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Originally published as JCO Early Release 10.1200/JCO.2005.04.2200 on March 6 2006 © 2006 American Society of Clinical Oncology. Risk of Second Malignancy After Non-Hodgkin's Lymphoma: A British Cohort Study
From the Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey; British National Lymphoma Investigation, Cancer Trials Centre, London; Department of Haematology, University College London Medical School, London; Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield; Clinical Oncology, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom Address reprint requests to N.Y. Mudie, MD, PhD, Section of Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom; e-mail: nadejda.mudie{at}icr.ac.uk
PURPOSE: To assess long-term site-specific risks of second malignancy following non-Hodgkin's lymphoma (NHL) in relation to treatment and demographic factors. PATIENTS AND METHODS: A cohort of 2,456 patients with NHL who were first treated from 1973 to 2000 and were younger than 60 years from centers in the British National Lymphoma Investigation were observed, and occurrences of second malignancy was compared with expectations based on general population cancer rates in England and Wales. RESULTS: In total, 123 second malignancies occurred. Relative risks (RRs) were significantly elevated for all malignancies combined (RR = 1.3; 95% CI, 1.1 to 1.6) and for leukemia (RR = 8.8; 95% CI, 5.1 to 14.1) and lung cancer (RR = 1.6; 95% CI, 1.1 to 2.3). RRs of malignancy overall diminished significantly with increasing age at first treatment. Leukemia risk was significantly increased after chemotherapy (RR = 10.5; 95% CI, 5.0 to 19.3) and mixed-modality treatment (RR = 13.0; 95% CI, 5.2 to 26.7). Relative risks of lung (RR = 1.9; 95% CI, 1.1 to 3.1) and colorectal (RR = 2.1; 95% CI, 1.1 to 3.6) cancers were significantly raised following chemotherapy. CONCLUSION: NHL patients are at elevated risk of developing second malignancy, particularly leukemia and lung cancer. The relative risk is greater with patients who are younger at first treatment. Chemotherapy predisposes patients toan increased risk of leukemia, and possibly lung and colorectal cancers. The role of specific drug treatments in the etiology of solid cancers after NHL deserves further investigation.
The incidence of non-Hodgkin’s lymphoma (NHL) has been increasing for the past 40 years in most Western countries.1,2 With better treatment, life expectancy of NHL patients has been improving,3 and hence the risk of iatrogenic malignancy is becoming an important concern in long-term survivors. Whereas considerable attention has focused on late sequelae of Hodgkin’s disease,4 relatively little information is available about second malignancies in NHL, as there have been few large studies with prolonged and complete follow-up. Several studies,5-9 but not all,10-14 have reported an elevated risk of second malignancy overall following NHL. Most studies have found increased risks of leukemia, especially acute nonlymphocytic leukemia (ANLL),6,9,11,14-17 associated with alkylating chemotherapy, alone or in combination with total nodal/body irradiation.18,19 Raised risk of bladder cancer has been linked to cumulative doses of cyclophosphamide and, to a lesser extent, to radiotherapy.20,21 There have been sporadic reports of raised risk of several other solid cancers5,6,8,9,13,20,21 and Hodgkin’s disease,9,22 but inconsistently and without an established relationship to treatment. Reports on cancer risks in NHL survivors beyond 15 years are limited to an international study conducted by Travis et al7 that demonstrated a persistent significantly elevated risk of all malignancies, as well as of cancers of several individual sites. With the exception of leukemia, bladder, and kidney cancer risks, few studies have examined the risk of specific second malignancies in relation to treatment12 and these studies usually only used data on the initial treatment in their analysis.6,14 The effect of age at first treatment on the risk of second malignancy has rarely been examined and has produced conflicting results.7,9,23 To evaluate the risk of second malignancy arising from different types of treatment for NHL, we assembled a retrospective cohort of 2,456 United Kingdom patients first treated at ages younger than 60 years, and observed them for up to 26 years.
The British National Lymphoma Investigation (BNLI) maintains a database on the treatment and follow-up of all patients with NHL from clinical trials treated in its participating hospitals. From this database, we extracted information on all patients first treated at ages younger 60 years, between June 1, 1973, and March 31, 2000, except for those who were foreign residents. The data on treatments, cancers, deaths, and follow-up to March 31, 2000, were then updated from case notes as necessary. Based on comparison of the BNLI files with case notes and other sources, we believe that the BNLI data have a high level of completeness regarding second malignancy.24 Sites of second cancer were coded according to the International Classification of Diseases (ICD),25 using the editions that were applicable in England and Wales at the time of diagnosis: ICD8 for 1968 through 1978, and ICD9 for 1979 through 2000. We bridge-coded the data to ICD9 categories. For each patient in the cohort, person-years at risk of second cancer were calculated by 5-year age group, sex, and calendar year, from 2 months after the date of first treatment (cancers and person-years in the first 2 months of follow-up were excluded from the analysis to avoid inadvertent inclusion of synchronous tumors6) to the date of the end of follow-up, or of second cancer incidence, death, or loss to follow-up, if earlier. Thirty-one patients were excluded from the study because less than 2 months of follow-up was available for them and a further six patients were excluded due to insufficient treatment data available. For analyses of time since first treatment and type of treatment, case subjects were allocated at each point in their follow-up to the analytic category applicable at that time. Type of treatment was categorized into chemotherapy, radiotherapy, and mixed-modality treatment. Sub-analyses were also conducted for the two most common chemotherapy regimens: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and chlorambucil, whether or not the patient had received radiotherapy or any other chemotherapy. It was not practical for us to obtain more detailed therapeutic information for the total cohort, and this will be addressed elsewhere by nested case-control studies. Expected numbers of cancers incident in the cohort were calculated for each cancer site by multiplying age-, sex-, and calendar year–specific person-years at risk in the cohort by the corresponding cancer registration rates in the general population of England and Wales. Completeness of cancer registration in England and Wales has been assessed to be 90%1; however, cases of nonmelanoma skin cancer were excluded from the analysis as their registration is seriously incomplete.1 The ratio of observed to expected numbers of incident cancers, the standardized incidence ratio (SIR, referred to in the text as relative risk [RR]) was calculated with likelihood-based 95% CI from Poisson models.26 Absolute excess risks of second cancer were calculated by subtracting the expected from the observed number of cases and dividing by the person-years at risk. Cumulative (actuarial) probabilities of second cancer were calculated by the Kaplan-Meier method.27 Tests for trend and heterogeneity were calculated as described in Breslow and Day.28 All significance levels cited are two-sided.
The cohort consisted of 2,456 patients (Table 1), 58% (n = 1,413) of whom were male. The average age at first treatment was 46.5 years (range, 3 to 59 years), with more than a third of the cohort (n = 932) younger than 45 years. The mean age at first treatment was not significantly different between calendar periods of the study (P = .20). The majority of patients were treated with chemotherapy, either alone (52%) or in combination with radiotherapy (35%). The most common forms of chemotherapy were CHOP, received by 1,219 patients (mean age, 46 years; 61% male, mainly treated from 1980 to 1994) and chlorambucil, received by 752 patients (mean age, 48 years; 54% male, mainly treated from 1973 to 1989).
During follow-up, 123 patients (5.0%) developed a second malignancy, 1,230 others died, seven emigrated, 37 patients (1.5%) were lost to follow-up in other ways, and the remaining 1,059 patients survived without second cancer to the end of the study period. No patients developed a third primary cancer during the follow-up period. Total follow-up was 18,430 person-years, a mean of 7.7 years (maximum 26.8 years) per cohort member. The mean length of follow-up was slightly longer for those patients who were younger when first diagnosed with NHL than those who were older, ranging from 8.4 years for those younger than 45 years to 6.8 years for those patients ages 55 to 59 years (data not shown). The risk of second malignancy overall was significantly increased (RR = 1.3; 95% CI, 1.1 to 1.6; P < .01; Table 2). The risks of lung cancer (RR = 1.6; 95% CI, 1.1 to 2.3) and leukemia (RR = 8.8; 95% CI, 5.1 to 14.1) were also significantly raised. The risks of several gastrointestinal and genitourinary cancers, bone and soft tissue cancers, and Hodgkin’s disease were also raised, albeit not significantly. Lung cancer and leukemia were the main contributors to the raised absolute excess risk. Five of the cases of lung cancer were squamous cell, three were adenocarcinoma, two were oat/small cell, one was hurtle cell, one was non–small-cell, four were poorly differentiated carcinomas, and 12 were of unknown histology.
The raised risk of second cancers overall was confined to men (RR = 1.6, 95% CI, 1.3 to 2.0 for men; RR = 1.0, 95% CI, 0.7 to 1.3 for women; Pheterogeneity [lt] .05). There were significantly increased risks in men for leukemia (RR = 9.7; 95% CI, 5.0 to 16.9) and oropharyngeal cancer (RR = 3.6; 95% CI, 1.2 to 8.3; data not shown). Significant raised risks of leukemia (RR = 7.2; 95% CI, 2.3 to 16.8) and soft tissue cancer (RR = 10.4; 95% CI, 1.3 to 36.5) occurred in women. Relative risk of leukemia increased with stage of NHL at diagnosis (Ptrend < .05) and was only significant in patients diagnosed with stage III disease (RR = 9.4; 95% CI, 2.6 to 24.1) and stage IV disease (RR = 18.7; 95% CI, 9.0 to 34.4; data not shown). This trend was not apparent for all malignancies overall or for any individual solid cancer sites. The relative risk of malignancy overall was raised for each histologic subtype of NHL, although it was significant for only the most common type, diffuse large cell NHL (RR = 1.4; 95%CI, 1.0 to 1.8; data not shown). Similarly, the risk of leukemia was raised for each histologic subtype, and was raised significantly for follicular NHL (RR = 10.4; 95% CI, 4.5 to 20.5), lymphocytic NHL (RR = 19.5; 95% CI, 4.0 to 56.9), and diffuse NHL (RR = 6.2; 95% CI, 2.0 to 14.5). The relative risk of second cancer overall diminished with increasing age at first treatment (Ptrend < .05; Table 3), and significant diminution of relative risk with age was also apparent for cancers of the mouth and pharynx, stomach (data not shown), and bladder and urethra. For second cancers overall, absolute excess risk per 10,000 person-years (AER) diminished with age, though the opposite was true for lung and colorectal cancers and leukemia. Breast cancer risk was significantly reduced in women first treated at ages 45 to 54 years, but not for those women who were younger or older than this range.
The risk of second malignancies overall was raised up to 15 years from diagnosis, but not thereafter, although with wide confidence intervals (Table 4). The relative risk of leukemia was elevated during the first 10 years of follow-up, but then diminished, and no cases of leukemia were diagnosed beyond 15 years. The relative risk of lung cancer was raised significantly only during the period 5 to 9 years following first treatment.
Relative risk of second malignancies overall was raised for each treatment modality (Table 5), but not significantly. Significantly increased risk of leukemia was confined to patients who had received chemotherapy, with or without radiotherapy. No cases of leukemia were observed in patients treated with radiotherapy only. The relative risk of leukemia in the patients who were treated with CHOP was 14.2 (95% CI, 6.8 to 26.2) and in the RR for those treated with chlorambucil was 19.2 (95% CI, 9.6 to 34.3; data not shown).
The relative risk of mouth and pharynx cancers was significantly increased in patients treated with mixed modalities and not significantly after radiotherapy alone. Risk of colorectal cancer was increased significantly only in the chemotherapy-treated group (RR = 2.1; 95% CI, 1.1 to 3.6), particularly in those patients who were treated with CHOP (RR = 2.4; 95% CI, 1.1 to 4.3), but not those treated with chlorambucil (RR = 1.4; 95% CI, 0.5 to 3.2). Risk of female breast cancer was significantly reduced (P < .01) in the chemotherapy-only group. Risk of lung cancer was significantly increased (P < .05) in patients treated with only radiotherapy (nine cases, seven of whom received radiotherapy above and two below the diaphragm). The risk was also increased in those patients treated with only chemotherapy, but based on small numbers it was not increased in those with mixed-modality treatment (three cases, for whom site of radiotherapy is not known). The relative risk of lung cancer was significantly raised in the CHOP subcohort (RR = 2.1; 95% CI, 1.1 to 3.7), but not in those patients treated with chlorambucil (RR = 1.1; 95% CI, 0.4 to 2.4). The risk of bladder and urethra cancers was significantly raised only after radiation treatment (five cases, of whom two received radiotherapy below and two above the diaphragm, and for one patient the site of radiotherapy was unknown). All three cases of bladder and urethra cancer among the chemotherapy-treated patients occurred within the CHOP subcohort (RR = 1.7; 95% CI, 0.3 to 4.9). Overall, the risk of all malignancy was significantly raised in the CHOP subcohort (RR = 1.6; 95% CI, 1.2 to 2.1), mainly due to the raised risks of leukemia, lung, and colorectal cancers. The risk of second malignancy overall in the chlorambucil subcohort was borderline significantly raised (RR = 1.4; 95% CI, 1.0 to 1.9), primarily due to the high risk of leukemia in this group. The 15-year cumulative risk of second malignancy in the total cohort was 11.2% (95% CI, 9.1 to 13.7). Cumulative risks were greater for males (13.6%; 95% CI, 10.5 to 17.5) than females (8.3%; 95% CI, 5.8 to 11.3), and were much greater in patients who were first treated at 50 years of age and older (17.5%; 95% CI, 13.6 to 22.3) than for those who were treated at a younger age (7%; 95% CI, 5.0 to 9.9). The main contributors to the overall 15-year risk were lung cancer (2.8%), leukemia (1.5%), colorectal cancer (1.5%), and breast cancer (1.2%; data not shown).
This cohort of British NHL patients had a 30% higher rate of second malignancy than in the general population of England and Wales, primarily due to elevated risks of leukemia and lung cancer. The results may have been biased slightly upwards, because cancer registration in England and Wales is only approximately 90% complete,1 however, the results are comparable to the raised risks of 18% to 37% in other large cohort studies.5-9 Also similar to previous reports among NHL patients,5-7 the raised relative risk was greater in male than female patients. Only a few studies have examined age at first treatment in relation to risk of second malignancy following NHL, and the evidence has been conflicting. An American study of childhood NHL,23 based on 497 cases, reported a much higher relative risk of malignancy overall (RR = 10.8; 95% CI, 6.1 to 16.9) than in adult cohorts, whereas a smaller Italian study29 of children with NHL reported no raised risk. An international cohort study7 found no difference in relative risk of malignancy overall between NHL patients aged younger and older than 40 years at diagnosis, whereas a Swedish study9 found greater relative risks at younger ages. Similar to the Swedish study, we found that risk decreased significantly with increasing age at first treatment. Long-term risk of second malignancy after NHL has been examined previously by Travis et al,7 who found raised risks beyond 15 years of follow-up. In this study, with a similar mean length of follow-up, RRs of second malignancy were raised for the first 15 years, with no evident raised risk thereafter. The 15-year cumulative risk of all second malignancies in our study was a little lower than the one found in the study by Travis et al7 (11% v 15%), probably reflecting the younger mean age of our cohort (46.6 v 56.1 years). Raised relative risks (two- to eight-fold) of leukemia among NHL patients have been demonstrated previously in adult cohort studies.6,7,9,11-13 The relative risk was even greater (200-fold) in children.23 High relative risks have been linked to alkylating chemotherapy, including chlorambucil and cyclophosphamide specifically,17 which were associated with raised risk in our data, and have been shown to be leukemogenic when used to treat Hodgkin’s disease and other malignancies.30-32 Involved-field radiation treatment did not materially increase the risk of leukemia in previous studies of patients treated for NHL12,17 and Hodgkin’s disease,4,32other than the risk conferred by alkylating chemotherapy, but low-dose total-body irradiation did.15-18,33,34 In our study, radiotherapy-treated patients predominantly received involved-field treatments, and no cases of leukemia occurred in the group treatedwith radiation only. The relative risks of leukemia were similarly raised in the chemotherapy- and mixed-modality–treated groups. The high relative risk of leukemia seen after CHOP and chlorambucil chemotherapies is of a similar order of magnitude to the risks observed following treatment with alkylating regimens such as MOPP (mechlorethamine, vincristine, procarbazine, prednisone) in Hodgkin’s disease patients.4 As in previous reports,15-17 we found that patients who presented with advanced stages of NHL were more likely to develop leukemia. This reflects their treatment; it has been found that NHL stage was not associated with leukemia after the risks were adjusted for the effect of alkylating agents.17 The relative risk of leukemia in our study diminished with patient age at first treatment, as has been observed after chemotherapy for Hodgkin’s disease.24 As is usual in chemotherapy-induced leukemia,34 including leukemia after NHL,7 the risk of leukemia was raised significantly during the 10 years after first treatment, and then diminished. In a large case-control study of bladder cancer after NHL, Travis et al21 demonstrated that risk of this cancer is strongly associated with cumulative dose of cyclophosphamide, with the lowest doses (up to 20g) having a nonsignificant two-fold increased risk. In this cohort, we found a not significantly increased risk of bladder cancer in patients treated with CHOP, who were generally administered between 6 to 9 cycles of treatment with no long-term maintenance, which would give a cumulative cyclophosphamide dose of about 20g or less. We observed a significantly raised risk of bladder cancer in the radiotherapy-only treated group, in accordance with the elevated bladder cancer risks shown in radiotherapy-treated NHL patients6 and other radiation-exposed cohorts.35,36 Several studies have shown lung cancer as the most common second malignancy among NHL patients, with risks raised by 36% to 90%.5-7 We found a 60% raised risk of this cancer, and a significantly raised risk after radiotherapy. Although previous studies6,12 of NHL patients have not found a significantly increased risk of lung cancer following radiation treatment, it is well established that exposure to ionizing radiation can increase the risk of lung cancer.36 We do not have comprehensive data on field of radiotherapy for the overall cohort, and an additional limitation of our study is that data on smoking was also unavailable. Raised risks of lung cancer after chemotherapy for NHL have been demonstrated in one US cohort,6 but not in another.12 A recent French study14 found a significantly raised risk of this malignancy in men following the CHOP-like regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone). Raised risks of lung cancer have also been seen after alkylating chemotherapy for Hodgkin’s disease.37,38 Risk of lung cancer in our cohort was significantly elevated after CHOP but was not evident in chlorambucil-treated patients. This warrants more detailed investigation, which we plan to do with a nested case-control approach. Modest nonsignificant increases in the risk of colorectal cancer after NHL have been observed in some previous studies,6-8 but not all.9 In our study, the raised risk was only statistically significant when following chemotherapy, specifically CHOP. To our knowledge, the risk of colorectal cancer following chemotherapy in NHL has not been reported before. A multicenter study of second malignancy after Hodgkin’s disease showed a large significant risk of digestive and peritoneal cancers following treatment with doxorubicin (RR = 23), which is part of the CHOP regimen, but did not report the specific cancer sites associated with this treatment.39 Two components of CHOP, namely cyclophosphamide and doxorubicin, have been shown to cause solid tumors in rodent models.40 The risk of colorectal cancer in relation to chemotherapy for NHL, specifically CHOP, needs further investigation. Several NHL cohort studies have noted a reduction in breast cancer risk,6-9,14 though only two studies found the diminution to be statistically significant.6,9 Where examined, no significant relation was found to any specific type of treatment.6,12,14 We found a significant diminution of risk for women treated with chemotherapy. A significantly reduced risk of breast cancer has been shown repeatedly in Hodgkin’s disease patients treated with alkylating chemotherapy; the effect was greater with an increasing number of cycles, and related to premature menopause as a consequence of treatment.34 Drugs used to treat NHL are capable of causing premature menopause. Ovarian failure following treatment with cyclophosphamide is well documented, with most studies showing a linear correlation between cumulative dose of cyclophosphamide and reduction in age at menopause.41 It may therefore be the case that for NHL, as for Hodgkin’s disease, chemotherapy can cause reduced breast cancer risk via induction of premature menopause. Significantly reduced risk of endometrial malignancy (RR = 0.51) was found in a recent Swedish study of NHL patients,9 and we also noted a deficit, which might perhaps relate to treatment-induced premature menopause. In conclusion, long-term follow-up of this cohort of British NHL patients treated under the age of 60 years revealed an increased risk of second malignancy, with a 15-year cumulative probability of 11.2%. After chemotherapy there was an elevated risk of leukemia, as would be expected, but also of lung and colorectal cancers and there was a diminution of the risk of breast cancer. These potential effects of treatment need to be taken into account during clinical follow-up.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the collaborators at the British National Lymphoma Investigation (BNLI) whose patients are included in this cohort.
Supported by The Lymphoma Research Trust. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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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 40. IARC working group on the evaluation of carcinogenic risks to humans: Overall evaluation of carcinogenicity: An updating of IARC Monographs volumes 1-42. Lyon, France, IARC, 1987 41. Meistrich ML, Vassilopoulou-Sellin R, Lipshultz LI: Gonadal disfunction, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncolgy. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 2560-2574 Submitted September 29, 2005; accepted January 23, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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