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Lung Cancer After Hodgkin’s Disease: A Nested Case-Control Study of the Relation to Treatment

From the Section of Epidemiology, Academic Unit of Radiotherapy and Oncology, and Lymphoma Unit, Institute of Cancer Research, Royal Marsden Hospital, and Royal Marsden National Health Service Trust, Sutton, Surrey; Radiotherapy and Oncology Department, Deanesly Centre, New Cross Hospital, Wolverhampton; Department of Medical Statistics and Evaluation, Imperial College School of Medicine; Imperial Cancer Research Fund Medical Oncology Unit, St Bartholomew’s Hospital; British National Lymphoma Investigation, University College Hospital, London; and Oncology Centre, Addenbrooke’s National Health Service Trust, Cambridge, United Kingdom.

Address reprint requests to A.J. Swerdlow, DM, Institute of Cancer Research, Section of Epidemiology, D Block, Cotswold Rd, Sutton, Surrey SM2 5NG, United Kingdom.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkin’s disease, and in particular the relationship to treatment.

PATIENTS AND METHODS: A nested case-control study was conducted within a cohort of 5,519 patients with Hodgkin’s disease treated in Britain during 1963 through 1993. For 88 cases of lung cancer and 176 matched control subjects, information on treatment and other risk factors was extracted from hospital case-notes, and odds ratios for lung cancer in relation to these factors were calculated.

RESULTS: Risk of lung cancer was borderline significantly greater in patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy than those who did not receive this treatment (relative risk [RR] = 1.66; 95% confidence interval [CI], 0.99 to 2.82), and increased with number of cycles of MOPP (P = .07). Exclusion of lung cancers for which histologic confirmation was not available strengthened these associations (RR = 2.41; 95% CI, 1.33 to 4.51; P = .004 for any MOPP and P = .007 for trend with number of cycles of MOPP). Risks were not raised, however, after chlorambucil, vinblastine, procarbazine, and prednisone treatment. There was evidence that the raised risk of lung cancer occurring in relation to radiotherapy was restricted to histologies other than adenocarcinoma.

CONCLUSION: The results suggest that MOPP chemotherapy may lead to elevated risk of lung cancer, at least in certain subgroups of patients. The role of chemotherapy in the etiology of lung cancer after Hodgkin’s disease deserves further investigation.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MODERN THERAPY for Hodgkin’s disease has greatly improved survival, but one of the costs of this success has been a raised risk of second malignancy. In most large long-term cohort studies of patients with Hodgkin’s disease, lung cancer accounts for a larger proportion of the excess risk of solid second malignancies than does cancer of any other site.^1-4 In a U.K. cohort, it accounted for a quarter of all excess second cancers, and the relative risk (RR) was particularly large in patients treated at young ages.⁴

The role of treatment in causing this risk is therefore an important issue, but is not yet fully resolved. Risk is raised in relation to radiotherapy,^2-6 as would be expected from the lung carcinogenicity of radiation in many other circumstances.⁷ In two studies in 1992, however, a significantly raised risk was also found in relation to chemotherapy.^8,9 Subsequent publications, and aggregation of earlier data, support this in some instances^4,10-12 but not others.^2,5,6 Several alkylating agents, including mustine and chlorambucil, have been found to cause lung cancer in experimental animals,¹³ and it is possible that the inconsistent results so far in man reflect a causal relation restricted to a particular chemotherapeutic agent or subgroup of patients with Hodgkin’s disease, which may have been more greatly represented in some published studies than others. To investigate this further, we undertook a case-control study in Britain, with a similar number of cases to that in the international study by Kaldor et al,⁹ and much larger numbers than in any other published study.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The study was of nested case-control design. The cases were all of the lung cancers that occurred within the British collaborative Hodgkin’s disease cohort⁴ during follow-up to the start of the present investigation, and the control subjects were other patients with Hodgkin’s disease selected from the same cohort according to the matching criteria described below. The construction of the cohort has been described in detail elsewhere.⁴ In brief, it consisted of 3,772 patients from the British National Lymphoma Investigation (BNLI) with Hodgkin’s disease incident since 1970, 1,039 from the Royal Marsden Hospital incident since 1963, and 708 from St Bartholomew’s Hospital incident since 1967, monitored for second cancer and mortality to dates during 1991 through 1995, depending on the center (slightly longer follow-up at the BNLI and Royal Marsden than in the previous cohort publication⁴). Follow-up was 97% complete. For each patient in the cohort who developed lung cancer, we identified all other cohort members of the same sex who had survived without a second cancer for at least as long as the period from diagnosis of Hodgkin’s disease to incidence of lung cancer in the case. We then selected as controls from among these subjects the two patients who were closest to the case with regard to age at first treatment of Hodgkin’s disease and date of first treatment. For each case and control, data were extracted from hospital case-notes on smoking, stage of Hodgkin’s disease, splenectomy, chemotherapy and radiotherapy for Hodgkin’s disease, and for cases, date of incidence and histology of lung cancer. The data were extracted using a standardized data collection instrument, by personnel with many years of experience of examining cancer case-notes and who, with the exception of an author who extracted a minority of the data, had not been involved in determining the study purposes and design.

The information collected about radiotherapy included the dates of treatment, fields irradiated, and doses. We then categorized the field of irradiation as none, small, medium, or large, based on an estimate of the proportion of total lung volume in the direct beam. The small volume was defined as less than 5%, medium as 5% to 10%, and large as greater than 10%. Thus a standard mantle radiation field, the extended field commonly used for supradiaphragmatic radiation, would count as a large lung volume, whereas involved field treatments to particular nodal areas around the thorax would be categorized as either small or medium. Among the 189 patients who had been treated with radiotherapy, 184 had prescription doses of greater than 20 Gy (predominantly within the range of 35 to 40 Gy), four had doses of 6 to 20 Gy, and one, who was omitted from the analyses, had an unknown dose. We downgraded the four exposures of 20 Gy or less by one category (eg, from medium to small) to compensate for their lower doses. For chemotherapy, we collected information on the dates of treatment, agent(s), and number of cycles (or that the chemotherapy was maintenance). When analyzing the treatment history of cases, we considered only treatments occurring before the incidence of lung cancer. For controls, we considered only treatments occurring during the equivalent period to the duration from Hodgkin’s disease to lung cancer incidence in the matched case. When this resulted in part of a cycle of chemotherapy occurring before the cutoff date and part after this, we rounded the fraction of a cycle to the nearest whole number. There were no subjects for whom a similar problem occurred for radiotherapy. For analyses of risk in relation to number of cycles, we counted 1 month of maintenance chemotherapy as equivalent to one cycle; there were no subjects in the study, however, for whom altering this equivalence moderately (for instance, equating 1 month of maintenance treatment with one half of a cycle, or with two cycles) would have affected their categorization in the analysis.

Odds ratios were calculated to estimate relative risks (RRs) of lung cancer in relation to the therapeutic and other risk factors. In general the analyses were based on matched sets, using conditional logistic regression. For analysis of the effect of radiotherapy in smokers there were few matched pairs, however, and for analysis of the effect of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) by stage of Hodgkin’s disease, there was a great loss of data by restriction to matched pairs, so in these instances we conducted an unmatched analysis, using unconditional logistic regression, with adjustment for sex, age at first treatment, and year of first treatment of Hodgkin’s disease.

Probability ( P ) values and 95% confidence intervals (CIs) were obtained via likelihood ratio tests.¹⁴ All P values are two-sided. Chi-square tests for heterogeneity of unadjusted and adjusted odds ratios were conducted based on a log likelihood ratio test comparing the model including the categorical variable and the model without this variable, with the number of degrees of freedom equal to the number of parameters of this variable. ² tests for trend were based on a log likelihood ratio test comparing the model with the predictor variable fitted as scores (ie, the ordered categorical variable) and the model without this variable. The analyses were conducted using EPICURE software.¹⁵ Because the random selection of controls produced, by chance, an unbalanced distribution of controls across the three study centers, we repeated all analyses with adjustment for center.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eighty-eight cases and 176 controls were included in the study; one further lung cancer diagnosed 2 months after Hodgkin’s disease diagnosis was excluded from analysis because a lung lesion had been present on chest x-ray and computed tomography scan at Hodgkin’s disease diagnosis, although not then diagnosed as lung cancer. Descriptive features of the study subjects are listed in Table 1. Three quarters of the cases (and controls) were male, half were younger than 50 years of age at incidence of Hodgkin’s disease, and in half the lung cancer had occurred less than 10 years after Hodgkin’s disease incidence. Three cases were incident between 8 and 12 months after incidence of Hodgkin’s disease, and the remainder at more than 1 year. Forty-nine percent of cases with known histology of lung cancer had squamous cell tumors, and 24% had adenocarcinomas. Most (64%) of the controls were matched exactly to their case on year of first treatment of Hodgkin’s disease, and the remainder were matched within 1 (28%) or 2 years (8%). Matching on age at first treatment was also exact for the majority of controls (54%), and was within 1 year for a further 31%, 2 years for a further 10%, and 3 to 9 years for the remaining 5%.

Much the most common type of chemotherapy received was MOPP (we also included in this analytic category treatments in which vinblastine had been substituted for vincristine). Ever-treatment with MOPP was associated with a borderline significantly increased risk of lung cancer (RR = 1.66; 95% CI, 0.99 to 2.82; data not shown), and there was some evidence of a trend in risk in relation to number of cycles of treatment (P = .07; Table 3). The results were similar, but with smaller numbers, not significant, if only treatments received more than 5 years before the outcome date were considered. Adjustment of these results for radiotherapy did not alter the point estimates of risk appreciably, but the CIs were wider as a consequence of the adjustment process. Adjustment for stage of tumor also did not alter the point estimates (data not shown). When MOPP cycles were considered as a continuous variable rather than categorized, the relation to lung cancer risk fitted best as a quadratic function, with a maximum risk at 5.6 cycles. Exclusion of the 16 lung cancer cases for which histologic confirmation was not available, and their matched controls, strengthened the findings regarding MOPP: the RR for ever-treatment with MOPP was 2.41 (95% CI, 1.33 to 4.51; P = .004), and the trend in risk in relation to MOPP cycles was significant (P = .007).

Because MOPP therapy includes both mechlorethamine and procarbazine, it was not possible entirely to separate the relations of these two alkylating agents to risk. There were, however, many subjects (12 cases, 33 controls) who had been treated with chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP), in which mechlorethamine is replaced with chlorambucil (we included with this, for analysis, treatments with vincristine substituted for vinblastine). The RR of lung cancer for patients treated with ChlVPP was not elevated (RR = 0.62; 95% CI, 0.27 to 1.35), and corresponding with this indication that mechlorethamine might be the most hazardous agent, the RR for patients ever-treated with mechlorethamine was 1.69 (95% CI, 1.01 to 2.86) compared with 1.36 (95% CI, 0.81 to 2.32) for those ever-treated with procarbazine and 0.69 (95% CI, 0.33 to 1.37) for those ever-treated with chlorambucil. Treatment with other alkylating agents was far less common than with those above, but there was no indication of raised risk in relation to these: lomustine had been received by four cases and 11 controls, and dacarbazine by one case and three controls.

Table 4 shows the relation of lung cancer to MOPP chemotherapy in various subgroups of subjects. There was no substantial difference in risk between the sexes, but the risk was more apparent at older than younger ages: in patients first treated for Hodgkin’s disease at ages 50 years and older, there was a significant trend of greater risk with more cycles of MOPP, whereas there was almost no trend for younger patients. The interaction between the effects of number of cycles of MOPP and age was not significant, however (P = .31). The trend in risk with extent of MOPP treatment was nearly significant in patients with late stage (III and IV) but not those with early stage Hodgkin’s disease; again, however, the interaction was not significant (P = .46). Within subjects for whom smoking status was known, risks adjusted for radiotherapy were significantly greater in patients exposed to both MOPP and smoking than in smokers not receiving MOPP or in MOPP-treated nonsmokers (RRs of 1.00, 0.11 [0.01 to 0.78] and 0.08 [0.01 to 0.71], respectively), and no cases occurred in nonsmokers not treated with MOPP, despite 15 controls with these characteristics (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Lung cancer is one of the main malignancies occurring in excess after Hodgkin’s disease, and is rapidly fatal. Its etiology and prevention are therefore important if long-term survival of patients with Hodgkin’s disease is to be improved. Smoking and ionizing radiation are well-established lung carcinogens, and it is unsurprising that increased risk should have occurred in relation to these. It should be noted that a consequence of the use of nested case-control methodology for the study is to make the treatment-related risks look far lower than they would in a cohort study using a general population comparison, because in the case-control analysis they are assessed relative to internal baseline groups who have themselves received carcinogenic modalities, rather than to a totally unexposed group. Thus the RR for large field compared with lesser field or no direct lung radiotherapy was only modestly increased, but this should be interpreted in the context of the RR in the cohort analysis of these patients⁴ of 2.9 for radiotherapy-treated patients overall compared with the general population (and likewise the chemotherapy results should be interpreted in the context of the RR of 3.3 for this treatment in the cohort, compared with the general population).⁴ Also, differentiation of the amount of radiation exposure was limited in our study because we could not gain sufficient information about the anatomic location of tumors within the lung to estimate risks in relation to doses to the affected part of the lung.

Although our data on smoking were incomplete, which weakens the analysis, it seems unlikely that this would have been biased between cases and controls according to treatment category, and thus unlikely that the apparent restriction of the radiotherapy-related risk to smokers was related to incomplete smoking data. Furthermore, this finding concurs with that of van Leeuwen et al⁶ who had virtually complete information on smoking.

Another notable aspect of the radiotherapy risk was the histologic types of lung cancer that occurred: only 13% of the cases in patients treated solely with radiotherapy were adenocarcinoma, compared with about 33% expected among lung cancers in general.¹⁸ This accords with the findings on radiation-induced lung cancers in atomic bomb survivors and uranium miners, in whom the RR of adenocarcinoma was less elevated than that for other histologies.¹⁷

The main finding of our study, however, and the exposure for which the previous literature has been far less consistent, relates to chemotherapy. In cohort studies that have analyzed the risk of lung cancer (or of respiratory and intrathoracic tumors as a group) in relation to chemotherapy overall, RRs have been increased to a similar extent to those after radiotherapy in some instances,^4,10,11 but not increased in others.^2,5 The negative results were based on comparatively small numbers of patients who had received solely chemotherapy, and in each instance less than one lung cancer after such treatment was expected.

The relation of the lung cancer risk to treatment has been addressed in detail in only two previous investigations: an international collaborative case-control study with 98 cases of lung cancer⁹ and a Dutch study with 30 cases.⁶ The former found, as in the present study, a greater risk in chemotherapy-treated than radiotherapy-treated patients, whereas the latter found the opposite, although with CIs that would include the present results. These studies, unlike ours, did not find any indication of a risk relating specifically to MOPP or a dose-response relation for MOPP.^6,9 Both our results and those of van Leeuwen et al⁶ are anchored in cohort studies in which the basic finding of a highly significant increased risk of lung cancer in patients treated with chemotherapy⁴ or of no such increased risk² was present. There may have been a small overlap of cases (and perhaps controls) between our study and that by Kaldor et al,⁹ inasmuch as almost a third of the subjects in the latter study were from England, and some of these could have been patients from hospitals included in the present investigation. It is a weakness of our results that we were not able to gain data on MOPP dose, because although the intended dose is usually standard, it may be reduced ad hoc at the time of administration without being recorded in the case-notes that are preserved. We therefore have had to use number of cycles of treatment as a proxy for cumulative dose. There is no obvious confounder to explain our results that was not addressed by matching or adjustment. Our study did not match on treatment center, because in principle this is undesirable and can lead to overmatching. Our results for MOPP were not a consequence of differences in treatment center between the cases and controls, however, and indeed the associations were stronger if adjustment for treatment center was undertaken. Our study had the deficit that despite extensive attempts, there were 16 lung cancer cases for which we could not obtain histologic confirmation—mainly because the diagnosis had been solely on a clinical basis or from death certificates only. The results were not due to inclusion of these cases, however, and indeed exclusion of them strengthened the main findings—the effect that would be expected if the relation were real.

The differences between our results on MOPP and those in the two previous studies^6,9 might have been due to chance; the results most different from ours were those from much the smallest study of the three,⁶ with confidence limits that would include our findings. Furthermore, the previous studies included far fewer patients who had received MOPP than did ours. It seemed worthwhile, however, to examine whether the positive results in our data might have derived from effects occurring mainly (or entirely) in particular subgroups of subjects, who might be more common in our study than the others. We therefore analyzed risk in various subgroups, although aware that such analyses have the potential to find either true variations or subgroups with elevated risk by chance alone. These analyses found the elevated risk in relation to MOPP was restricted to patients aged 50 years and older at treatment. The previous studies have certainly included substantial numbers of subjects aged 50 and older, but we do not know whether these patients received MOPP. The relation to age in our data is at least in part an artefact of the case-control method: because radiotherapy causes lung cancer with a far greater RR at young than at older ages, whereas for chemotherapy there are similar RRs of lung cancer at all ages,⁴ the effect of chemotherapy will be more apparent at older ages than at younger ages in a case-control analysis in which the unexposed group has received radiotherapy. There was also evidence that the risk in MOPP-treated patients was mainly (or perhaps solely) present in smokers—a category well-represented in the previous studies. To some extent these categories of patients overlapped: older patients were more likely to be smokers, and numbers were too small to separate the effects of these factors. The restriction of the MOPP-related risk to smokers is reminiscent of the similar restriction for the radiotherapy-related risk in both our study and that of van Leeuwen et al.⁶

The apparent confinement of the chemotherapy-related risk to adenocarcinoma of the lung cannot be interpreted decisively, particularly as it is based on incomplete ascertainment of histology (although unlikely to be treatment-biased). It may, at least in part, be a corollary of the low risk of adenocarcinoma compared with other histologic types in relation to radiotherapy. If MOPP causes adenocarcinoma and other lung cancer histologies equally, whereas radiotherapy causes nonadenocarcinoma histologies preferentially and with a similar risk to that from chemotherapy, then one would expect an increased risk of adenocarcinoma but not other histologies for chemotherapy-treated patients relative to those treated with radiotherapy alone. This would accord with the similar proportions of lung cancers of known histology that were adenocarcinoma in patients receiving chemotherapy alone (28%) or mixed-modality treatment (29%) to the percentage found in lung cancers in general (about 33%),¹⁸ whereas after radiotherapy alone, as noted above, the percentage was much less. To some extent the same explanation could apply to the restriction of significant dose-response relations for chemotherapy to adenocarcinoma and not other histologies, but this would not explain the lack of change in trend with adjustment for radiotherapy. The possibility that there may truly be a selective risk for adenocarcinoma after MOPP needs clarification by further data.

The increased risk of lung cancer after MOPP but not ChlVPP in our data implies a relation to mechlorethamine rather than procarbazine, as the latter is present in ChlVPP. Treatment with ChlVPP was introduced more recently than MOPP, but there were large proportions of patients with the former as well as the latter treatment who had been observed for many years in our cohort, and therefore who could plausibly have been at risk of treatment-induced second malignancy: for instance, 82% of controls treated with MOPP began treatment before 1980, and 96% before 1985, whereas the corresponding percentages for ChlVPP were 42% and 79%. The possibility that mechlorethamine might cause lung cancer has some plausibility. Mechlorethamine is certainly carcinogenic in man, as demonstrated by the high risks of leukemia associated with its use. It has been shown to cause lung cancer in animal experiments,¹³ and respiratory exposure to mustard gas, from which mechlorethamine was originally derived, during its manufacture led to substantially increased risks of lung cancer.^19,20 The relation of chemotherapy, and in particular mechlorethamine, to risk of lung cancer after Hodgkin’s disease, needs examination in further data.

	ACKNOWLEDGMENTS

 
Supported by funding from the Medical Research Council, London, to the Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine; Lymphoma Research Trust and Cancer Research Campaign, London, Lisa Lear Fund, Windsor, and Isle of Man Anti-Cancer Association, Isle of Man to the British National Lymphoma Investigation; and Imperial Cancer Research Fund, London, to the Department of Medical Oncology, St Bartholomew’s Hospital.

We thank the collaborators in the British National Lymphoma Investigation whose patients are included in this study. We also thank S. Milan, J. Nicholas, L. Wickens, and A. Wilson for help in obtaining data, and E. Middleton and M. Snigorska for secretarial help.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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3. van Leeuwen FE, Swerdlow AJ, Valagussa P, et al: Second cancers after treatment of Hodgkin’s disease, in Mauch PM, Armitage JO, Diehl V, et al (eds): Hodgkin’s Disease. Philadelphia, PA, Lippincott Williams & Wilkins, 1999, pp 607-632

4. Swerdlow AJ, Barber JA, Vaughan Hudson G, et al: Risk of second malignancy after Hodgkin’s disease in a collaborative British cohort: The relation to age at treatment. J Clin Oncol 18: 498-509, 2000[Abstract/Free Full Text]

5. Abrahamsen JF, Andersen A, Hannisdal E, et al: Second malignancies after treatment of Hodgkin’s disease: The influence of treatment, follow-up time, and age. J Clin Oncol 11: 255-261, 1993[Abstract/Free Full Text]

6. van Leeuwen FE, Klokman WJ, Stovall M, et al: Roles of radiotherapy and smoking in lung cancer following Hodgkin’s disease. J Natl Cancer Inst 87: 1530-1537, 1995[Abstract/Free Full Text]

7. National Research Council: Health effects of exposure to low levels of ionizing radiation. BEIR V. Washington, DC, National Academy Press, 1990

8. Swerdlow AJ, Douglas AJ, Vaughan Hudson G, et al: Risk of second primary cancers after Hodgkin’s disease by type of treatment: Analysis of 2846 patients in the British National Lymphoma Investigation. BMJ 304: 1137-1143, 1992

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11. Boivin JF, Hutchison GB, Zauber AG, et al: Incidence of second cancers in patients treated for Hodgkin’s disease. J Natl Cancer Inst 87: 732-741, 1995[Abstract/Free Full Text]

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17. Land CE, Shimosato Y, Saccomanno G, et al: Radiation-associated lung cancer: A comparison of the histology of lung cancers in uranium miners and survivors of the atomic bombings of Hiroshima and Nagasaki. Radiat Res 134: 234-243, 1993[Medline]

18. Berg JW: Morphologic classification of human cancer, in Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention, ed 2. New York, NY, Oxford University Press, 1996, pp 28-44

19. Wada S, Miyanishi M, Nishimoto Y, et al: Mustard gas as a cause of respiratory neoplasia in man. Lancet 1: 1161-1163, 1968[Medline]

20. Easton DF, Peto J, Doll R: Cancers of the respiratory tract in mustard gas workers. Br J Indust Med 45: 652-659, 1988.[Medline]

Submitted April 12, 2000; accepted December 5, 2000.

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