Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Annals of Oncology 11: 1091-1096, 2000 © 2000 Khmer Academic Publishers. Printed in the Netherlands Review Strategies to reduce the risk of virus-related cancers S. Franceschi Epidemiology Unit, Centro di Riferimento Oncologico, Aviano, Italy; Current address- the International Agency for Research on Cancer, Lyon, France vaccination aimed at cancer prevention is already a reality or a possibility. Whereas HBV vaccination already emerged as Background: Experimental and epidemiological evidence has one of the most cost-effective ways to reduce adult cancer established an association between at least eight viruses and mortality, for HPV vaccination some technical problems still various cancer sites. Recent estimates (at least 10% of cancer await a solution. For other infectious agents (e.g., HCV, HIV) worldwide) have revealed that viruses, together with tobacco prospects for a vaccine are not immediate. and diet, account for the largest proportion of cancer in the Conclusions: In order to apply new knowledge on viruses world. to cancer prevention, large vaccination trials are warranted. Results: Improvements in the detection of viruses and bio- These will have to be large (many thousands of people), markers of chronic infection have led to the identification of prolonged (5-10 years), and match scientific excellence with a strong associations with cancer, particularly for human papil- feasible design. Mistrust between scientists and the public will lomavirus (HPV), hepatitis B virus (HBV), and human immu- have to be prevented by means of absolute openness in sciennodeficiency virus (HIV). For some cancer viruses (e.g., HIV tific information and economical interests involved. and hepatitis C virus, HCV), the spectrum of malignancies involved has still to be well defined. For HBV and HPV, Key words: cancer, HBV, HCV, HIV, HPV, vaccination, viruses Summary Introduction The elucidation of the role of a few human cancer viruses has been one of the major breakthroughs in cancer research in the last 20 years. Progress has been made possible by improvements in the detection of certain viruses (or subgroups of) and biomarkers of chronic infection [1]. In their estimate of proportions of cancer deaths attributed to various factors in the US, Doll and Peto [2] assigned 10% to infections, with 1% as a lower confidence limit. However, only two specific human cancer viruses, Epstein-Barr virus (EBV) and hepatitis B virus (HBV) were mentioned [2]. As of 2000, experimental and epidemiological evidence has firmly established an association between various cancer sites and at least eight viruses, in addition to a few parasites (Schistosomes and liver flukes), and one bacterium, Helicobacter pylori [3-7]. Approximately 15% of cancers worldwide (i.e., nine million new cases in 1990), 23% in developing countries, are now attributed to infectious agents [8]. Most of this burden is related to viral infections (i.e., 10% worldwide, 17% in developing countries). Infectious agents represent, therefore, with tobacco and diet [2, 8, 9], priorities in cancer prevention. Strategies to reduce the risk of virus-related cancers include: 1) research into the strength of the association between viruses and cancer and the spectrum of cancer sites involved, in order to set priorities; 2) behavioural changes (e.g., safe sex, avoidance of breast feeding, etc.); 3) avoidance of infection by screening for cancer viruses in traditional sources (e.g., blood and blood derivatives, cervical smears, etc.) or carriers (e.g., pregnant women, organ donors, etc.); 4) active host immunization through prophylactic and therapeutic vaccines [1, 10]; and 5) antiviral treatment to prevent chronic carrier status [11]. In the following, I will not deal in detail with all viral infections related to cancer in humans nor with all prevention strategies above. Indeed, strategy 3) is routinely performed for known cancer viruses which can be parenterally transmitted whereas strategy 5) is still hampered by the limitations of antiviral drugs [11]. I will, however, consider, by means of examples, some of the most important achievements and future challenges of strategies 1) and 4). Strength of virus-cancer link Virologists chiefly classify established human tumour viruses as direct or indirect carcinogens (also referred to as cofactors), chiefly on the basis of knowledge of specific viral oncogenes [1]. From an epidemiologist's viewpoint, viral infections would be usefully classified by the consistency and strength of their association with cancer, as expressed by relative risk (RR) estimates from case-control and cohort studies. This classification has 1092 Table I. Relation between selected human viruses and various cancer sites by relative risk (RR) level. Relative risk Virus Very high >1000 > 100 HIV-1 HIV-1 > 100 Kaposi's sarcoma Non-Hodgkin's lymphoma HPV 16, Cervical cancer 18, etc. ~20 HBV -20 HCV Moderate ~10 2-10 2-10 Undefined, but elevated HIV-1 HIV-1 HTLV-I EBV HHV-8 Undefined Cancer Not yet identified Comments CofactorofHHV-8 CofactorofEBV Squamous-cell and adenocarcinomas. Other anogenital cancers Hepatocellular carcinoma Hepatocellular carcinoma Hodgkin's disease Cervical and anal cancer T-cell leukemia/ lymphoma Burkitt's lymphoma Hodgkin's disease Non-Hodgkin's lymphoma Nasopharyngeal carcinoma Kaposi's sarcoma Primary effusion lymphoma Lymphomas and leukaemias Bladder Skin Table 2. Increases in relative risk (RR) estimates for HPV and cervical lesions as detection techniques improved. Study (location) Viral detection RR Franceschi et al., Genital warts 1983 (UK) Comment 5.8 Cytological abnormalities; compared to other sexually-trasmitted diseases Reeves et al, 1989 (Latin America) Filter in situ hybridization, HPV 16, 18 Munozet al., 1992 (Spain and Columbia) PCR, any HPV Ngelangel et al., 1998 (Philippines) PCR, any HPV 156 111 Squamous-cell carcinoma Adenocarcinoma PCR, HPV 16 506 549 Squamous-cell carcinoma Adenocarcinoma 9.1 Cervical cancer 28.8 Cervical cancer CofactorofHPV Endemic in Japan, the Caribbean, and West Africa Malaria as cofactor In immunodepressed individuals Suggested by epidemiological evidence been attempted in Table 1. It is important to bear in mind that an RR is greatly influenced by background risk in a given population (i.e., the prevalence and importance of other risk factors), especially when a virus is an indirect cause of cancer (i.e., neither sufficient nor necessary). An RR is also affected by the accuracy with which the relevant agent or biomarker of chronic infection can be detected. Thus low RR for certain viruses may be attributable to the importance of other risk factors in certain populations or to a lack of sensitivity or specificity of available tests. Human papillomavirus (HPV) provides an outstanding example of the gradual discovery of an important human cancer virus [5]. The relationship between a woman's promiscuity (and her partners' number of partners) and cervical cancer has been known for decades [2]. Virtually all sexually transmitted agents, most notably herpes simplex type II, were taken into consideration before suspecting HPV. First isolations of novel virus types (HPV 16 and 18) directly from cervical cancer date back to 1983 [1], but, earlier, in the absence of better markers of HPV-status, the risk of cervical intra-epithelial neoplasm was compared in women with genital warts (as a proxy of HPV-carriage) and women with genital herpes, trichomoniasis, and gonorrhoea [12]. Genital warts were associated with an RR of 5.8 compared to other sexually transmitted agents. Less than two decades later, polymerase chain reaction (PCR)-based tests targeting different open reading frames of HPV were able to identify the virus in 99.7% of approximately 1000 cervical cancer specimens from 22 countries worldwide [13, 14]. Selected studies at Table 2 show the steady increase in the magnitude of HPV-associated RRs as methods for viral detection improved and the most oncogenic HPV types were identified [15, 16]. In one of the most recent studies [17], HPV-16 was associated with a RR of 506 (95% confidence interval (CI): 178-1436) for squamous-cell carcinoma of the cervix (i.e., one of the most elevated RRs ever found for any cancer risk factor). The same was found for adenocarcinoma of the cervix, most notably for HPV 18 (RR = 549; 95% CI: 44-6912). Following the recognition of the central role of HPV in cervical cancer aetiology, HPV testing is being evaluated as an adjunct to Pap smear in screening programs. Main purposes may be HPV typing (for prognostic purposes), avoidance of over-treatment or, in HPV-negative middleaged women, avoidance of further screening [10]. The most recent commercially available HPV diagnostic test (Hybrid Capture II) uses hybridization and a cocktail of HPV-specific probes to detect and type (high-risk vs. low-risk) HPV [18]. For the time being, however, it is unclear how HPV testing will alter the usual clinical care for a positive Pap smear or whether it will make screening more cost-effective. Aside viruses whose link with cancer is well quantified, Table 1 includes several instances where the computation of a precise RR is not possible. Such an estimate has been, so far, hampered by the complicated pattern of infection involved in cancer causation (e.g., EBV) or by 1093 the novelty of virus discovery (e.g., human herpes in addition to disrupted immunosurveillance, chronic virus 8, HHV-8) [7]. Finally, the fourth group in Table 1 antigen stimulation and cytokine dysregulation conincludes some cancer sites for which an infectious agent tribute to cancer onset. has not been identified as yet, but is strongly suspected Marked increases in Kaposi's sarcoma (KS, with RR on account of either a peculiar geographic cancer distri- in the order of 1000) and NHL (with RR in the order of bution (e.g., childhood leukaemia [19]) or of an associa- 100) were among the earliest features of the AIDS tion with recurrent infections (bladder [20]) or immune epidemic (Table 1) [6]. In the largest study so far [28] impairment (e.g., non-Hodgkin's lymphoma (NHL), from the US, the RR for NHL after AIDS was 112.9 non-melanomatous skin cancer [21]). Such malignancies, (95% CI: 103.6-123.4). The striking associations between albeit not yet susceptible to prevention strategies, should HHV-8 and KS [7] and between EBVand certain NHLs also be a research priority since long awaited advances [7] suggest that the role of HIV may be indirect. Indeed, in agent identification may soon become available. the incidence of KS and NHLs increases markedly as HIV-related immunosuppression progresses. Initial reports of Hodgkin's disease (HD) in patients Spectrum of virus-cancer link with HIV/AIDS came from case-series [29] and were taken with skepticism since no clear excess of HD had For many viral infections the full spectrum of associated previously emerged among iatrogenically immunomalignancies has still to be clarified. This particularly suppressed patients [21]. Registry-linkage studies, from applies to two important viruses: hepatitis C virus the US, Italy, and Australia showed, for HD in people with HIV/AIDS, consistent RRs of approximately 10 (HCV)andHIV-l. HCV has infected an estimated 170 million people and [30]. In the largest US study [28], the RR for HD after is the major cause of parenterally transmitted hepatitis AIDS was 7.6 (95% CI: 4.1-13.1). worldwide [4]. Only 20%-30% of new HCV infections Excesses in people with HIV/AIDS have been represent with clinically apparent hepatitis, although 75%- ported also for squamous-cell carcinoma of the anus, 85% of infected persons develop a persistent infection particularly among homosexual men in North America [22]. HCV does not integrate in host genome and, there- and northern Europe [5], and of the conjunctiva in Africa fore, hepatocellular carcinoma is thought to result from [31]. With respect to invasive cervical cancer, marked prolonged liver necrosis and regeneration. HCV-specific increases in HIV-infected women have emerged in studies cytoxic T-lymphocytes (CTL) compartmentalize to the in southern Europe, e.g., RR = 15.5, 95% CI: 4.0-40.1 liver in chronic infection and the response is polyclonal [30] and 12.8, 95% CI: 6.6-22.4 [32]. In the US, women and multispecific [23]. It is not clear as yet whether CTL with HIV/AIDS showed an approximately five-fold response protects against disease or whether it causes increased risk of invasive cervical cancer [33], but pretissue damage. HCV genome and its replicative inter- invasive cervical lesions were greatly increased [28]. mediate have been detected in peripheral blood mono- Higher RRs in southern Europe than in the US may be nuclear cells of patients with chronic infection. The attributable to the higher proportion of intravenous persistence of HCV in these cells may chronically stim- drug users and/or less widespread screening for cervical cancer (and, therefore, less frequent diagnosis at preulate B-lymphocytes [24]. HCV increases significantly the risk of hepatocellular invasive stages). The impact of HIV on cervical cancer in carcinoma. In a meta-analysis of 32 case-control studies high-risk developing countries is not clear as yet. In [25], the RR for anti-HCV ab or HCV-RNA positivity Uganda, the incidence of cervical cancer increased by was 11.5 (95% CI: 9.9-13.3), i.e., similar to the one two-fold from 1960-1971 to 1995-1997 [31], but the RRs for HBsAg positivity (13.7; 95% CI: 12.2-15.4). The RR in HIV-positive women from case-control studies were was more elevated (16.8; 95% CI: 11.9-24.1) in studies not significantly elevated [5], in Japan and the Mediterranean countries, where HCV By and large, the involvement of a broader spectrum infection is more frequent than HBV infection among of tissues or sites than originally suspected seems a hepatocellular carcinoma patients. An association of characteristic of several well-established cancer viruses. HCV with NHL has also been reported [26, 27]. A 51- HPV, besides causing anogenital malignancies, is susfold elevated risk (95% CI: 9.3-286) emerged for extra- pected to be implicated in some carcinomas of the upper nodal NHL of the liver and salivary glands in an Italian aerodigestive tract [34, 35] and, perhaps, of the skin [5]. EBV is implicated in epithelial as well as lymphatic case-control study [27]. malignancies, whereas HHV-8 is strongly associated In respect to HIV, as of the end of 1999, approxiwith a rare type of NHL (primary effusion lymphoma), mately 34 million people were living with HIV infection in addition to KS [7]. or AIDS world-wide. Retroviruses HIV-1 and 2 cause a steady decline of immunity, particularly cellular immunity [6]. Thus, the AIDS epidemic is going to represent an unprecedented source of information on immunity and Cancer prevention through vaccines cancer since follow-up studies of patients receiving organ or bone marrow transplants have involved only a The close link between certain cancer sites and viral few thousand subjects [21]. In HIV infection, however, infections opens the possibility of using vaccinations in 1094 Table 3. Open issues in the development of prophylactic HPV vaccines. cheap and produce a strong and long-lasting immunological response. In fact, the burden of exposure for Issue Comments sexually transmitted agents such as HPV can be especially heavy and prolonged. As shown by experience with Ideally, prophylactic and therapeutic Type of vaccine HBV, routine immunization of infants and/or adolesAt least 30 oncogenic types exist, but HPV HPV types to be cents, girls and boys, appears to be, in the long-term, the 16 accounts for 50%, HPV 18, 31, and 45 included sole effective immunization strategy (Table 3). for further 30% of cervical cancers A few prophylactic HPV vaccines are already availRoute of administration Ideally, through genital mucosae able [36]. The presence of viral oncogenes in HPVs Ideally infants, girls and boys Target population posed theoretical obstacles to the development of a Cost It should be low, perhaps using bacterial prophylactic vaccine that carries the viral genome. vectors or transgenic plants Therefore, efforts have been aimed at developing subunit vaccines (i.e., virus-like particles, VLPs). The VLPs were cancer prevention, and, perhaps, treatment. Such possible obtained by expression of the major HPV capsid protein vaccinations include: 1) prophylactic vaccination, with LI, alone or in combination with L2. Systemic vaccinathe aim to prevent or modify primary viral infection; tion with VLPs has resulted in 90%-100% protection 2) post-infection vaccination, with the aim to modify against species-specific papillomavirus in three animal the existing immune status of an infected individual; and models (rabbits, cattle, and dogs) and in a few early3) therapeutic vaccination, targeted against viral anti- phase human clinical trials (against HPV) (6,11, and 16) [36]. These experiences have opened the door to phase gens expressed in tumour cells. For two viruses in the group showing the most ele- III randomized trials in the year 2000. Several therapeutic HPV vaccines are also available vated RRs in Table 1 (i.e., HBVand HPV), prophylactic vaccination aimed at cancer prevention is already a and are being used in phase I—II trials [36]. The aim of reality or a possibility [36]. For HBV a vaccine based on therapeutic vaccines would be to induce cellular immunity HBsAg particles produced by recombinant DNA tech- against cells expressing viral proteins, in order to induce nology is available at a relatively low cost ($1 per dose) the regression of pre-malignant and malignant cervical [36]. Vaccination at birth or in early childhood prevented lesions. They thus target E6 and E7 oncoproteins of 70%-85% chronic carriers in China, but 90% in Africa, HPV 16 and 18. Some of the vaccines are peptide based where perinatal transmission is less common [4]. Pro- whereas others are based on a recombinant vaccinia tection has been shown to persist up to age nine [37], i.e., vector expressing E6 and E7 [5]. Chimeric (or combined) when the risk of carriage substantially declines. The only vaccines will contain both LI or L1-L2 and E6 or E7 large-scale comparative study, started in The Gambia in proteins, and thus they should allow prevention as well 1986 on about 60,000 infants [38] has not yet provided as regression of cervical lesions [36]. For other viruses related to cancer, prospects for a estimates of HBV vaccination efficacy to prevent cancer. However, 6-10 years after the institution of Taiwan's vaccine are not immediate. HCV, for instance, shares program of universal HBV vaccination, the incidence with HIV an extreme genetic heterogeneity, including of childhood hepatocellular carcinoma declined signifi- hypervariable regions. Patients tend to harbour a mix of cantly [39]. In West Africa it has been estimated that $30 viral genomes and those who clear natural infection can can prevent one chronic carrier and $130 one hepato- be re-infected [41]. An HIV-1 vaccine offers the best long-term hope to cellular carcinoma [40]. The rationale for developing an HPV vaccine includes control the AIDS pandemic, especially in developed the frequency of the HPV infection world-wide (it has countries [42]. Although small-scale clinical trials of been estimated that at least 50% of sexually active adults HIV-1 vaccines have been underway since 1987, the first have had a genital HPV infection), and the well-docu- phase III efficacy trials started only in 1998 in the US mented role of humoral and cellular immunity in the (5400 volunteers) and Thailand (2500 volunteers). Vaccontrol of HPV lesions [36]. However, several issues cines in such trials are based on the envelope glycoprotein remain open, as briefly outlined at Table 3. The ideal gp 120, but other candidate vaccines use live recombinant vaccine against HPV should target different viral anti- vectors and, more recently, DNA immunization [41]. On gens, in order to have potentials for preventing and account of the disease severity, even an HIV-1 vaccine clearing HPV infection and, possibly, induce tumour with a partial efficacy or one able to modify infection regression. Although HPV 16 predominates in severe (i.e., reduce viral load), albeit not to induce sterilizing cervical lesions and carcinomas (approximately 50%), immunity, may also merit to be considered [42]. Vaccination strategies with recombinant subunit viral at least a dozen other types (including 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) can be found, accounting, proteins (e.g., gp 350) and live recombinant virus for about 30% additional cases. Thus, a polyvalent vac- vectors are also being developed against EBV [7]. In the cine would be preferable. Since the principal aim of HPV absence of a satisfactory animal system, however, EBV vaccines is to prevent genital infection, optimal routes of vaccines will have to be evaluated directly in human administration to elicit protection in the genital mucosa trials, after immunogenicity and toxicity have been aswill have to be identified. Finally, vaccine should be sessed in animals. 1095 Concluding remarks References Technological progresses have overcome former inaccuracies in the detection of viruses and virus carrier status, thus firmly establishing a link between cancer and at least eight viruses. Great efforts in preventing virus-associated cancers, most notably through vaccination, are clearly justified from a public health viewpoint. In fact, at least for certain cancer viruses, large risk increases and substantial attributable fractions for common cancers are at stake, particularly in developing countries. Furthermore, the prevention of certain infections would allow not only to avoid cancer, but also to diminish the substantial health burden associated with such viruses. It is sufficient to consider, for HBV and HCV, morbidity and mortality associated with acute and chronic hepatitis and cirrhosis, or, for HPV, the difficulty and cost of mass screening for early diagnosis of HPV-associated premalignant lesions of the cervix. Finally, a major strength of cancer prevention through effective vaccination is the potential for involvement of large populations, at costs possibly affordable by less wealthy countries, and without a need to tackle deeply rooted lifestyle habits. 1. Zur Hausen H. Viruses in human cancers. Eur J Cancer 1999; 35: 1878-85. 2. Doll R, Peto R. The causes of cancer. J Natl Cancer Inst 1981; 66: 1191-308. 3. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Schistosomes, Liver Flukes and Helicobacter Pylori, Vol. 61. Lyon: International Agency for Research on Cancer 1994. 4. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Hepatitis Viruses, Vol. 59. Lyon: International Agency for Research on Cancer 1994. 5. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, Human Papillomaviruses, Vol. 64. Lyon: International Agency for Research on Cancer 1995. 6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs in the Evaluation of the Carcinogenic Risks to Humans, Human Immunodeficiency Viruses and Human T-cell Lymphotropic Viruses, Vol. 67. Lyon: International Agency for Research on Cancer 1996. 7. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs in the Evaluation of the Carcinogenic Risks to humans, Epstein-Barr Viruses and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8, Vol. 70. Lyon: International Agency for Research on Cancer 1998. 8. Parkin DM, Pisani P, Munoz N, Ferlay J. The global health burden of infection associated cancers. Cancer Surv 1999; 33: 5-33. 9. Peto, R, Lopez AD, Borham J et al. Mortality from Smoking in Developed Countries 1950-2000: Indirect Estimates from National Vital Statistics. Oxford: Oxford University Press 1994. 10. Stevenson FK. DNA vaccines against cancer: From genes to therapy. Ann Oncol 1999; 10: 1413-8. 11. Zuckerman AJ, Lavanchy D. Treatment options for chronic hepatitis. Antivirals look promising. BMJ 1999; 319: 799-800. 12. Franceschi S, Doll R, Gallwey J et al. Genital warts and cervical neoplasia: An epidemiological study. Br J Cancer 1983; 48: 621-8. 13. Bosch FX, Manos MM, Mufioz N et al. Prevalence of human papillomavirus in cervical cancer: A worldwide perspective. J Natl Cancer Inst 1995; 87: 796-802. 14. Walboomers JMM, Jacobs MV, Manos MM et al. Human papilloma virus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189: 12-9. 15. Reeves WC, Brinton LA, Garcia M et al. Human papillomavirus infection and cervical cancer in Latin America. N Engl J Med 1989; 320: 1437-41. 16. Munoz N, Bosch FX, De Sanjose S et al. The causal link between human papillomavirus and invasive cervical cancer: A population-based case-control study in Colombia and Spain. Int J Cancer 1992; 52: 743-9. 17. Ngelangel C, Munoz N, Bosch FX et al. Causes of cervical cancer in the Philippines: A case-control study. J Natl Cancer Inst 1998; 90: 43-9. 18. Cain JM, Howett MIC. Preventing cervical cancer. Science 2000; 288:1753-4. 19. Kinlen LJ. Epidemiological evidence of an infective basis in childhood leukaemia. Br J Cancer 1995; 71: 1-5. 20. Kantor AF, Hartge P, Hoover RN et al. Urinary tract infection and risk of bladder cancer. Am J Epidemiol 1984; 119:510-5. 21. Kinlen LJ. Immunologic factors, including AIDS. In Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology and Prevention, 2nd edition. New York: Oxford University Press 1996; 532^15. 22. Hoofnagle JH. Hepatitis C: The clinical spectrum of disease. Hepatology 1997; 26 (Suppl 1): 15S-20S. 23. Koziel MJ. The role of immune responses in the pathogenesis of hepatitis C virus infection. J Viral Hepat 1997; 4 (Suppl 2): 31-41. However, there are still several technical and practical problems that need to be solved before safe, effective and inexpensive vaccines against cancer viruses are produced [10, 36, 42]. A crucial step is going to be the organization of phase III vaccination trials. Since such trials will have to include many-thousand persons and at least 10-year follow-up, scientific excellence will have to be matched with a simple and feasible design. In a rapidly evolving field such as infectious diseases and cancer, long-term involvement of dozens of thousands people and many-hundreds of health professionals is a great challenge. A few examples, including the recent stop to HBV vaccination in France out of largely unsubstantiated fears of neurodegenerative side effects, highlight the growing unease of the public and their political representatives with biotechnological advances. Furthermore, the high costs and uncertainties of vaccine development and the prospect of much higher profitability from investments in other products do not stimulate the interest of the pharmaceutical industry in the field. A substantial public involvement is, therefore, mandatory [43]. Longterm mutual confidence can only be based on great attention to ethical aspects of study design (e.g., careful evaluation of pros and cons of placebo use) and absolute openness in scientific information (e.g., even remote adverse responses) and economical interests involved. Acknowledgements Italian Association for Research on Cancer and Ministero della Sanita, Istituto Superiore di Sanita; Grant number: 20B/1.1 Special thanks to Dr N. Munoz and Prof. C. La Vecchia for their useful comments and to Mrs L. Mei and H. Lorenzen for editorial assistance. 1096 24. Ferri C, La Civita L, Zignego AL, Pasero G. Hepatitis-C virus infection and cancer. Int J Cancer 1997; 71: 1113-5. 25. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998; 75- 347-54. 26. Zuckerman E, Zuckerman T, Levine AM et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin's lymphoma. Ann Intern Med 1997; 127: 423-8. 27. De Vita S, Zagonel V, Russo A et al. Hepatitis C virus, nonHodgkin's lymphomas and hepatocellular carcinoma. Br J Cancer 1998; 77: 2032-5. 28. Goedert JJ, Cote TR, Virgo P et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998; 351: 1833-9. 29. Franceschi, S, Dal Maso L. Arniani S et al. Risk of cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma in persons with AIDS in Italy. Br J Cancer 1998; 78: 966-70. 30. Franceschi S, Dal Maso L, La Vecchia C. Advances in the epidemiology of HIV-associated non-Hodgkin's lymphoma and other lymphoid neoplasms. Int J Cancer 1999; 83: 481-5. 31. Parkin DM, Wabinga H, Nambooze S, Wabwire-Mangen F. AIDS-related cancers in Africa: Maturation of the epidemic in Uganda. AIDS 1999; 13: 2563-70. 32. Serraino D, Carrieri P, Pradier C et al. Risk of invasive cervical cancer among women with, or at risk for, HIV infection. Int J Cancer 1999; 82: 334-7. 33. Selik RM, Rabkin CS. Cancer death rates associated with human immunodeficiency virus infection in the United States. J Natl Cancer Inst 1998; 90: 1300-2. 34. Franceschi S, Munoz N, Bosch X et al. Human papillomavirus and cancer of the upper aerodigestive tract: A review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev 1996; 5: 567-75. 35. Gillison ML, Koch WM, Capone RB et al. Evidence for a causal 36. 37. 38. 39. 40. 41. 42. 43. association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92: 709-20. Coursaget P, Munoz N. Vaccination against infectious agents associated with human cancer. Cancer Surv 1999; 33: 355-81. Viviani S, Jack A, Hall AJ et al. Hepatitis B vaccine efficacy at nine years of age following infant vaccination in the Gambia. Vaccine 1999; 17: 2946-50. The Gambia Hepatitis Intervention Study Group. The Gambia Hepatitis Intervention Study. Cancer Res 1987; 47: 5782-7. Chang M-H, Chen C-J, Lai M-S et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 1997; 336: 1855-9. Hall AJ, Smith PG. Prevention of hepatocellular cancer: One of the most cost-effective ways to reduce adult mortality? Br J Cancer 1999; 81: 1097-8. Randal J. Hepatitis C vaccine hampered by viral complexity, many technical restraints. J Natl Cancer Inst 1999; 91: 906-8. Esparza J, Bhamarapravati N. Accellerating the development and future availability of HIV-1 vaccines: Why, when, where, and how? Lancet 2000; 355: 2061-6. Keusch GT, Bart KJ. Immunization principles and vaccine use. In Fauci AS, Martin JB, Braunwald E et al. (eds): Harrison's Principles of Internal Medicine, 14th edition. New York: McGrawHill 1998; 758-71. Received 10 April 2000; accepted 3 August 2000. Correspondence to • S. Franceschi, MD Unit of Field and Intervention Studies International Agency for Research on Cancer 150, Cours Albert Thomas 69372 Lyon Cedex 08 France E-mail: [email protected]