and/or at low dose rates are less known. Almost all cancers have been associated with radiation exposure. although the breast, thyroid, and bone marrow appear to be the most radiosensitive sites. The excess risk of leukemia attributable to radiation is observed within a few years of exposure with a peak after 6-8 years, and declines thereafter. The most recent follow-up of subjects exposed to the atomic bombings in Japan in 1945 showed that leukemia mortality was still increased nearly threefold in 198 1- 1985 (25). An increased risk of solid cancers usually does not appear until 10 years or more after radiation exposure and extends beyond 30 years after such an exposure (32, 33). Cancer risk usually increases with the radiation dose received by the organ or tissue of interest. Animal studies indicate that the dose-response varies with dose rate and radiation quality (that is alpha, beta, gamma, and x rays). Among biological factors affecting the risk estimates are the type of tissue irradiated, age at exposure, sex, and ethnic group. Young persons are more sensitive to radiogenie cancer than are adults (32, 33). Observations of radiation-induced cancers have mostly been limited to populations who were exposed to relatively high radiation doses in various ways and for various rea-
INTRODUCTION
Exposure to ionizing radiation can have untoward somatic and genetic sequelae. The most serious late somatic effect following such exposure is the induction of malignant tumors. Because of the professional and public interest in the carcinogenic effects of ionizing radiation, these effects have been investigated more thoroughly than those of any other environmental agent. During the past decades, our knowledge about radiation effects in humans has increased considerably and several comprehensive reviews have been published by the United Nations Scientific Committee on the Effects of Atomic Radiation (32, 33) and by the National Academy of Sciences in the U.S.A. (7). Radiation-induced cancers are indistinguishable from those occurring from other causes, and their existence can therefore be deduced only in terms of a statistical excess above the natural incidence or mortality. As yet there is no accepted method of extrapolating the data obtained from experimental animals to man. Hence the risk estimates of cancer induction in man are essentially based on studies on exposed human populations. An increase of several types of malignant tumors in human populations has been observed with an increasing radiation dose (7, 33). The majority of these studies concern exposure to moderate or high doses, usually > 1 Sv, and at high dose rates. The observations made in different exposed populations are usually in relatively good agree-
Accepted for publication 24 May 1990.
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sons. In studies on the effects following exposure to lowlevel radiation, very large sample sizes are required and it is not possible to control adequately for other factors that influence cancer risks. Studies of populations medically exposed to radiation at moderate to high doses can therefore contribute important information on radiation risks in humans. Such populations usually have good dosimetry data, careful follow-up of the individuals, and often also contain non-exposed groups for comparison purpose. Among the disadvantages are the potential effect of the disease-for which the patients have been irradiatedon cancer risks and the partial-body nature of the radiation exposures (2). The observations of cancers following chemotherapy come from populations of patients treated for cancer or other serious illnesses. Both radiation and many of the agents used in cancer chemotherapy interact with cellular DNA. Agents that are used to kill cancer cells may therefore also be cytotoxic or genotoxic to normal cells. In the last 2 decades, several studies have shown that chemotherapy with alkylating agents carries a risk for induction of leukemia, and in some cases bladder carcinomas (for review see reference 19). The leukemia risk in patients receiving chemotherapy for various malignant diseases has been found to be several hundred times higher than expected. The risk increases rapidly after treatment, as in the case of radiation exposure.
METHODS
AND MATERIALS
Populations studied Important surveys of medically irradiated populations include patients treated in infancy or adulthood for benign as well as malignant diseases, for example, tinea capitis
Table 1. Examples of studies of populations irradiated for benign and malignant diseases Reason for radiotherapy Benign Ankylosing spondylitis
Postpartum mastitis Supposed thymus enlargement Tinea capitis Hemangioma Malignant Cervical cancer
Pediatric cancers Hodgkin’s disease
Excess cancers Leukemia, lymphomas, lung, stomach, esophagus, central nervous system Breast Thyroid, leukemia Thyroid, brain, skin, leukemia Breast, soft tissue Bladder, rectum, bone, soft tissue, small intestine, leukemia, ovary Leukemia, thyroid, breast, bone Leukemia, non-Hodgkin’s lymphoma
November 1990, Volume 19, Number 5
(23,24), hemangioma ( 12,2 1), presumed enlarged thymus gland (27), mastitis (26) hyperthyroidism (18), pediatric cancers (20, 30), cervical cancer (3,4), Hodgkin’s disease (5), and polycythemia vera (1) (Table 1). The types of irradiation include external x-ray therapy as well as internally deposited radioactive compounds, for example, 13rI and 32P. It is not within the scope of this paper to review all types of studies. The purpose is to discuss cancer risks following external radiotherapy and chemotherapy in childhood and adulthood. Exposure in childhood Childhood is a period characterized by actively growing tissues, something that may have an impact on the susceptibility to radiation-induced cancer. Data on childhood medical exposure emanate from two sources: children treated for benign conditions and patients receiving radiotherapy, often in combination with chemotherapy, for pediatric cancers. These groups may not be directly comparable, since the groups treated for malignant disease are also comprised of individuals with a genetic predisposition to cancer. Radiotherapy has been used in various benign conditions in childhood. The exposures mainly involve the upper part of the body, for example, tinea capitis (23, 24) and presumed thymic enlargement (27). Leukemias and thyroid cancer are the most common malignancies following such exposures (Table l), although other cancers have also been reported. Tissues that involve non-proliferating cells appear to be relatively non-susceptible to radiation carcinogenesis. The cancers are expressed at the normal adult ages for cancer even when exposure occurs in childhood (33). Consequently, the defined cohorts of exposed children must be followed for several decades to provide better estimates of the cancer risks following radiation exposure in childhood. More than 10,000 persons who were treated with X rays for ringworm of the scalp in childhood have been followed-up in Israel together with more than 16,000 matched subjects and siblings (23, 24). An increased risk for thyroid cancer has been observed above doses of 0.09 Gy. Increased risks have also been observed for leukemia, tumors of the nervous system, and of the head and neck. In studies of children irradiated for a presumed thumus enlargement increased risks for cancers of the thyroid, breast, and skin have been observed (17, 27). Many children have been irradiated to treat skin hemangiomas and two large Swedish cohorts now together comprise more than 28,000 children irradiated between 1920 and 1959 (12, 2 1). The mean age at exposure was 6 months. In one of these studies, significantly increased relative risks (RR) of cancer were found for all sites combined [RR = 1.18; 95% confidence interval (CI) = 1.031.351, breast cancer (RR = 1.65; 95% CI = 1.26-2.13) and soft tissue tumors (RR = 2.73; 95% CI = 1.18-5.38) in patients irradiated with 226-Ra or orthovoltage X rays
Cancer after radiotherapy 0 L.-E. HOLM eful.
(15). RR for thyroid cancer was 1.85 (95% CI = 0.993.17). No increased risks were observed in patients treated with contact x-ray therapy or in those not receiving radiotherapy. Cancer mortality was also significantly increased for all sites combined (13). For non-malignant causes of death, the relative risks did not differ significantly from unity. An increased risk for thyroid cancer was observed already at doses above 0.1 Gy and for tumors of bone and soft tissue at doses of 0.5 Gy or more (14). The evidence from children irradiated because of a primary cancer shows a high susceptibility to second cancers. These populations contain a relatively high fraction of children who are genetically susceptible to cancer and therefore may be different from other children. The results from exposure following childhood cancers can therefore not be used for estimating risks in the general population. Studies of two large cohorts of irradiated children indicate a relative risk of 15 or more for a second cancer of any site (20, 22, 29, 30, 3 1). The cumulative probability of a second cancer 25 years after diagnosis of first cancer was 12% (30). Two-thirds of all second cancers were observed in the field of irradiation with a median latency period of 10 years. The second cancers were concentrated in patients originally treated for tumors of genetic origin and in patients with a primary cancer in sites known to be radiogenic, that is, hematopoietic and bone tissues. In more than 9,000 children with pediatric cancer, the leukemia risk was increased following treatment with alkylating agents (RR = 4.8) but not after radiotherapy (3 1). A marked dose-response relationship was observed for alkylating agents, and RR for leukemia reached 23 in the highest dose category. The subsequent risk of bone sarcoma in the same cohort was also increased following radiotherapy as well as after chemotherapy with alkylating agents (27). Overall RR for bone sarcoma was 133 (95% CI = 98-176) with a cumulative risk of 2.8% after 20 years of follow-up. Radiotherapy resulted in a RR of 2.7 after a mean dose of 27 Gy with no increased risk at doses less than 10 Gy. Above that dose, RR increased with dose and was 40-fold at doses of more than 60 Gy. Treatment with alkylating agents was associated with RR = 4.7 (95% CI = 11.0-22.3) after adjustment for radiotherapy, and the risk increased with the cumulative drug exposure. Children with retinoblastoma were at high risk for osteosarcoma (RR = - 1,000) and connective tissue (RR = 235) (30). The cumulative risk for second cancers in retinoblastoma patients was 14% after 20 years (29). In patients with Wilms’ tumor the highest risks were observed for cancers of the thyroid (RR = 136) bone (RR = 127) and connective tissue (RR = 84) (30). Li (20) calculated the cumulative risk for second cancer in patients with Wilms’ tumor to 18% after 34 years. In patients with Ewing’s sarcoma, elevated RRs were observed for osteosarcoma (RR = 649) and leukemia (RR = 62) (28). The cumulative cancer risk following radiotherapy was estimated to 35% after 10 years.
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Studies of patients treated for Hodgkin’s disease have reported increased risks for cancers of bone (RR = 106) leukemia (RR = 89) and thyroid (RR = 68) (30). In a study from Stanford (28) of 1,500 patients with Hodgkin’s disease, RR for leukemia was 11 after radiotherapy alone, 117 after adjuvant chemotherapy containing alkylating agents, and 130 after chemotherapy alone. The mean 15year actuarial risk of all second cancers in that study was 17.6%, of which 13.2% were solid tumors. Long-term survivors of a pediatric cancer thus have an elevated risk of developing a second cancer, reaching 12% by 25 years of follow-up. Each cancer has an array of second tumors and some of the combinations appear to reflect genetic factors or susceptibility to the treatment (30). Exposure in adulthood
Most adult exposures are the result of radiotherapy. The major sources of information come from patients irradiated for ankylosing spondylitis ( 10) and for cervical cancer (3,4), although other cohorts have also contributed with valuable information, for example, patients treated for Hogdkin’s disease (5) and mastitis (26). Such patients, however, may not be representative of the general population, since the obtained data may have been confounded by the underlying disease or by treatment other than radiation. Patients who received x-ray therapy for ankylosing spondylitis had a three-fold increase in mortality from leukemia compared to the general population (10). The highest risk was observed between 3-5 years after treatment and then declined. A considerable excess of cancers occurring in heavily irradiated organs was also observed, such as lung, stomach, and esophagus. The largest study of second tumors in cervical cancer patients was comprised of over 182,000 patients from eight countries (3, 4). Of 5,146 cancers, at most 5% were attributable to the radiation exposure. High doses to the pelvic region was associated with increased risk of cancer to exposed organs, including bladder, rectum, bone, connective tissue, and small intestine. RR for leukemia other than cronic lymphocytic leukemia was 2.0, and the risk increased with increasing radiation dose until about 4 Gy and then decreased at higher doses due to cell killing. Patients given X-ray therapy for post-partum mastitis have contributed information concerning radiation-induced breast cancer (26). RR for breast cancer was 3.2 for the irradiated breast. The relation between dose and breast cancer risk was consistent with linearity up to 7 Gy. Harvey and Brinton (16) observed an RR of second primary breast cancer of 3.9 (95% CI = 3.6-4.2) in patients irradiated for breast cancer compared to 1.5 (95% CI = 1.5- 1.6) for women treated without radiation. In a study by Curtis et al. (9) of 39,000 breast cancer patients, the RR for leukemia was 1.O following surgery, 1.7 for radiation only, and 3.8 for chemotherapy alone.
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Table 2. Leukemias and solid cancers following Hodgkin’s disease in relation to type of treatment (5) Leukemias
Cancers
No. per
1000 PY *
9590 CI
No. per 1000 PY *
95% CI
No intensive therapy Intensive radiotherapy Intensive chemotherapy Intensive radiotherapy + intensive chemotherapy
0 1.0 4.0
o.o- 1.2 0.3-2.4 1.5-8.8
4.8 3.4 7.5
3.0-7.5 1.5-6.7 3.4-14
7.0
4.0-I 1
9.3
3.0-22
Total
2.3
1.5-3.4
5.1
3.7-12
Type of treatment
* PY = person-years.
Among 440,000 cancer patients the RR of leukemia was 1.0 after surgery, 1.4 after radiation only, and 2.3 after chemotherapy alone (9). In a recent study of a cohort of 22,800 breast cancer patients treated with radiation, the RR for leukemia was 1.16 (90% CI = 0.6-2. I) and there was no dose-response pattern (8). The result excluded an association between leukemia and radiotherapy for breast cancer of 2.2-fold with 90% confidence. The risk for leukemia following adjuvant chemotherapy for breast cancer was reported by Fisher et al. (I 1) to be 1.7% at 10 years after surgery compared to 1.4% after radiotherapy. The risk figures may change with an increasing period of follow-up. In adult patients treated for Hodgkin’s disease leukemia is the most common second cancer and particularly acute non-lymphocytic leukemia (ANLL). X-ray therapy alone does not seem to be a major risk factor for leukemias in these patients. Chemotherapy has been strongly associated with second leukemias and combined therapy appears to increase the risk further (Table 2) (5). The actuarial risk of developing secondary ANLL following radiotherapy plus adjuvant MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) was in the range of 5-7% at 7 years of follow-up (6). Second leukemias have been observed after different regimens containing nitrogen mustard as well as nitrosourea combinations. In contrast, no increased risk of ANLL has been demonstrated following chemotherapy with doxorubicin, bleomycin, vinblastin, and dacarbazine, suggesting that this regimen carries a lower leukemogenic risk. The age of the patients at the time of treatment appears to be of importance, and in the older age group, the actuarial risk of secondary leukemia exceeds 20%. With sufficiently long follow-up, the risk for solid tumors at 10 years exceeds that of leukemia (6). The risk of acute leukemia in 431 patients with polycythemia vera was 2.3 times higher after chlorambucil treatment than after 32P therapy and 13.5 times that in patients treated with phlebotomy alone (1). The excess in 32P patients relative to phlebotomy-treated patients was
not statistically significant. Thus, the excess incidence in patients treated with chlorambucil was 3.5 (95% CI = 1.67.6) times that in patients in the other two groups combined. DISCUSSION The risks for radiation-induced cancer following radiotherapy are relatively small and the cancers appear after long latency periods. The risk can be reduced further by more careful staging of tumors and improved radiotherapeutic techniques, such as better definition of the target volume, and the use of higher energies which yield a more exact dose distribution. Chemotherapy appears far more potent than radiotherapy in inducing leukemia. On the other hand, chemotherapy does not increase the risk of other cancers (with the possible exception of bladder cancer), as is the case with radiotherapy. The introduction of chemotherapy in the treatment of cancer has resulted in a higher proportion of patients being cured of their first cancer. Without these agents, many patients with, for example, pediatric cancers, testicular cancer, and Hodgkin’s disease would never have lived sufficiently long to be at risk for a second cancer. The risks following chemotherapy must be carefully analyzed over the next decade when large cohorts have sufficiently long periods of follow-up. The increasing use of adjuvant chemotherapy for early stages of cancer raises concern as to the possible late effects of such a treatment. The potential hazards of cancer treatments should be weighed against the consequences of not using such treatments. The choice of radiotherapy and chemotherapy in oncology should not solely be based on the risk for second primary cancers but rather on the risk for acute side effects and on the chance for cure. The benefits exceed the risk for second primary cancers. Efforts should, however, be directed towards identifying those patients who will benefit from the treatments so that only they are exposed to the risk.
Cancer after radiotherapy 0 L.-E. HOLM eta/.
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REFERENCES 1. Berk, P. D.; Goldberg, J. D.; Silverstein, M. N.; Weinfeld, A.; Donovan, P. B.; Ellis, J. T.; Landaw, S. A.; Laszlo, J.; Najean, Y.; Pisciotta, A. V.; Wasserman, L. R. Increased incidence of acute leukemia in polycythemia vera associated with chlorambycil therapy. N. Engl. J. Med. 304:44 l-447; 1981. 2. Boice, J. D., Jr. Carcinogenesis-a synopsis of human experience with external exposure in medicine. Health Phys. 55:621-630; 1988. 3. Boice, J. D., Jr.; Blettner, M.; Kleinerman, R. A.; Stovall, M.; Moloney, W. C.; Engholm, G.; Austin, D. F.; Bosch, A.; Cookfair, D. L.; Krementz, E. T.; Latourette, H. B.; Peters, L. J.; Schultz, M. D.; Lundell, M.; Pettersson, F.; Storm, H. H.; Bell, C. M. J.; Coleman, M. P.; Fraser, P.; Palmer, M.; Prior, P.; Choi, N. W.; Hislop, T. G.; Koch, M.; Robb, D.; Robson, D.; Spengler, R. F.; von Fournier, D.; Frischkorn, R.; Lockmiiller, H.; Pompe-Kim, V.; Rimpela, A.; Kjerstad, K.; Pejovic, M. H.; Sigurdsson, K.; Pisani, P.; Kucera, H.; Hutchinson, G. B. Radiation dose and leukemia risk in patients treated for cancer of the cervix. JNCI 79:1295-1311; 1987. 4. Boice, J. D., Jr.; Day, N. E.; Andersen, A.; Brinton, L. A.; Brown, R.; Choi, N. W.; Clarke, E. A.; Coleman, M. P.; Curtis, R. E.; Flannery, J. T.; Hakama, M.; Hakulinen, T.; Howe, G. R.; Jensen, 0. M.; Kleinerman, R. A.; Magnin, D.; Magnus, K.; Makela, K.; Malker, B.; Miller, A. B.; Nelson, N.; Patterson, C. C.; Pettersson, F.; Pompe-Kim, V.; Primic-Zakelj, M.; Prior, P.; Ravnihar, B.; Skeet, R. G.; Skjerven, J. E.; Smith, P. G.; Sok, M.; Spengler, R. F.; Storm, H. H.; Stovall, M.; Tomkins, G. W. 0.; Wall, C. Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries. JNCI 74:955-975; 1985. 5. Boivin, J. F.; Hutchinson, G. B. Second cancers after treatment for Hodgkin’s disease: a review. In: Boice, J. D., Jr.; Fraumeni, J. F., Jr., eds. Radiation carcinogenesis: epidemiology and biological significance. Progress in cancer research and therapy, Vol. 26. New York: Raven Press; 1984: 181-198. 6. Coleman, C. N. Secondary malignancy after treatment of Hodgkin’s disease: an evolving picture. J. Clin. Oncol. 4: 821-824; 1986. 7. Committee on the Biological Effects of Ionizing Radiations. The effects on populations of exposure to low levels of ionizing radiation. Washington, DC: Natl. Acad. Press; 1980. 8. Curtis, R. E.; Boice, J. D., Jr.; Stovall, M.; Flannery, J. T.; Moloney, W. C. Leukemia risk following radiotherapy for breast cancer. J. Clin. Oncol. 7:2 l-29; 1989. 9. Curtis, R. E.; Hankey, B. F.; Myers, M. H.; Young, J. L., Jr. Risk of leukemia associated with the first course of cancer treatment: an analysis of the surveillance, epidemiology, and end results program experience. JNCI 72:531-544; 1984. 10. Darby, S. C.; Doll, R.; Gill, S. K.; Smith, P. G. Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis. Br. J. Cancer 55: 179-190; 1987. 11. Fisher, B.; Rockette, H.; Fisher, E. R.; Wickerham, D. L.; Redmond, C.; Brown, A. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience. J. Clin. Oncol. 3: 1640- 1658; 1985. 12. Fiirst, C. J. Late somatic effects following radiotherapy for hemangioma in children. Stockholm: Karolinska Institute; 1989.
13. Fiirst, C. J.; Silfverswtird, C.; Holm, L. E. Mortality in a cohort of radiation treated childhood skin hemangiomas. Acta Oncol. 28:789-794; 1989. 14. Fiirst, C. J.; Lundell, M.; Holm, L. E. Tumors after radiotherapy for skin hemangioma in childhood. A case-control study. Acta Oncol. 29:557-562; 1990. 15. Fi,irst, C. J.; Lundell, M.; Holm, L. E.; Silfverswgrd, C. Cancer incidence after radiotherapy for skin hemangioma: a retrospective cohort study in Sweden. JNCI 80: 1387- 1392; 1988. 16. Harvey, E. B.; Brinton, L. A. Second cancer following cancer ofthe breast in Connecticut 1935-1982. Natl. Cancer Inst. Monogr. 68:99-l 12; 1985. 17. Hildreth, N. G.; Shore, R. E.; Hempelmann, L. H.; Rosenstein, M. Risk of extrathyroid tumors following radiation treatment in infancy for thymic enlargement. Radiat. Res. 102:378-391; 1985. 18. Holm, L. E. Malignant disease following iodine- 13 1 therapy in Sweden. In: Boice, J. D., Jr.; Fraumeni, J. F., Jr., eds. Radiation carcinogenesis. Epidemiology and biological significance. Progress in cancer research and therapy, Vol. 26. New York: Raven Press; 1984:263-27 I. 19. International Agency for Research on Cancer. IARC Monographs on the evaluation of carcinogenic risks to humans. Overall evaluations of carcinogenicity: an updating of IARC Monographs Volumes 1 to 42 (Suppl. 7). Lyon: World Health Organization; 1987. 20. Li, F. P. Second malignant tumors after cancer in childhood. Cancer 40: 1899- 1902; 1977. 2 1. Lindberg, S.; Arvidsson, B.; Holmberg, E.; Lundberg, L. M. Late somatic and genetic effects studied in more than 10,000 individuals treated as infants with Ra-226 for hemangioma. Proceedings, 3rd Annual Meeting, European Society for Therapeutic Radiology and Oncology, Jerusalem, Sept. 915, 1985; 253. 22. Meadows, A. T.; Baum, E.; Fossati-Bellani, F.; Green, D.; Jenkin, R. D. T.; Marsden, B.; Nesbit, M.; Newton, W.; Oberlin, 0.; Sallan, S. G.; Siegel, S.; Strong, L. C.; Voute, P. A. Second malignant neoplasms in children: an update from the Late Effects Study Group. J. Clin. Oncol. 3:532538: 1985. 23. Ron, E.; Modan, B. Thyroid and other neoplasms following childhood scalp irradiation. In: Boice, J. D., Jr.: Fraumeni, J. F., Jr., eds. Radiation carcinogenesis. Epidemiology and biological significance. Progress in cancer research and therapy, Vol. 26. New York: Raven Press; 1984: 139- 15 1. 24. Ron, E.; Modan, B.; Boice. J. D., Jr. Mortality from cancer and other causes following radiotherapy for ringworm of the scalp. Am. J. Epidemiol. 127:7 13-725; 1988. 25. Shimizu, Y.; Kate, H.; Schull, W. J. Studies ofthe mortality ofA-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on recently revised doses (DS86). Radiat. Res. 121:120-141; 1990. 26. Shore, R. E.; Hildreth, N.; Woodard, E.; Dvoretsky, P.: Hempelmann, L.; Pastemack, B. Breast cancer among women given x-ray therapy for acute postpartum mastitis. JNCI 77:689-696; 1986. 27. Shore, R. E.; Woodard, E.; Hildreth, N.; Dvoretsky, P.: Hempelmann, L.; Pastemack, B. Thyroid tumors following thymus irradiation. JNCI 74: 1177- 1184; 1985. 28. Tucker, M. A.; Coleman, C. N.; Cox, R. S.; Varghese, A.; Rosenberg, S. A. Risk of second cancers after treatment for Hodgkin’s disease. N. Engl. J. Med. 3 18:76-8 I : 1988.
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29. Tucker, M. A.; D’Angio, G. J.; Boice, J. D., Jr.; Strong, L. C.; Li, F. P.; Stovall, M.; Stone, B. J.; Green, D. M.; Lombardi, F.; Newton, W.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Engl. J. Med. 317:588-593; 1987. 30. Tucker, M. A.; Meadows, A. T.; Boice, J. D., Jr.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Cancer risk following treatment of childhood cancer. In: Boice, J. D., Jr.; Fraumeni, J. F., Jr., eds. Radiation carcinogenesis: epidemiology and biological significance. Progress in cancer research and therapy, Vol. 26. New York: Raven Press. 1984:2 1 l-224.
November 1990, Volume 19, Number 5 3 1. Tucker, M. A.; Meadows, A. T.; Boice, J. D., Jr.; Stovall, M.; Oberlin, 0.; Stone, B. J.; Birch, J.; VoOte, P. A.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Leukemia after therapy with alkylating agents for childhood cancer. JNCI 78:459-464; 1987. 32. United Nations Scientific Committee on the Effects of Atomic Radiation. Genetic and somatic effects of ionizing radiation. 1986 report to the General Assembly, with annexes. New York: United Nations; 1986. 33. United Nations Scientific Committee on the Effects of Atomic Radiation. Sources, effects and risks of ionizing radiation. 1988 report to the General Assembly, with annexes. New York: United Nations; 1988.
19. pp.
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0360.3016190
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Copynght 0 I990
$3.00 + 00 Perganml Press plc
0 Oncology Intelligence
CANCER OCCURRING AFTER RADIOTHERAPY LARS-ERIK Department
of Cancer Prevention,
HOLM,
Radiumhemmet,
M.D.,
AND CHEMOTHERAPY
PH.D.
Karolinska Hospital, S- 104 0 1 Stockholm, Sweden
Radiotherapy and chemotherapy can effectively control cancer but can also cause new cancers to develop as longterm complications. Almost all types of cancer have been associated with radiotherapy. The breast, thyroid, and bone marrow are the organs most susceptible to radiation carcinogenesis. The bone marrow is also most frequently involved by chemotherapy and the leukemia risk is much higher than after radiotherapy. The combination of intensive radiotherapy and chemotherapy is particularly leukemogenic. The latent period between radiotherapy/ chemotherapy and the appearance of a second primary cancer ranges from a few years to several decades. The risk for a second primary cancer following radiotherapy or chemotherapy emphasizes the need for life long follow-up of patients receiving such treatments. This is particularly the case in individuals with long life expectancy, for example, patients treated for childhood neoplasms. The benefits of radiotherapy and chemotherapy in oncology exceed the risks for second primary cancers. Efforts should be directed towards identifying those patients who will benefit from the treatments so that only they are exposed to the risk. Radiotherapy,
Chemotherapy,
Second cancers, Radiation-induced.
ment. Thus, for purpose of risk evaluation, the data for any given type of malignant tumor have been considered applicable, within certain limits, to other populations. The effects of exposure to radiation at low doses and/or at low dose rates are less known. Almost all cancers have been associated with radiation exposure. although the breast, thyroid, and bone marrow appear to be the most radiosensitive sites. The excess risk of leukemia attributable to radiation is observed within a few years of exposure with a peak after 6-8 years, and declines thereafter. The most recent follow-up of subjects exposed to the atomic bombings in Japan in 1945 showed that leukemia mortality was still increased nearly threefold in 198 1- 1985 (25). An increased risk of solid cancers usually does not appear until 10 years or more after radiation exposure and extends beyond 30 years after such an exposure (32, 33). Cancer risk usually increases with the radiation dose received by the organ or tissue of interest. Animal studies indicate that the dose-response varies with dose rate and radiation quality (that is alpha, beta, gamma, and x rays). Among biological factors affecting the risk estimates are the type of tissue irradiated, age at exposure, sex, and ethnic group. Young persons are more sensitive to radiogenie cancer than are adults (32, 33). Observations of radiation-induced cancers have mostly been limited to populations who were exposed to relatively high radiation doses in various ways and for various rea-
INTRODUCTION
Exposure to ionizing radiation can have untoward somatic and genetic sequelae. The most serious late somatic effect following such exposure is the induction of malignant tumors. Because of the professional and public interest in the carcinogenic effects of ionizing radiation, these effects have been investigated more thoroughly than those of any other environmental agent. During the past decades, our knowledge about radiation effects in humans has increased considerably and several comprehensive reviews have been published by the United Nations Scientific Committee on the Effects of Atomic Radiation (32, 33) and by the National Academy of Sciences in the U.S.A. (7). Radiation-induced cancers are indistinguishable from those occurring from other causes, and their existence can therefore be deduced only in terms of a statistical excess above the natural incidence or mortality. As yet there is no accepted method of extrapolating the data obtained from experimental animals to man. Hence the risk estimates of cancer induction in man are essentially based on studies on exposed human populations. An increase of several types of malignant tumors in human populations has been observed with an increasing radiation dose (7, 33). The majority of these studies concern exposure to moderate or high doses, usually > 1 Sv, and at high dose rates. The observations made in different exposed populations are usually in relatively good agree-
Accepted for publication 24 May 1990.
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sons. In studies on the effects following exposure to lowlevel radiation, very large sample sizes are required and it is not possible to control adequately for other factors that influence cancer risks. Studies of populations medically exposed to radiation at moderate to high doses can therefore contribute important information on radiation risks in humans. Such populations usually have good dosimetry data, careful follow-up of the individuals, and often also contain non-exposed groups for comparison purpose. Among the disadvantages are the potential effect of the disease-for which the patients have been irradiatedon cancer risks and the partial-body nature of the radiation exposures (2). The observations of cancers following chemotherapy come from populations of patients treated for cancer or other serious illnesses. Both radiation and many of the agents used in cancer chemotherapy interact with cellular DNA. Agents that are used to kill cancer cells may therefore also be cytotoxic or genotoxic to normal cells. In the last 2 decades, several studies have shown that chemotherapy with alkylating agents carries a risk for induction of leukemia, and in some cases bladder carcinomas (for review see reference 19). The leukemia risk in patients receiving chemotherapy for various malignant diseases has been found to be several hundred times higher than expected. The risk increases rapidly after treatment, as in the case of radiation exposure.
METHODS
AND MATERIALS
Populations studied Important surveys of medically irradiated populations include patients treated in infancy or adulthood for benign as well as malignant diseases, for example, tinea capitis
Table 1. Examples of studies of populations irradiated for benign and malignant diseases Reason for radiotherapy Benign Ankylosing spondylitis
Postpartum mastitis Supposed thymus enlargement Tinea capitis Hemangioma Malignant Cervical cancer
Pediatric cancers Hodgkin’s disease
Excess cancers Leukemia, lymphomas, lung, stomach, esophagus, central nervous system Breast Thyroid, leukemia Thyroid, brain, skin, leukemia Breast, soft tissue Bladder, rectum, bone, soft tissue, small intestine, leukemia, ovary Leukemia, thyroid, breast, bone Leukemia, non-Hodgkin’s lymphoma
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(23,24), hemangioma ( 12,2 1), presumed enlarged thymus gland (27), mastitis (26) hyperthyroidism (18), pediatric cancers (20, 30), cervical cancer (3,4), Hodgkin’s disease (5), and polycythemia vera (1) (Table 1). The types of irradiation include external x-ray therapy as well as internally deposited radioactive compounds, for example, 13rI and 32P. It is not within the scope of this paper to review all types of studies. The purpose is to discuss cancer risks following external radiotherapy and chemotherapy in childhood and adulthood. Exposure in childhood Childhood is a period characterized by actively growing tissues, something that may have an impact on the susceptibility to radiation-induced cancer. Data on childhood medical exposure emanate from two sources: children treated for benign conditions and patients receiving radiotherapy, often in combination with chemotherapy, for pediatric cancers. These groups may not be directly comparable, since the groups treated for malignant disease are also comprised of individuals with a genetic predisposition to cancer. Radiotherapy has been used in various benign conditions in childhood. The exposures mainly involve the upper part of the body, for example, tinea capitis (23, 24) and presumed thymic enlargement (27). Leukemias and thyroid cancer are the most common malignancies following such exposures (Table l), although other cancers have also been reported. Tissues that involve non-proliferating cells appear to be relatively non-susceptible to radiation carcinogenesis. The cancers are expressed at the normal adult ages for cancer even when exposure occurs in childhood (33). Consequently, the defined cohorts of exposed children must be followed for several decades to provide better estimates of the cancer risks following radiation exposure in childhood. More than 10,000 persons who were treated with X rays for ringworm of the scalp in childhood have been followed-up in Israel together with more than 16,000 matched subjects and siblings (23, 24). An increased risk for thyroid cancer has been observed above doses of 0.09 Gy. Increased risks have also been observed for leukemia, tumors of the nervous system, and of the head and neck. In studies of children irradiated for a presumed thumus enlargement increased risks for cancers of the thyroid, breast, and skin have been observed (17, 27). Many children have been irradiated to treat skin hemangiomas and two large Swedish cohorts now together comprise more than 28,000 children irradiated between 1920 and 1959 (12, 2 1). The mean age at exposure was 6 months. In one of these studies, significantly increased relative risks (RR) of cancer were found for all sites combined [RR = 1.18; 95% confidence interval (CI) = 1.031.351, breast cancer (RR = 1.65; 95% CI = 1.26-2.13) and soft tissue tumors (RR = 2.73; 95% CI = 1.18-5.38) in patients irradiated with 226-Ra or orthovoltage X rays
Cancer after radiotherapy 0 L.-E. HOLM eful.
(15). RR for thyroid cancer was 1.85 (95% CI = 0.993.17). No increased risks were observed in patients treated with contact x-ray therapy or in those not receiving radiotherapy. Cancer mortality was also significantly increased for all sites combined (13). For non-malignant causes of death, the relative risks did not differ significantly from unity. An increased risk for thyroid cancer was observed already at doses above 0.1 Gy and for tumors of bone and soft tissue at doses of 0.5 Gy or more (14). The evidence from children irradiated because of a primary cancer shows a high susceptibility to second cancers. These populations contain a relatively high fraction of children who are genetically susceptible to cancer and therefore may be different from other children. The results from exposure following childhood cancers can therefore not be used for estimating risks in the general population. Studies of two large cohorts of irradiated children indicate a relative risk of 15 or more for a second cancer of any site (20, 22, 29, 30, 3 1). The cumulative probability of a second cancer 25 years after diagnosis of first cancer was 12% (30). Two-thirds of all second cancers were observed in the field of irradiation with a median latency period of 10 years. The second cancers were concentrated in patients originally treated for tumors of genetic origin and in patients with a primary cancer in sites known to be radiogenic, that is, hematopoietic and bone tissues. In more than 9,000 children with pediatric cancer, the leukemia risk was increased following treatment with alkylating agents (RR = 4.8) but not after radiotherapy (3 1). A marked dose-response relationship was observed for alkylating agents, and RR for leukemia reached 23 in the highest dose category. The subsequent risk of bone sarcoma in the same cohort was also increased following radiotherapy as well as after chemotherapy with alkylating agents (27). Overall RR for bone sarcoma was 133 (95% CI = 98-176) with a cumulative risk of 2.8% after 20 years of follow-up. Radiotherapy resulted in a RR of 2.7 after a mean dose of 27 Gy with no increased risk at doses less than 10 Gy. Above that dose, RR increased with dose and was 40-fold at doses of more than 60 Gy. Treatment with alkylating agents was associated with RR = 4.7 (95% CI = 11.0-22.3) after adjustment for radiotherapy, and the risk increased with the cumulative drug exposure. Children with retinoblastoma were at high risk for osteosarcoma (RR = - 1,000) and connective tissue (RR = 235) (30). The cumulative risk for second cancers in retinoblastoma patients was 14% after 20 years (29). In patients with Wilms’ tumor the highest risks were observed for cancers of the thyroid (RR = 136) bone (RR = 127) and connective tissue (RR = 84) (30). Li (20) calculated the cumulative risk for second cancer in patients with Wilms’ tumor to 18% after 34 years. In patients with Ewing’s sarcoma, elevated RRs were observed for osteosarcoma (RR = 649) and leukemia (RR = 62) (28). The cumulative cancer risk following radiotherapy was estimated to 35% after 10 years.
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Studies of patients treated for Hodgkin’s disease have reported increased risks for cancers of bone (RR = 106) leukemia (RR = 89) and thyroid (RR = 68) (30). In a study from Stanford (28) of 1,500 patients with Hodgkin’s disease, RR for leukemia was 11 after radiotherapy alone, 117 after adjuvant chemotherapy containing alkylating agents, and 130 after chemotherapy alone. The mean 15year actuarial risk of all second cancers in that study was 17.6%, of which 13.2% were solid tumors. Long-term survivors of a pediatric cancer thus have an elevated risk of developing a second cancer, reaching 12% by 25 years of follow-up. Each cancer has an array of second tumors and some of the combinations appear to reflect genetic factors or susceptibility to the treatment (30). Exposure in adulthood
Most adult exposures are the result of radiotherapy. The major sources of information come from patients irradiated for ankylosing spondylitis ( 10) and for cervical cancer (3,4), although other cohorts have also contributed with valuable information, for example, patients treated for Hogdkin’s disease (5) and mastitis (26). Such patients, however, may not be representative of the general population, since the obtained data may have been confounded by the underlying disease or by treatment other than radiation. Patients who received x-ray therapy for ankylosing spondylitis had a three-fold increase in mortality from leukemia compared to the general population (10). The highest risk was observed between 3-5 years after treatment and then declined. A considerable excess of cancers occurring in heavily irradiated organs was also observed, such as lung, stomach, and esophagus. The largest study of second tumors in cervical cancer patients was comprised of over 182,000 patients from eight countries (3, 4). Of 5,146 cancers, at most 5% were attributable to the radiation exposure. High doses to the pelvic region was associated with increased risk of cancer to exposed organs, including bladder, rectum, bone, connective tissue, and small intestine. RR for leukemia other than cronic lymphocytic leukemia was 2.0, and the risk increased with increasing radiation dose until about 4 Gy and then decreased at higher doses due to cell killing. Patients given X-ray therapy for post-partum mastitis have contributed information concerning radiation-induced breast cancer (26). RR for breast cancer was 3.2 for the irradiated breast. The relation between dose and breast cancer risk was consistent with linearity up to 7 Gy. Harvey and Brinton (16) observed an RR of second primary breast cancer of 3.9 (95% CI = 3.6-4.2) in patients irradiated for breast cancer compared to 1.5 (95% CI = 1.5- 1.6) for women treated without radiation. In a study by Curtis et al. (9) of 39,000 breast cancer patients, the RR for leukemia was 1.O following surgery, 1.7 for radiation only, and 3.8 for chemotherapy alone.
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Table 2. Leukemias and solid cancers following Hodgkin’s disease in relation to type of treatment (5) Leukemias
Cancers
No. per
1000 PY *
9590 CI
No. per 1000 PY *
95% CI
No intensive therapy Intensive radiotherapy Intensive chemotherapy Intensive radiotherapy + intensive chemotherapy
0 1.0 4.0
o.o- 1.2 0.3-2.4 1.5-8.8
4.8 3.4 7.5
3.0-7.5 1.5-6.7 3.4-14
7.0
4.0-I 1
9.3
3.0-22
Total
2.3
1.5-3.4
5.1
3.7-12
Type of treatment
* PY = person-years.
Among 440,000 cancer patients the RR of leukemia was 1.0 after surgery, 1.4 after radiation only, and 2.3 after chemotherapy alone (9). In a recent study of a cohort of 22,800 breast cancer patients treated with radiation, the RR for leukemia was 1.16 (90% CI = 0.6-2. I) and there was no dose-response pattern (8). The result excluded an association between leukemia and radiotherapy for breast cancer of 2.2-fold with 90% confidence. The risk for leukemia following adjuvant chemotherapy for breast cancer was reported by Fisher et al. (I 1) to be 1.7% at 10 years after surgery compared to 1.4% after radiotherapy. The risk figures may change with an increasing period of follow-up. In adult patients treated for Hodgkin’s disease leukemia is the most common second cancer and particularly acute non-lymphocytic leukemia (ANLL). X-ray therapy alone does not seem to be a major risk factor for leukemias in these patients. Chemotherapy has been strongly associated with second leukemias and combined therapy appears to increase the risk further (Table 2) (5). The actuarial risk of developing secondary ANLL following radiotherapy plus adjuvant MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone) was in the range of 5-7% at 7 years of follow-up (6). Second leukemias have been observed after different regimens containing nitrogen mustard as well as nitrosourea combinations. In contrast, no increased risk of ANLL has been demonstrated following chemotherapy with doxorubicin, bleomycin, vinblastin, and dacarbazine, suggesting that this regimen carries a lower leukemogenic risk. The age of the patients at the time of treatment appears to be of importance, and in the older age group, the actuarial risk of secondary leukemia exceeds 20%. With sufficiently long follow-up, the risk for solid tumors at 10 years exceeds that of leukemia (6). The risk of acute leukemia in 431 patients with polycythemia vera was 2.3 times higher after chlorambucil treatment than after 32P therapy and 13.5 times that in patients treated with phlebotomy alone (1). The excess in 32P patients relative to phlebotomy-treated patients was
not statistically significant. Thus, the excess incidence in patients treated with chlorambucil was 3.5 (95% CI = 1.67.6) times that in patients in the other two groups combined. DISCUSSION The risks for radiation-induced cancer following radiotherapy are relatively small and the cancers appear after long latency periods. The risk can be reduced further by more careful staging of tumors and improved radiotherapeutic techniques, such as better definition of the target volume, and the use of higher energies which yield a more exact dose distribution. Chemotherapy appears far more potent than radiotherapy in inducing leukemia. On the other hand, chemotherapy does not increase the risk of other cancers (with the possible exception of bladder cancer), as is the case with radiotherapy. The introduction of chemotherapy in the treatment of cancer has resulted in a higher proportion of patients being cured of their first cancer. Without these agents, many patients with, for example, pediatric cancers, testicular cancer, and Hodgkin’s disease would never have lived sufficiently long to be at risk for a second cancer. The risks following chemotherapy must be carefully analyzed over the next decade when large cohorts have sufficiently long periods of follow-up. The increasing use of adjuvant chemotherapy for early stages of cancer raises concern as to the possible late effects of such a treatment. The potential hazards of cancer treatments should be weighed against the consequences of not using such treatments. The choice of radiotherapy and chemotherapy in oncology should not solely be based on the risk for second primary cancers but rather on the risk for acute side effects and on the chance for cure. The benefits exceed the risk for second primary cancers. Efforts should, however, be directed towards identifying those patients who will benefit from the treatments so that only they are exposed to the risk.
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29. Tucker, M. A.; D’Angio, G. J.; Boice, J. D., Jr.; Strong, L. C.; Li, F. P.; Stovall, M.; Stone, B. J.; Green, D. M.; Lombardi, F.; Newton, W.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Bone sarcomas linked to radiotherapy and chemotherapy in children. N. Engl. J. Med. 317:588-593; 1987. 30. Tucker, M. A.; Meadows, A. T.; Boice, J. D., Jr.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Cancer risk following treatment of childhood cancer. In: Boice, J. D., Jr.; Fraumeni, J. F., Jr., eds. Radiation carcinogenesis: epidemiology and biological significance. Progress in cancer research and therapy, Vol. 26. New York: Raven Press. 1984:2 1 l-224.
November 1990, Volume 19, Number 5 3 1. Tucker, M. A.; Meadows, A. T.; Boice, J. D., Jr.; Stovall, M.; Oberlin, 0.; Stone, B. J.; Birch, J.; VoOte, P. A.; Hoover, R. N.; Fraumeni, J. F., Jr.; for the Late Effects Study Group. Leukemia after therapy with alkylating agents for childhood cancer. JNCI 78:459-464; 1987. 32. United Nations Scientific Committee on the Effects of Atomic Radiation. Genetic and somatic effects of ionizing radiation. 1986 report to the General Assembly, with annexes. New York: United Nations; 1986. 33. United Nations Scientific Committee on the Effects of Atomic Radiation. Sources, effects and risks of ionizing radiation. 1988 report to the General Assembly, with annexes. New York: United Nations; 1988.
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