solid cancer risk after treatment of hodgkin's disease

Solid Cancer Risk After Treatment of Hodgkin’s Disease

JEAN-FRANCOIS BOIVIN, MD, SCD,’ AND KATHERINE O’BRIEN, BSCt

We pooled the data from seven studies of second cancer risk after treatment of Hodgkin’s disease (HD) and estimated the relative risks (RR) of solid cancers (SC) for the following two treatment groups: (1) radiotherapy, with or without chemotherapy; and (2) chemotherapy alone. For all treatment groups combined, the RR of SC was 2.1 (95% confidence limits: 1.8 to 2.4). In the radiotherapy group, statistically significant RR were found for SC for all anatomic sites (RR: 2.2; 95% confidence limits: 1.9 to 2.6) and for SC of the bones and joints (RR 20.0), soft tissues (RR 18.3), non-HD lymphomas (RR 8.1), melanomas of the skin (RR 6.7), buccal cavity and pharynx (RR 4.1), nervous system (RR 3.6), respiratory system (RR: 2.5), and digestive system (RR 1.8). In the chemotherapy alone group, none of the RR differed significantly from unity, and the RR for SC of all sites was 1.1 (95% confidence limits: 0.5 to 1.9). The average duration of follow-up for patients with chemotherapy was shorter than the duration of follow-up for patients with radiotherapy. This may explain the general absence of elevated RR after chemotherapy.

Cancer 61:2541-2546,1988.

URING THE 1960s, the treatment of Hodgkin’s dis- D ease (HD) changed considerably with, in particular, the introduction of intensive radiotherapy and intensive chemotherapy. Survival improved but at the same time side effects were recognized from these new treatment methods. A side effect of special impor- tance was the occurrence of second cancers, which was reported as early as 1972 by Arseneau et al.’ among patients treated intensively for HD. Since then, other investigators have described studies about this ques-

Several of these studies have demonstrated a strong association between intensive chemotherapy for HD and the risk of subsequent leukemia. However, no clear pattern of excess solid cancer (SC) risk after intensive treatment for HD has emerged from the published literature yet. Several studies suggested that an increased SC risk may exist,l,l 1,18.21,24,30,31,34,38 whereas no excess was found in other s t ~ d i e s . ~ ~ , ~ ’ Treatments found to be

From the Faculty of Medicine, McGill University, Montrkal, Can- ada.

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

* Recipient of a National Health Research Scholar award from the National Health Research and Development Program of Canada.

t Recipient of a Terry Fox Cancer Research Clerkship award from the National Cancer Institute of Canada.

The authors thank Dr. George B. Hutchison (Harvard University) for suggestions.

Address for reprints: Jean-FranGois Boivin, MD, ScD, Department of Epidemiology and Biostatistics, McGill University, 1020 Pine Ave- nue West, MontrCal, QuCbec, Canada H3A 1A2.

Accepted for publication November 30, 1987.

associated with an increased risk of SC varied from study to study. For example, Henry-Amar3’ suggested that intensive chemotherapy may cause SC, whereas Boivin et al.34 found no such increase in risk after intensive chemotherapy. However, Boivin et observed a large and statistically significant increase after intensive radiotherapy.

Several explanations may account for this lack of a clear pattern in the incidence of SC after intensive treatment for HD. A minimum latency period of 10 to 15 years after exposure to carcinogens may be necessary before substantial excesses in SC risk may be observed, and in some studies, the average duration of the follow- up may have been too short. Also, sample sizes often were too small to detect small increases that may exist after short latency periods (ix, 10 years). Finally, site- specific analyses generally were not presented in the published studies, yet it is probable that if solid cancers are caused by treatments for HD, the excess risk will vary by anatomic site. Therefore, analyses grouping all cancer sites together may be less likely to detect associations between treatment of HD and SC risk than site- specific analyses.

To gain further insights into this question of SC risk after intensive treatment of HD, we pooled data from seven studies of the incidence of second cancers in patients with HD. This pooled analysis could not over- come the problem of follow-up of short duration. How- ever, because of the large sample size obtained by com- bining data from several studies, the statistical power to detect early rises in second cancer risk was increased. In

254 1

2542 CANCER June 15 1988 Vol. 61

addition, we were able to carry out site-specific analyses, which were not presented in the individual studies we reviewed.

Methods

We restricted our review ofthe literature to studies of series of patients with HD in which incidence rates of second cancers had been determined. Therefore, we excluded from our review case reports of individual patients in whom multiple primary cancers were observed. We identified 38 studies that gave data on the incidence of second cancers after treatment of HD with modern modalities.'-38 Some of these studies also included data on patients treated before the general introduction of intensive therapy in the late 1960s. From these 38 studies, we selected all of the studies that met the following criteria:

1. The study gave incidence data for all types of SC. Therefore, studies restricted to specific second cancer sites, such as non-Hodgkin's lymphoma or bone cancer, were excluded. Some studies could not be used because they presented data for the incidence of leukemia only.

2. The presence or absence of chemotherapy and radiotherapy could be determined for all study subjects.

When two or more studies appeared to describe over- lapping series of patients, we chose the study that provided the most useful data for our analyses.

The following treatment groups were defined for the analyses: (1) some radiotherapy and some chemotherapy (RC); (2) some radiotherapy and no chemotherapy (Re) ; ( 3 ) no radiotherapy and some chemotherapy (Rf); and (4) no radiotherapy and no chemotherapy (Re).

Seven studies met our criteria and were used for our pooled For each treatment category, the ratio of the observed number of second cancers to the number expected on the basis of general population cancer incidence rates was obtained. Observed numbers were obtained by adding the observed numbers reported in each of the seven studies. Expected numbers were calculated by multiplying the estimated age-sex-specific distribution of person-years for the total of the seven studies by the age-sex-specific cancer incidence rates obtained by the Third National Cancer Sur- ~ e y . ' ~ Our study was restricted to the analysis of SC risk. Therefore, this study does not show data on observed and expected cases of leukemia.

The number of person-years in each treatment group was specified in only two of the seven studies retained for our a n a l y ~ e s . ' ~ , ~ ~ For two other studies,'"'' we estimated the number of person-years in each treatment group as the number of subjects in the treatment group

multiplied by the median duration of follow-up for the subjects in that group. In three s t ~ d i e s , ~ ~ , ~ ' , ~ ' the number of person-years in each treatment group was estimated as the number of subjects in the treatment group multiplied by the median duration of follow-up for the subjects in the entire series in the particular study.

None of the seven studies gave the distribution of the person-years by age and sex. However, it was possible to obtain the age-sex distribution of the person-years for each treatment category for one of these studies, the study published by Boivin et al.,34 because the raw data from that study were available to us. The appendix table gives the distribution of the person-years in the data set analyzed by Boivin et u I . , ~ ~ by age and sex, for all treatments and for the categories RC, Re, RC, and Rc. In our analyses of the data from the seven studies, we sim- ply assumed that the age-sex distribution of the person- years within treatment categories in the seven studies was identical to the age-sex distribution shown for each treatment category in the appendix table.

Exact confidence limits of the observed-to-expected ratios were estimated as suggested by Rothman and B~ice,~ ' dividing confidence limits of the observed number of cancers by the expected number. The confidence limits of the observed numbers were obtained from a table presented by Pearson and Har t l e~ .~ ' For observed numbers greater than 30, approximate confidence limits were computed with the use of a method proposed by Byar and described by Rothman and B~ice.~ ' Observed- to-expected ratios whose 95% confidence limits did not include unity were considered statistically significant at the 5% level.

Throughout this study, we used the terms relative risk (RR) and observed-to-expected ratio synonymously.

Results

Table 1 lists the seven studies selected for our analyses. The total number of subjects was 65 13 and the number of person-years was 34,780. The number of SC included in the subsequent analyses was 154. Fifty-eight SC were excluded from all subsequent analyses because they belonged to categories also excluded from the rates published by the Third National Cancer Survey,39 our source of incidence rates for the calculation of expected numbers. These 58 cancers included 49 squamous cell or basal cell skin cancers, eight in situ carcinomas of the cervix uteri, and one histiocytosis X.

Table 2 presents the distribution of the SC and person-years for the seven studies by treatment. In the treatment category RC, one cancer, a squamous cell carcinoma of the base of the tongue, was observed in 120 person-years at risk. Because these numbers are very small their statistical precision is very limited, and we

No. 12 SOLID CANCERS AFTER HODGKIN’S DISEASE - Boivin and O’Brien 2543

TABLE I . Studies Selected for Pooled Analyses

Authors

Baccarani et al. l 2

Nelson et Coleman et a/.” VaIagussa et Henry-Amar3’ Boivin et Tester et al.” All studies

No. of solid second cancers

Median or average Included in No. of length of follow-up No. of subsequent

patients ( Y d person-years* analyses

613 3.6 2368 5 248 5.3 1277 9

1222 5.4 6666 31 1032 4.2 4300 18 334 10.0 3340 16

2591 4.4 1 1,446 52 413 11.4 5383 23

6513 5.3 34,780 154

Excluded from subsequent

analyses

0 0 5 5 3

43 2

58

* The number of person-years is not always exactly equal to the number of patients multiplied by the median or average length of

excluded the data from this treatment group from all subsequent tables.

Table 3 gives RR of SC by anatomic site and by treatment for HD. The RR for SC of all anatomic sites for the total series (i.e., RC + RC + RC) was 2.1, with 95% confidence limits of 1.8 and 2.4. For radiotherapy with chemotherapy, the RR was 2.6 (limits: 2.0 to 3.2). For radiotherapy alone, it was 1.9 (limits: 1.5 to 2.5). For chemotherapy alone, it was 1.1 (limits: 0.5 to 1.9).

The site-specific RR given in Table 3 indicated mod- erate to large increases in cancer risk for some anatomic sites, and no increase or very small increases for other sites. The pattern of increase in risk was very similar for the two radiotherapy groups, RC and RC. These two groups were pooled in the analyses shown in Table 4. Therefore, Table 4 presents results for the following two categories: ( 1) radiotherapy, with or without chemotherapy; and (2) chemotherapy alone. In the radiotherapy group, statistically significant increases in the risk of cancer were found for the buccal cavity and pharynx, digestive system, respiratory system, bones and joints, soft tissues, melanomas of skin, brain and other nervous system, and non-Hodgkin’s lymphomas. The female breast, a recognized radiosensitive did not show any excess in risk.

TABLE 2. Solid Second Cancers and Person-Years, by Treatment

Solid Treatment second cancers Person-years

RC 78 16,948 RC 64 14,383 RC 11 3329 RC 1 120 All treatments 154 34,780

RC: some radiotherapy and spme chemotherapy; RC: some radiotherapy and_ no chemotherapy; R C no radiotherapy and some chemotherapy; RC: no radiotherapy and no chemotherapy.

follow-up, because of rounding in the calculations.

All four cancers of the endocrine system observed in the radiotherapy group were cancers of the thyroid gland, another radiosensitive organ.42 Therefore, we estimated RR for cancer of the thyroid gland alone. The estimates were identical to those given in Tables 3 and 4 for the whole endocrine system. There was a suggestion of an increased risk, but the excess was not statistically significant.

In the chemotherapy group, the RR generally were not elevated and none were statistically significant.

This discrepancy between our findings for radiotherapy and chemotherapy may be due, in part, to the na- ture of the data available to us. Table 2 shows that only 10% of the person-years accrued in the seven pooled studies occurred after chemotherapy alone. Our power to detect associations between chemotherapy and cancer risk was, therefore, less than the power for the radiotherapy data. In addition, data from some of the studies that we reviewed suggest that the average duration of follow- up for patients with chemotherapy alone was less than the corresponding duration for the radiotherapy groups. For example, we were able to determine the distribution of the SC by latency period for five of the seven pooled studies. 12,16,30,34,37 Th e percentages of SC observed beyond 10 years after diagnosis of HD were as follows: (1) 23% for RC, (2) 35% for RC, and (3) 18% for RC. We also estimated the average duration of follow-up for the patients by treatment for the five studies that provided this data.12,16,21.27.30 Th e average durations of follow-up were as follows: (1) 60.0 months for RC, (2) 7 1.4 months for RC, and (3) 43.0 months for RC.

Discussion

We found in our pooled analyses a 2.1 -fold increase in the risk of SC of all anatomic sites after treatment of HD (Table 3). A statistically significant RR of 2.2 was found

2544 CANCER June 15 1988 Vol. 61

TABLE 3. Relative Risks of Solid Cancers After Treatment for Hodgkin’s Disease

Observedfexpected = relative risk in treatment groups

Anatomic site RC RC RC RC + RC t RC

Buccal cavity and pharynx 511.3 = 3.8 611.4 = 4.3 110.5 = 2.0 1213.2 = 3.8 Digestive system 1216.7 = 1.8 1417.8 = 1.8 212.6 = 0.8 28117.1 = 1.6

32112.8 = 2.5 Respiratory system 1315.2 = 2.5 1415.7 = 2.5 511.9 = 2.6 Bones and joints 310.1 = 30.0 110.1 = 10.0 010.03 = 0.0 410.2 = 20.0 Soft tissues 810.3 = 26.7 310.3 = 10.0 010.1 = 0.0 1110.7 = 15.7

Breast 614.5 = 1.3 214.4 = 0.5 011.3 = 0.0 8110.2 = 0.8 918.5 = 1.1 616.2 = 1.0 Male genital system 312.3 = 1.3 313.0 = 1.0 010.9 = 0.0

Urinary system 311.9 = 1.6 312.2 = 1.4 110.7 = 1.4 7/43 = 1.5

511.6 = 3.1 Endocrine system 110.8 = 1.3 310.7 = 4.3 010.2 = 0.0 411.7 = 2.4 Non-Hodgkin’s lymphomas 910.8 = 11.3 410.8 = 5.0 110.2 = 5.0 1411.8 = 7.8

Unknown primary site 210.9 = 2.2 011.1 = 0.0 110.4 = 2.5 312.4 = 1.3 153174.0 = 2.1 All sites 78130.5 = 2.6 64133.1 = 1.9

Melanomas of skin 610.8 = 7.5 410.7 = 5.7 010.2 = 0.0 1011.7 = 5.9

Female genital system 413.8 = 1.1 513.7 = 1.4 01 1 .0 = 0.0

Eye and orbit 0/0.I = 0.0 0/0.1 = 0.0 010.03 = 0.0 010.2 = 0.0 Brain and other nervous system 310.7 = 4.3 210.7 = 2.9 010.2 = 0.0

Multiple myeloma 010.3 = 0.0 010.4 = 0.0 0/0.1 = 0.0 010.8 = 0.0

I1/10.4 = 1.1

RC: some radiotherapy and some chemotherapy; RC: some radio-

after radiotherapy, whereas the RR after chemotherapy alone was 1.1 (Table 4).

Our results for non-Hodgkin’s lymphomas were similar for the two treatment groups. The RR were 8.1 for radiotherapy and 5.0 for chemotherapy alone, respec- tively (Table 4). This suggests that the risk of non- Hodgkin’s lymphomas may be elevated in all patients with HD, and that the development of non-Hodgkin’s lymphomas is part of the natural history of HD. How- ever, because of the potential difficulties in distinguish- ing clinically and pathologically between recurrences or metastases of HD and occurrences of non-Hodgkin’s lymphomas, these data must be interpreted very cautiously.

In patients with radiotherapy, several statistically significant RR were found for various anatomic sites, ranging from 1.8 for second cancers of the digestive system to 20.0 for cancers of the bones and joints. Ionizing radiation is believed to cause cancer at most anatomic sites, and it is likely that some of the elevated RR that we observed in our analyses reflect radiation-induced cancers. The large RR of 20.0 for the bones and joints and 18.3 for soft tissues are particularly likely to reflect causal associations. However, small increases in risk must be interpreted very cautiously as various biases may explain at least part of the results. Our RR estimates were based on general population comparisons. Populations of patients treated for HD may differ from general populations in various relevant ways, for example, in terms of smoking, drinking, and diet. The ascer- tainment of cases of cancer in published series of patients with HD also may be sometimes more thorough than in surveys of the general population. Finally, in our

therapy and no chemotherapy; RC: no radiotherapy and some chemotherapy.

analyses, the age and sex distribution of the person-years for the entire study population was assumed to be identical to the age and sex distribution observed in one subgroup of that population, namely the patients included in the study published by Boivin et This method of analysis may have introduced some impreci- sion in our estimates of RR.

In our analyses we could not take into account the

TABLE 4. Relative Risks of Solid Cancers After Radiotherapy and After Chemotherapy Alone

Relative risk (95% confidence limits) in treatment groups

Radiotherapy Chemotherapy Anatomic site (RC + RC) alone (RC)

Buccal cavity and pharynx 4.1 (2.0-7.3) 2.0(0.1-11.1) Digestive system 1.8 (1.2-2.6) 0.8 (0.1-2.8) Respiratory system 2.5 (1.6-3.6) 2.6 (0.9-6.1) Bones and joints 20.0 (5.5-51.2) 0.0 (0.0-123.0) Soft tissues 18.3 (9.1-32.8) 0.0 (0.0-46.1) Melanomas of skin 6.7 (3.2-12.3) 0.0 (0.0-18.5) Breast 0.9 (0.4-1.8) 0.0 (0.0-2.8) Female genital system 1.2 (0.5-2.3) 0.0 (0.0-3.7) Male genital system 1 . 1 (0.4-2.5) 0.0 (0.0-4.1) Urinary system 1.5 (0.5-3.2) 1.4 (0.0-8.0) Eye and orbit 0.0 (0.0-18.5) 0.0 (0.0-123.0)

Endocrine system 2.7 (0.7-6.8) 0.0 (0.0-18.5)

Multiple myeloma 0.0 (0.0-5.3) 0.0 (0.0-36.9) Unknown primary site 1.0 (0.1-3.6) 2.5 (0.1-13.9) All sites 2.2 (1.9-2.6) 1.1 (0.5- 1.9)

Brain and other nervous system 3.6 (1.2-8.3) 0.0 (0.0-18.5)

Non-Hodgkin’s lymphomas 8.1 (4.3-13.9) 5.0 (0.1-27.9)

RC: some radiotherapy and spme chemotherapy: RC: some radiotherapy and no chemotherapy: RC: no radiotherapy and some chemotherapy.

2545 No. 12 SOLID CANCERS AFTER HODGKIN’S DISEASE - Boivin and O’Brien

relationship between radiation treatment fields and the site of occurrence of the SC, because this information was not always available from the seven studies that we reviewed. This may have introduced some error into the calculation of the observed and the expected numbers of second cancers. In irradiated patients, observed tumors that actually may have occurred outside radiation fields were classified as having occurred after radiotherapy, and some of the expected cancers that were calculated concerned sites that were not always irradiated. These potential errors in the calculation of observed and expected numbers may have cancelled out in estimating observed-to-expected ratios. However, this is not certain and this lack of information about radiation fields must be kept in mind when assessing the causality of the associations reported here. We also can speculate that irradiation causes cancers outside irradiated fields through various mechanisms, including scattered radiation and “abscopal” effects43 (i.e., hormonal changes). If this is true, then analyses such as ours, in which radiation fields were not taken into account, are relevant to the determi- nation of radiation effects.

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APPENDIX

Person-Years in Data Set Analyzed by Boivin et

Person-years by treatment and by sex

All treatments RC RC RC RC

Age (Y r) M F M F M F M F M F

0 0.6 2.8 0.6 0.2 5 50.2 17.6 21.9 9.7

10 161.5 94.6 58.2 47.8 15 321.1 345.2 144. I 170.3 20 808.8 900.6 362.7 403.9 25 1062.4 1061.4 445.6 464.3 30 856.7 861.2 401.5 365.3 35 580.1 562.4 282.5 242.8 40 617.5 343.4 274. I 173.3 45 483.7 245.8 196.8 100.6 50 352.0 239.9 125.1 91.7 55 263.9 245.3 83.7 90.7 60 182.4 225.6 59.4 68.0 65 117.1 157.4 44.5 49.9 70 77. I 72.0 27.2 18.3 15 54.2 31.0 11.0 9.6 80 27.2 8.3 3.1 4.4 85 3.2 3.5 0.0 0.0

RC: some radiotherapy and spme chemotherapy; RC: some radiotherapy and no chemotherapy; RC: no radiotherapy and some chemo-

0.0 2.6 0.0 0.0 0.0 0.0 28.3 7.8 0.0 0.1 0.0 0.0 98.7 40.6 4.5 2.2 0.1 4.0

156.8 150.9 19.8 18.8 0.4 5.2 395.8 447.2 45. I 44.0 5.2 5.5 516.5 544.0 88.5 50.7 11.8 2.4 408.2 458.5 38.8 33.7 8.2 3.7 268.9 277.8 24.0 41.5 4.7 0.3 313.2 144.6 29.9 21.9 0.3 3.6 244.0 136.6 41.1 12.0 1.8 5.6 175.4 129.1 48.9 11.0 2.6 8.1 152.1 124.6 28.1 17.2 0.0 12.8 97.6 118.2 25.4 29.3 0.0 10.1 55.4 81.9 13.1 20.6 4.1 5.0 40.9 37.5 6.2 14.3 2.8 1.9 35.2 21.2 1.2 0.2 6.8 0.0 18.4 2.3 4.4 0.0 1.3 I .6 2.8 2.9 0.4 0.0 0.0 0.6

therapy; RC: no radiotherapy and no chemotherapy; M: male; F female.

solid cancer risk after treatment of hodgkin's disease

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