Journal of the National Cancer Institute Advance Access originally published online on April 8, 2008
JNCI Journal of the National Cancer Institute 2008 100(8):600-601; doi:10.1093/jnci/djn086
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Published by Oxford University Press 2008.
CORRESPONDENCE |
Response: Re: Second Cancers Among 104760 Survivors of Cervical Cancer: Evaluation of Long-Term Risk
Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (AKC, EAE, ESG, BEC, RAK, LBT); Danish Cancer Society, Copenhagen, Denmark; (HS, MA); The University of Iowa, Iowa City, IA (CFL); Karolinska Institutet, Stockholm, Sweden (PH, MK); Cancer Registry of Norway, Oslo, Norway (FL, SDF); Finnish Cancer Registry, Helsinki, Finland (EP); Helsinki University Central Hospital, Helsinki, Finland (HJ); International Epidemiology Institute, Rockville, MD (JDB); Vanderbilt-Ingram Cancer Center, Nashville, TN (JDB)
Correspondence to: Anil K. Chaturvedi, PhD, Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd, EPS 7072, Rockville, MD 20852 (e-mail: chaturva{at}mail.nih.gov).
We thank Cai et al. for their interest in our study describing the long-term risk of second cancers among cervical cancer survivors (1). In our study, we assessed second cancer risk among 104760 cervical cancer survivors in Denmark, Finland, Norway, Sweden, and, based on data from the Surveillance, Epidemiology, and End Results program, the United States. Compared with women in the general population, we observed statistically significant increased risks of urinary bladder cancer among cervical cancer survivors who initially received radiotherapy (536 bladder cancers among 52613 women; standardized incidence ratio [SIR] = 3.51; 95% confidence interval [CI] = 3.22 to 3.83) and among women who did not receive radiotherapy initially (109 cancers among 27382 women; SIR = 1.93; 95% CI = 1.59 to 2.34) (1).
Cai et al. raise the following questions: 1) whether the increased urinary bladder cancer risk among cervical cancer survivors, particularly among women who did not receive radiotherapy, could be due to an etiologic role for human papillomavirus (HPV) infection in bladder cancer and 2) what proportion of the 109 bladder cancer cases who did not receive radiotherapy were smokers. We did not have information regarding noncervical HPV infections or cigarette smoking in our study (1), thus precluding any assessment of the contribution of either HPV infection or cigarette smoking to the increased bladder cancer risk among women who did not receive radiotherapy.
Although we did not have information on smoking behaviors, it is well established that cigarette smoking is etiologically related to both cervical cancer and bladder cancer, with approximately twofold to threefold increased risks for each cancer among smokers as compared with nonsmokers (2). Thus, the elevated risk for bladder cancer among survivors who did not receive radiotherapy may, in part, be due to a high prevalence of smoking. Increased bladder cancer risk among survivors who did not receive radiotherapy could have also arisen from misclassification of radiation treatment. Although treatment misclassification among cervical cancer patients is low (3), it is possible that some women classified as not receiving radiotherapy may have actually received radiotherapy, as indicated by their increasing bladder cancer risk over follow-up time (1), a pattern that is consistent with the late effects of radiotherapy.
Cai et al. suggest a model wherein HPV infection causes cervical cancer and then, after a subsequent latency, causes bladder cancer. HPV has been implicated in the etiology of primary urinary bladder cancers (4,5). Benign HPV-related condylomas, although rare, are known to occur in the bladder, indicating that HPV infection of the bladder is plausible (4). Further, HPV DNA has been detected in both transitional cell carcinomas and squamous cell carcinomas of the bladder (4). However, results have been inconsistent across studies, with HPV DNA prevalence in bladder cancer tissues varying from 0% to 80% (4,5). Gillison and Shah (4) recently reviewed criteria to evaluate the plausibility of a HPV etiology for noncervical cancers, including epidemiological and virological characteristics such as increased incidence of the cancer under question among populations with high-risk sexual behavior and immunosuppressed populations, expression of viral oncogenes in the tumors, and the presence of serum antibodies to HPV oncogenes (E6 and E7) (4). Although bladder cancer has been associated with a history of sexually transmitted diseases such as gonorrhea, this is believed to be due to urinary tract inflammation and/or urinary stasis, rather than increased HPV infections (6). Bladder cancer incidence is not increased in immunosuppressed HIV-infected individuals (7). Finally, no studies have evaluated either HPV oncogene expression in tumors or the presence of HPV E6 and E7 serum antibodies among bladder cancer patients. Thus, we believe that there is currently insufficient evidence in the literature to link HPV infection with urinary bladder cancer, either among cervical cancer survivors or in the general population.
REFERENCES
1. Chaturvedi AK, Engels EA, Gilbert ES, et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst (2007) 99(21):1634–1643.
2. Schottenfeld D, Fraumeni JF Jr, eds. International Collaboration of Epidemiological Studies of Cervical Cancer. In: Cancer Epidemiology and Prevention (2006) 3rd ed. New York: Oxford University Press.
3. Boice JD Jr, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res (1988) 116(1):3–55.[Web of Science][Medline]
4. Gillison ML, Shah KV. Chapter 9: role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr (2003) 31:57–65.
5. Youshya S, Purdie K, Breuer J, et al. Does human papillomavirus play a role in the development of bladder transitional cell carcinoma? A comparison of PCR and immunohistochemical analysis. J Clin Pathol (2005) 58(2):207–210.
6. Michaud DS, Platz EA, Giovannucci E. Gonorrhoea and male bladder cancer in a prospective study. Br J Cancer (2007) 96(1):169–171.[CrossRef][Web of Science][Medline]
7. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS (2006) 20(12):1645–1654.[Web of Science][Medline]
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J Natl Cancer Inst 2008 100: 600.
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