131 Malignant mesothelioma as a second primary malignancy

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Saturday, October 21, 2006 / Oral session: Epidemiology III Staging of peritoneal mesothelioma?

P. Sugarbaker, D. Yoo, T. Yan. Washington Cancer Institute, Washington, DC, USA Background: Currently, there is no staging system for peritoneal mesothelioma that has international acceptance. The TNM system is not applicable. An IMIG peritoneal mesothelioma staging system would greatly facilitate progress in this disease especially in the comparison of benefits of treatment between institutions. A clinical (pre-treatment) and pathologic (post-treatment) staging system is needed. Methods: The assessments currently available to estimate prognosis of peritoneal mesothelioma include the preoperative CT of chest, abdomen and pelvis, laparoscopic biopsy, peritoneal cancer index (PCI), completeness of cytoreduction score (CCR), and histopathology of specimens removed at cytoreduction including lymph nodes. At the Washington Cancer Institute these were assessed in 70 patients treated in a uniform manner with cytoreductive surgery and perioperative intraperitoneal chemotherapy. A few patients recently treated received systemic chemotherapy. Results: The CT of chest, abdomen and pelvis was shown to predict the likelihood of survival by using tumor volume >5 cm in the epigastric region and loss of architecture of the small bowel regions (p<0.001) as parameters. Laparoscopic biopsy, if there is adequate sampling, may allow histomorphologic prognosis assessment but no data was available. The peritoneal cancer index recorded at the time of abdominal exploration provides useful prognostic information (p=0.038) as did the completeness of cytoreduction score (p=0.010). A complete histologic assessment of the clinical material made available by cytoreduction was significant if nuclear size and chromatin pattern of the nucleus were the determinants (p<0.001). Also, histologic type (sarcomatoid and biphasic vs. epithelial) was significant (p<0.001). Lymph node positive patients had an extremely poor prognosis (p<0.001). The presence vs. absence of extraperitoneal disease did not show significance. Conclusion: Radiologic and histologic parameters can be combined to stage peritoneal mesothelioma. An IMIG format for prognosis assessment with a uniform treatment should be formalized and prospectively tested at selected treatment centers in North America and Europe.

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Multi-center clinical trials for peritoneal mesothelioma: Can they be done and what are the questions to be answered?

R. Hassan. National Cancer Institute, Bethesda, USA Information regarding the management of patients with peritoneal mesothelioma comes from a few specialized centers that treat these patients. These patients are treated either off protocol or on protocols that have evolved at those institutions over time. Data obtained from these single institution studies can at times be difficult to compare with results from other institutions because of differences in patient selection, pathology, surgical techniques and chemotherapy administered. To standardize patient management it would be useful if investigators from these specialized centers review their results and procedures. This could result in clinical trials that can be done at all these centers and therefore increase the number of patients receiving similar treatment and give more statistical power to the results. In addition, a centralized pathology review would make it possible to compare the prognosis of the different subtypes of peritoneal mesothelioma. However, as with any multi-center clinical trials there would be issues related to agreement on a common treatment approach, institutional review board approval, patient selection and funding to co-ordinate these trials. Despite the difficulty of conducting these studies, the information gained form these multi-institutional clinical trials will move the field forward and establish a platform to evaluate more innovative therapies for the treatment of peritoneal mesothelioma.

Saturday, October 21, 2006

8:00–9:15

ORAL SESSION

Epidemiology III

130

Exposure to polio vaccine possibly contaminated with simian virus 40 and subsequent risk of malignant mesothelioma

K. Kjærheim 1 , O.D. Roe 2 , T. Waterboer 3 , P. Sehr 3 , R. Rizk 3 , H. Sandeck 3 , E. Larsson 4 , H.Y. Dai 2 , A. Andersen 1 , P. Boffetta 5 , M. Pawlita 3 . 1 Cancer Registry of Norway, Oslo, Norway; 2 St. Olavs Hospital, Trondheim, Norway; 3 German Cancer Research Center, Heidelberg, Germany; 4 Norwegian University of Science and Technology, Trondheim, Norway; 5 International Agency for Research on Cancer, Lyon, France Background: Malignant mesothelioma (MM) is associated with asbestos exposure. Recent evidence has however linked disease risk also to infection with simian virus 40 (SV40), a possible contaminant of polio vaccine during 195663. The aim of the study was to investigate if risk of MM was associated with the presence of pre-diagnostic SV40 antibodies and DNA fragments. Methods: Eighty MM cases were identified by linkage of the Norwegian Cancer Registry to the Janus serum bank. In addition to histological verification at the time of diagnosis tumor tissue samples were re-examined with at least four immumohistochemical stainings and reviewed independently by two pathologists, leaving 49 cases to be included in the analyses. Three controls were selected per case, matched by age, gender, period of serum sampling, and county. Data on occupation were obtained from national censuses, and were used to code asbestos exposure in four levels. Sera were tested for antibodies against the viral capsid protein VP1 and the large T antigen of primate polyomaviruses SV40, BKV and JCV. Conditional logistic regression analysis was used. Results: Odds Ratio (OR) was 4.5 (95% CI 1.0-20.9) for those with the highest level of asbestos exposure. Risk of MM was 50% higher in the group testing positive for SV40 VP1 (OR 1.5, 95% CI.0.89-2.53) compared to the group with negative test. Non-significant elevations of risk were seen specifically among those who were classified as most probably exposed to potentially contaminated vaccine, among those who had never been asbestos exposed, and those with a short period between serum sampling and diagnosis. Conclusions: No significant associations between SV40 and risk of MM was seen in this study using pre-diagnostic sera. Non-significantly elevated ORs in some strata deserves further study in larger samples.

131

Malignant mesothelioma as a second primary malignancy

S. Burgers, M. Tiemessen, J. Kegjens, P. Baas. Netherlands Cancer Institute, Amsterdam, Netherlands Background: Exposure to asbestos is the main cause of malignant mesothelioma (MM). It can be established in more than 80% of the patients. Only case reports are available on other potential etiological mechanisms like man made mineral fibers, organic chemicals and radiotherapy. We have reviewed our database for patients presenting with MM as a second primary tumor and focussed on a possible causal relation between the primary tumor, its treatment and the development of the mesothelioma. Methods: The database of the NKI-AVL was surveyed for all MM that occurred as secondary or third primary malignancy. The individual files were retreived and details of the malignancies and the treatment were noted. Missing data were completed via the databases of the general practitioner, other radiotherapy institutions, the National Mesothelioma Panel and the National Cancer Registry. Results: From 1977 until December 2005, 846 mesothelioma patients visited our clinic. The mesothelioma was preceded by one other malignancy in 36 and by two others in 6 patients. Characteristics: median age at diagnosis of first malignancy 56y (range 9 - 79y); male:female 33:9; asbestos exposure professionally 28 - via family members 2 - none 9 - unknown 2. Pleural: abdominal was 36:6. Primary malignancies: prostate 8, Hodgkin’s 5, melanoma 5, breast 5, bladder 4, colon-sigmoid 4 and remaining group all 1. We focussed on the patients with a greater than 10 yrs interval between the tumors and who had radiotherapy as treatment for the primary tumor. Eleven patients fulfilled these criteria 5 males, 6 females; median age at diagnosis primary tumor 22 y (9-45y); 2 exposed to asbestos via family members, 5 without asbestos exposure, 3 with professional exposure and 1 exposure unknown. These patients included all Hodgkin’s patients in our series, a thymoma, a sarcoma of the jaw, seminoma testis, vaginal cancer (DES daughter), ovarial dysgerminoma and mammary cancer. In 9 patients the mesothelioma was located in the previous radiotherapy field, in 1 patient a causal relation between previ-

Saturday, October 21, 2006 / Oral session: Epidemiology III ous irradiation of the breast and the peritoneal mesothelioma was suggested, in 1 patient a causal relation was considered unlikely. Conclusions: Radiotherapy can induce mesothelioma. A likely or possible causal relation between previous radiotherapy and the induction of a malignant mesothelioma in our series was detected in 10 out of 846 patients. The relatively high number of females and low number of patients exposed to asbestos also indicates that radiotherapy may be a causative agent for the development of MM.

132

The mesothelioma epidemic and the hidden asbestos-related lung cancer epidemic

C. Rake 1 , C. Gilham 1 , J. Hodgson 2 , J. Peto 3 . 1 Institute of Cancer Research, Sutton, UK; 2 Health and Safety Executive, Bootle, UK; 3 London School of Hygiene and Tropical Medicine, London, UK Background: A British case-control study including 425 patients with lung cancer (294 men, 131 women, all born since 1940), 624 with mesothelioma (513 men, 111 women) and 1,420 population controls (1,112 men, 308 women) identified occupations conferring a high mesothelioma risk (see Abstract by Peto et al.). Methods and results: Odds ratios (ORs) for lung cancer adjusted for socioeconomic status were calculated for non-smokers, ex-smokers, and current smokers. Lung cancer risk was further assessed in relation to smoking duration and smoking dose (average cigarettes/day while smoking) in analyses restricted to cigarette smokers who either smoked continuously without changing the amount they smoked by more than 10 cigarettes/day, or stopped and did not start again. The lung cancer incidence rate was proportional to the fifth power of duration of smoking, with a linear-quadratic dose-response for cigarettes/day. The effect of asbestos exposure on lung cancer risk was then examined by analysing duration of work in construction and other high mesothelioma risk occupations before age 35, adjusting for socio-economic status and smoking. Numbers of lung cancers and controls were 123 and 212 respectively with >5 years exposure in a high-risk occupation (OR 2.0, 95%CI 1.4-2.8), 46 and 108 with <5 years exposure (OR 1.4, CI 0.9-2.3), and 125 and 508 unexposed (ref.). Conclusions: The estimated attributable fraction of lung cancers in British men born since 1940 due to these occupations is 22%. The ratio of male mesothelioma to lung cancer registrations below age 65 is now about 1:10 in Britain. If this excess were due entirely to asbestos and persisted in old age there would thus be slightly more than two excess lung cancers caused by asbestos exposure for each mesothelioma, or almost 4,000 lung cancers and 1,600 mesotheliomas per year in British men. Silica and other lung carcinogens may contribute, but past asbestos exposure is probably causing more lung cancers than mesotheliomas in British men.

133

Quantifying the risks of mesothelioma and lung cancer from environmental crocidolite exposure in Da-yao, China

T.D. Cheng 1 , C.P. Wen 2 . 1 Johns Hopkins School of Public Health, Baltimore, Maryland; 2 Center for Health Policy Research and Development, National Health Research Insitutes, Taipei, Taiwan Background: Da-yao is a rural county located in the Southwestern China, with a quarter million population. Part of its land surface is patch-like covered by crocidolite ore, and it has been widely used in the infrastructure of the county. The industry of clay stoves had caused significant crocidolite exposure among workers and family members in the last several decades. Thus, residents have been at risk of being exposed to crocidolite dust from birth. The mortality risk from environmental crocidolite is not well established and its attributable fraction to mesothelioma or lung cancer has never been reported. The objective of this study is to quantify the Rate Ratios (RRs) for mesothelioma from crocidolite exposure and crocidolite-attributable fraction of lung cancer. Methods: The data came from the update of a 15-year (1987-2001) follow-up of 6,254 residents presented in journal Occup Environ Med 2003; 60:35-42. A total of 20 deaths of mesothelioma and 56 deaths of lung cancer, among 1,165 total deaths, were observed. RRs were calculated by comparing rates from Dayao with respective rates from Taiwan, where no crocidolite exposure is known. Results: Mortality rates of mesothelioma in Da-yao cohort were 23.2 and 18.7 per 100,000 for males and females, and in Taiwan, 0.12 and 0.06, respectively. The RRs of crocidolite exposure for mesothelioma were 227 and 311 in males and females, respectively. Given the mortality rate difference for lung cancer (65.1/100,000 for Da-yao and 30.2/100,000 for Taiwan), and the prevalence difference for smoking (43% in Da-Yao and 26% in Taiwan), we found the crocidolite-attributable fraction of lung cancer to be close to one third (36%) of all lung cancer deaths. Conclusions: The mesothelioma risk from environmental crocidolite exposure was approximately 269 times greater in this community than in Taiwan. The crocidolite-attributable lung cancer in Da-yao was about to one third of all lung cancer mortality.

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Projected mesothelioma incidence in men in New South Wales, Australia

G. Berry 1 , M. Clements 2 , A. Johnson 3 , S. Ware 3 , D. Yates 3 . 1 School of Public Health, University of Sydney, Sydney, Australia; 2 NCEPH, Australian National University, Australia; 3 NSW DDB Research & Education Unit, Australia Background: Between 1972 and 2002 there had been 2461 cases of mesothelioma recorded in men living in New South Wales. This paper considers the use of these data to project the future number. Methods: Two approaches have been used. The first was the age and birth cohort model in which the incidence is related to year of birth and age. The second approach was based on the approach of Hodgson and colleagues (Brit J Cancer, 2005;92:587-593) in which exposure to asbestos was assumed to depend on calendar year and age in that year. Their approach was modified by modelling the calendar year and age effects as exponentials of natural splines, and this modification reduced the number of parameters to be estimated to 5 and simplified the fitting of the model. It was assumed that the incidence following exposure increased as the power of 3.5 of time since that exposure with a 5-year lag subtracted, and an elimination effect was included (half life 15 years). In both methods it was assumed that birth cohorts from 1970 were at negligible risk because of the phase out of amosite during the 1980s and the earlier discontinuation of crocidolite from 1970 (also there are few cases on which to base estimates). Results: In the first approach the age effect increased as (age-20) to the power of 3.5 up to 82 years, and the birth cohort effect showed the highest incidences for birth years 1920 to 1950 with a decrease for more recent cohorts. This model gave a predicted future number of cases of 5770 from 2003 and a peak incidence of 171 in 2014. In the second approach the exposure potential by age was estimated to give low rates for children, increasing to a peak at 40 years, and then declined with low rates after 55 years. The exposure potential by calendar year gave a rapid rise through the 1940s and 1950s to a peak in the early 1960s, and a rapid decline from the late 1970s. This model predicted 6352 more cases from 2004 with a peak of 192 in 2014. Conclusions: The two approaches gave fairly similar results. The pattern of calendar year and age effects in the second model corresponds to amphibole asbestos use in Australia.

135

The French national mesothelioma surveillance program

M. Goldberg 1 , E. Imbernon 1 , P. Rolland 1 , A.G.S. Ilg 1 , A. de Quillacq 2 , C. Frenay 3 , S. Chamming’s 4 , G. Launoy 5 , J.C. Pairon 6 , P. Astoul 3 , F. Galateau-Sallé 7 , P. Brochard 8 . 1 Institut de Veille Sanitaire, Saint Maurice, France; 2 Laboratoire d’Anatomie Pathologique Caen, Caen, France; 3 Faculté de médecine de la Timone, Marseille, France; 4 Institut Interuniversitaire Médecine Travail de Paris Ile de France, France; 5 Réseau des Registres du cancer FRANCIM, INSERM ERI3, France; 6 Institut Interuniversitaire Médecine Travail, INSERM E03-37; 7 Faculté Laboratoire d’Anatomie Pathologique, Caen, France; 8 Laboratoire Santé Travail Environnement, Bordeaux, France Background: The French National Mesothelioma Surveillance Program (PNSM) was established in 1998 by the National Institute for Health Surveillance (InVS). Its objectives are to estimate the trends in mesothelioma incidence and the proportion attributable to occupational asbestos exposure, to contribute to the research, to help improve its pathology diagnosis and to assess its compensation as an occupational disease. Methods: The PNSM records incident pleural tumours in 21 French districts that cover a population of approximately 16 million people. A standardized procedure of pathologic and clinical diagnosis ascertainment is used. Lifetime exposure to asbestos and to other factors (man made mineral fibres, ionizing radiations, SV40 virus) is reconstructed, and a case-control study was also conducted. We assessed the proportion of mesothelioma compensated as an occupational disease. Results: Depending on the hypotheses used, the estimated number of incident cases in 1998 ranged from 660 to 761 (women: 127 to 146; men: 533 to 615). Among men, the industries with the highest risks of mesothelioma are construction and ship repair, asbestos industry, manufacture of metal construction materials; the occupations at highest risk are plumbers, pipe-fitters, sheet-metal workers and welders. The attributable risk fraction for occupational asbestos exposure for men was 83.2% (95% CI: 76.8-89.6). Pathology review confirmed the initial pathologist’s diagnosis in 67% of cases, ruled it out in 13%, and left it uncertain in the others; for half of the latter, the clinical findings strongly supported a mesothelioma diagnosis. In all, 62% applied for designation of an occupational disease, and 91% of these were receiving workers’ compensation.