second cancers and other late side effects of cancer treatment.a review

Second Cancers and Other Late Side Effects of Cancer Treatment

A Review

JEAN-FRANCOIS BOIVIN, MD, SCD

The author reviewed the question of late side effects of cancer treatment. A late side effect was defined as an unwanted and deleterious effect observed for the first time 12 months or longer after treatment. In a survey of articles published by The New England Journal of Medicine and The Lancet from 1968 to 1988, nine categories of late side effects were identified: second cancers, hormonal and reproductive effects, effects on the immunologic system, heart disease, effects on kidney and urinary bladder, effects on gastrointestinal organs, neurologic and psychological effects, pulmonary toxicity, and osteonecrosis. The induction of second cancers is a particularly important late side effect of cancer treatment. Several epidemiologic studies demonstrated increased risks of leukemia and solid tumors in patients exposed to radiotherapy. Large increases in leukemia risk have also been observed after chemotherapy with alkylating agents. However, several research questions remain unanswered, including the duration of the excess cancer risk after treatment, and the independent effect of various drugs on second cancer risk.

Cancer 65:770-775, 1990.

UCH KNOWLEDGE IN medicine and biology is de- M rived from the investigation of side effects of medical interventions. For example, eight of the 50 agents classified as carcinogenic to humans by the International Agency for Research on Cancer are drugs or groups of drugs used for cancer treatment.' Similarly, much of our knowledge on the biological effects of ionizing radiation stems from the investigation of populations exposed to diagnostic or therapeutic irradiation.2 Other examples are the teratogenicity of thalid~mide,~ the effects of hormones on the cardiovascular ~ y s t e m , ~ and the effect of immu- nosuppression on the risk of in fe~t ion .~

In addition to furthering our understanding of biological phenomena, determining the incidence of side effects of medical interventions is essential to the clinical man- agement of patients; this is particularly true in oncology because of the intensity and potential toxicity of treat-

Presented at the National Conference on Advances in Cancer Man- agement, Los Angeles, California, December 7-9, 1988.

From the Department of Epidemiology and Biostatistics, McGill Uni- versity, Montrtal, Qutbec, Canada.

Supported by Public Health Service Grant 2R01CA-22849 from the National Cancer Institute of the United States.

Dr. Boivin was a recipient of a National Health Research Scholar award from the National Research and Development Program of Canada.

Address for reprints: Jean-FranCois Boivin, MD, ScD, Department of Epidemiology and Biostatistics, McGill University, 1020 Pine Avenue West, Montrkal, Qutbec, Canada H3A 1A2.

Accepted for publication June 6, 1989.

ments. With improvements in the survival of cancer patients, it has become useful to distinguish between early and late side effects of treatment. The objective of this article is to review the issue of late side effects of cancer treatment, with a special emphasis on second cancer risk.

The literature on late side effects of cancer treatment is vast. Reviews of the long-term effects of cancer treatment on normal tissues have already been p ~ b l i s h e d , ~ , ~ as well as reviews of specific categories of side effects, such as the carcinogenicity of antineoplastic agents.' My objective was to establish a general overview of the status of the literature by examining articles published in two major medical journals during a 20-year period, as well as to present a more detailed review of the problem of second cancer risk making wider use of the published literature.

Methods

I reviewed the tables of contents of The New England Journal of Medicine and of The Lancet for the period July 1968 through June 1988. Articles discussing late side effects of cancer treatment were identified and reviewed. I defined a late side effect as an unwanted and deleterious effect of treatment observed for the first time 12 months or longer after cancer treatment. Only articles having a title mentioning cancer treatment, and also indicating a possible side effect, were included. In The New England Journal of Medicine, Case Records of the Massachusetts

770

No. 3 LATE SIDE EFFECTS OF CANCER TREATMENT - Boivin 77 1

General Hospital and the correspondence section were not reviewed. In The Lancet, the letters to the editors were excluded. For the review of the issue of second cancer risk, the analysis of the literature was more general and was therefore not restricted to these two journals.

Results

Table 1 gives the distribution of the articles identified in this review, by journal and type of article. A total of 74 articles was inc l~ded .~ ,~-"

Table 2 indicates the late side effects that were described. Nine broad categories of late side effects were recognized:

1. Second cancers after radiotherapy, chemotherapy,

2. Hormonal and reproductive effects: hypothalamic- pituitary function after cranial radiotherapy, chemotherapy, or b ~ t h " , ~ ~ , ~ ~ , " ; gonadal histology and function in males after chemotherapy or testicular irradia-

in females after chemotherapy, radiotherapy, or

motherapy, radiotherapy, or both.50 3 . Effects on the immunologic system: immune func-

tion after chemotherapy, radiotherapy, or both,25,30,35955 and risk of infection after splenectomy. 13922362,76

4. Heart disease: cardiomyopathy after Adriamycin (Adria Laboratories, Columbus, OH)3 1,58 and pericarditis, coronary artery disease, cardiac function, and other cardiac end points after i r r a d i a t i ~ n . ~ ~ , ~ ~ , ~ ~ . ~ ~

5 . Effects on kidney and urinary bladder: nephropathy after radiation or radiation with ~ h e m o t h e r a p y ~ ~ , ~ ~ ; renal failure after meth~l-CCNU~~; cystitis after radiotherapy7'; and urinary bladder fibrosis and telangiectasia after cyclophosphamide.

6. Effects on gastrointestinal organs: hepatic changes resulting in portal hypertension after chem~therapy,~-'~ and damage to the small intestine, colon, and rectum after r a d i ~ t h e r a p y . ~ ~ . ~ ' , ~ ~

7. Neurologic and psychological effects: ataxia after 5- fluorouracil'6 and changes in neuropsychologic function, IQ score, cognitive function, and computed tomography (CT) scan after cranial irradiation with or without intrathecal chemotherapy. 18,27,68

or both.~~.l4,~5,l9,23,24,26,32,33,37,4O-42,46-49,5l-53,6~,64,73,79

tion28,29,38,45,54,60,66,67. , gonadal and reproductive function

both20.21,39,65. , and fertility in males and females after che-

TABLE I . Articles on Late Side Effects of Cancer Treatment from Julv 1968 Through June 1988

New England Type of article Journal of Medicine Lancet Total

Original article 35 16 51 Review article 2 2 4 Editorial 7 12 19

Total 44 30 14

TABLE 2. Distribution of the Articles by Late Side Effect

New England Journal of

Category of late side effect Medicine Lancet Total

Second cancers Hormonal and reproductive effects Effects on the immunologic

Heart disease Effects on kidney and urinary

bladder Effects on gastrointestinal organs Neurologic and psychological

Pulmonary toxicity Osteonecrosis Editorials or review articles

system

effects

discussing two or more of the categories of late side effects mentioned above

Total

19 9

5 3

2 1

3 1 0

1

44

5 24 8 17

3 8 3 6

3 5 4 5

1 4 0 1 1 1

2 3

30 14

8. Carmustine (BCNU) pulmonary 9. Osteonecrosis after combination ~hemotherapy .~~

Second Cancers

The induction of second cancers is a clinically important late side effect of cancer treatment. Increased risks of second cancers have been observed after radiotherapy and chemotherapy.

Radiotherapy and the Risk of Second Cancers

Many epidemiologic studies demonstrated that ionizing radiation is a cause of human cancer.2 Several of these studies were conducted in patients exposed to medical irradiation for diagnostic or therapeutic purposes. How- ever, in spite of the vast literature on this subject, several issues are still not completely understood. These include the shape of the dose-response curve, the influence of patient characteristics such as age, sex, or underlying medical condition on the risk of radiation-induced cancer, and the duration of the increased risk after exposure.

The epidemiologic characteristics of radiation-induced cancers vary by cancer site. In particular, the latency for radiation-induced leukemia is much shorter than that for solid cancers. Because of this difference between leukemias and solid cancers, the following sections treat these two categories of cancer separately.

Radiotherapy and the Risk of Leukemia

The risk of leukemia after radiotherapy was assessed in several groups of cancer patients, including patients with cervical cancer 82-90 and patients with Hodgkin's disease.26,40,91-97 I n some studies, patients with all types of first primary cancer were i n c l ~ d e d . ~ ' ? ~ ~ These studies sup-

Vol. 65 772 CANCER February I Supplement 1990

port the hypothesis that the dose-response curve for radiation-induced leukemia is not linear but follows a shape described by the following equation:

F(D) = (a + bD + cD2) exp(-fD - gD2)

where F(D) is leukemia incidence as a function of dose D and the constants a, b, c, f, and g are constrained to positive values. This formula implies that at high doses, such as those involved in modern radiotherapy, the risk of leukemia is actually decreased relative to the risk at intermediate doses, such as those given in the past for diseases like ankylosing spondylitis.

Epidemiologic studies are still required to determine the exact level of risk involved, and whether the cancer being treated and other patient characteristics have any effect on the susceptibility of the patient to radiation-induced leukemia.

Radiotherapy and the Risk of Solid Tumors

The Beir report”’ indicated that almost all types of cancer can be caused by exposure to ionizing radiation. However, certain organs, such as the thyroid gland and the female breast, appear to be more radiosensitive than others. Epidemiologic studies of large groups of patients are required over long periods of follow-up to quantify the risk of solid tumors after radiotherapy. Historically, these studies have been difficult to conduct because of the poor survival of cancer patients. With the steady improvements in survival observed for certain cancer sites since the 1950s and 1960s, however, epidemiologists now have more opportunities to investigate the risk of solid tumors after radiotherapy for diseases such as Hodgkin’s disease or cervical cancer. For example, Boice et aL9’ determined the risk of second cancer in 82,6 16 women ir- radiated for cervical cancer. Analyses were presented for second primary cancers at 27 anatomic sites. Boice et al. determined that “Sites in or near the radiation field that likely received over 100 rad included the stomach, small intestine, colon, rectum, liver, gallbladder, pancreas, uterine corpus, ovary, other genital organs, kidney, bladder, bone, and connective tis~ue”.~’ The relative risk of cancer for all these sites combined, 10 years or longer after treatment, was 1.3. The relative risk increased over time, reaching a maximum of 2.1 at 30 years or longer after treatment. The thyroid gland was classified among the sites remote from the cervix. The relative risk of thyroid cancer was 1.1. The authors indicated that “The thyroid is very sensitive to the carcinogenic action of ionizing radiation, especially in women . . .” and that the average dose of 15 rad received by the exposed women possibly caused the small observed excess in thyroid cancer risk. For cancers at other sites remote from the cervix, relative risks either were not increased beyond expectation, or were

probably elevated because of exposure to risk factors other than radiation.”

Boivin and OBrien”’ camed out a meta-analysis of seven studies of second cancer risk after treatment for Hodgkin’s disease. Statistically significant increases in the risk of solid cancer after radiotherapy were found for the buccal cavity and pharynx, digestive system, respiratory system, bones and joints, soft tissues, skin, brain and other nervous system, and non-Hodgkin’s lymphomas. The female breast, a recognized radiosensitive organ,’00 did not show any excess in risk. There was a suggestion of an increased risk of cancer of the thyroid gland, also considered to be a radiosensitive organ, but the excess was not statistically significant.

Further research is needed on the issue of solid cancer risk after radiotherapy, particularly to confirm excesses in risk suggested by currently available data, and to determine how long increases in risk persist after radiotherapy.

Chemotherapy and the Risk of Second Cancers

The International Agency for Research on Cancer reviewed the issue of the carcinogenicity of several drugs used for cancer treatment. In 1987, the agency published lists of agents carcinogenic to humans. ’ Carcinogenic substances were classified into three categories:

Group 1. Agents considered as established carcinogens for human beings: 50 agents including eight oncotherapeutic drugs or groups of drugs.

Group 2A. Agents probnbly carcinogenic to humans: 37 agents including eight oncotherapeutic drugs.

Group 2B. Agents possibly carcinogenic to humans: I59 agents including nine oncotherapeutic drugs or groups of drugs.

The oncotherapeutic drugs classified as carcinogenic, probably carcinogenic, or possibly carcinogenic are listed in Table 3. In general, useful epidemiologic data on the carcinogenicity of these drugs are only available for Group 1, i.e., for established carcinogens. Cases of bladder cancer were observed after exposure to chlornaphazine and cyclophosphamide.’ However, the most important second cancer after chemotherapy is acute nonlymphocytic leukemia. Epidemiologic studies demonstrated excess leukemia risks after treatment with Myleran (Burroughs Wellcome Co., Research Triangle Park, NC), chlorambucil, methyl-CCNU, cyclophosphamide, melphalan, the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP), and other combined chemotherapy including alkylating agents, and treosulfan.’ The relative risk of leukemia after exposure to alkylating agents can be extremely high, ie., 50 to 100 after MOPP treatment for Hodgkin’s disease, for example.

No. 3 LATE SIDE EFFECTS OF CANCER TREATMENT - BOiVZn 773

TABLE 3. Carcinogenicity of Oncotherapeutic Drugs*

Classification Drugs

Group 1 : Carcinogenic Chlomaphazine, Myleran (busulfan), chlorambucil, methyl-CCNU, cyclophosphamide, melphalan, MOPP and other combined chemotherapy including alkylating agents, treosulfan

Adriamycin (doxorubicin), BCNU, CCNU, Group 2A: Probably carcinogenic cisplatin, N-methyl-N-nitrosourea,

nitrogen mustard, procarbazine hydrochloride, thiotepa

Azaserine, bleomycins, dacarbazine,

acetate, merphalan, mitomycin C, streptozotocin, uracil mustard

Group 2B: Possibly carcinogenic daunomycin, medroxyprogesterone

* From the International Agency for Research on Cancer.’ MOPP, combined therapy with nitrogen mustard, vincristine, pro-

carbazine, and prednisone; BCNU: carmustine; CCNU: lomustine.

The strong leukemogenicity of several oncotherapeutic drugs suggests that these substances may also cause solid tumors. However, patients receiving chemotherapy fre- quently have a poor prognosis, and relatively few patients exposed to chemotherapy are currently available to determine the level of risk after the long latency intervals required for the development of solid cancers. As the prognosis of cancer patients continues to improve, long- term follow-up to determine solid cancer risk will become possible.

Conclusion

Late side effects of cancer treatment affect a wide variety of systems and organs. A large body of literature is rapidly accumulating on this issue. However, several of these effects remain poorly documented. In addition, the meaning of the word “late” is evolving. Until quite recently, the literature described late side effects as those occurring within a few years after cancer treatment. However, with increasing numbers of patients surviving decades after initial treatment with modern modalities, investigators are now turning their attention to longer spans of time. For example, Blayney et aL4’ recently described the risk of leukemia among 192 patients with Hodgkin’s disease who were followed for a median interval of over 15 years. Studies of solid cancer risk, which require long follow-up intervals, are also becoming more important.49 Studies of gonadal function after radiotherapy or chemotherapy, of- ten conducted relatively early after treatment, are now accompanied by studies of fertility, which require longer survival and follow-up.5o Eventually, children and young adults treated for cancer will have to be followed to determine the incidence of side effects several decades after initial treatment.

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