Malignant pleural mesothelioma causally linked to asbestos exposure is a relatively rare cancer, still estimated to affect 25,000 to 43,000 persons yearly worldwide.1–4 Although the overwhelming majority of pleural mesotheliomas are attributable to asbestos, a few other causes have been identified. There are indications that multiwalled nanotubes might be a potential mesothelioma risk factor.5 Mesothelioma is also a well-known complication of therapeutic radiation for lymphoma, breast cancer, lung cancer, and other malignancies.6
The latency period is thought to be as long as 40 years or more between asbestos exposure and the development of mesothelioma.7 The incidence of malignant pleural mesothelioma is significantly higher in men, possibly because of occupational asbestos exposure. As the commercial use of asbestos has been banned for some decades in Europe, it has been predicted that the incidence of male mesotheliomas will decline after 2015–2020.8 Recent studies have shown that patients with malignant mesothelioma have a median overall survival of 7 to 10 months.9,10
The results of curatively intended treatment for pleural mesothelioma are largely disappointing. Surgery may be an option for a small subset of patients whereas radiotherapy has only palliative effects. Mesothelioma was earlier regarded as chemoresistant, but this modality is now incorporated in standard care.
In this study we have population-based data of mesothelioma incidence and survival from Norway, in the period from 1970 to 2009. During this period, the diagnostic possibilities were improved, especially because of increased use of computed tomography scanning from the mid 1970s. Not the least, after the phase III study by Vogelzang et al.11 on pemetrexed in malignant pleural mesotheliomas, treatment with this antimetabolite was introduced in Norway in the early 2000s. We here report incidence and survival data on a national level, before and after introduction of this treatment.
PATIENTS AND METHODS
Norway, with a population of 5 million, has a universal public health service financed by taxation and a national insurance scheme accessible to all residents, independent of social or economic status. This includes funding of chemotherapy. In the period studied, the proportion of citizens of non-Western origin fluctuated from 1.3% to 4.9%. In our data set no subset analysis was conducted based on race, socioeconomic status, or geography.
Since 1952 all malignant neoplasms have been reported to the Cancer Registry of Norway. In addition, copies of cytology, biopsy, and autopsy reports are submitted from pathology laboratories and death certificate reports are submitted from the Cause of Death Register run by the National Statistics Bureau, Statistics Norway. Since 1998 all hospitals have filed discharge summaries electronically to the registry. The system of reporting to the Cancer Registry of Norway was evaluated in 2009, and overall completeness of reporting was estimated at 98.8%.12
Data on mesothelioma patients undergoing surgery were collected from the Norwegian register for general thoracic surgery13 and the Danish National Hospital, Copenhagen, Denmark.
Pemetrexed was introduced in Norway through a compassionate-use program initiated in 2003. Data on the usage of pemetrexed for mesothelioma patients the first 2 years was provided by Eli Lilly & Co. From 2005, pemetrexed was also given to lung cancer patients. From then on, no data are available on the selective use of pemetrexed in the mesothelioma population.
Mortality updates are conducted routinely by the Cancer Registry of Norway through linkage with the Cause of Death Register. In survival analyses, the primary outcome was survival after a diagnosis of mesothelioma. Follow-up was defined as the time from mesothelioma diagnosis to death as reported from the Cause of Death Register or to the last date of data submission for patients who were still alive, whichever came first.
We divided the study period into calendar years. Incidence data are presented as age-adjusted by the direct method to the standard world population. We calculated 1- and 5-year male and female relative survival for individuals diagnosed through successive 5-year calendar periods. We estimated relative survival for men and women using the method of Hakulinen, where the survival time of the matched individual is censored at the same survival time as that of the patient with cancer.14 Relative survival adjusts for competing causes of death expected for persons of the same sex, age, and calendar year of investigation (the ratio of observed survival in a population to the expected survival rate); hence, cause of death information is not required.
The incidence has increased steadily from 1970 to 2004, from 50 patients during 1970–1974 to 377 patients in the period 2005–2009 (Fig. 1A). The incidence is significantly higher in men than in women (p = 0.0016), with a male-to-female ratio of 4.0 to 4.8:1 throughout the period. The increase in men has been 7.8-fold over the 40-year period, whereas the increase in females has been 6.5-fold. The rates per 1,00,000 increased from 0.1 in 1970 in women to 0.3 in 2005–2009. In men the rates increased from 0.3 in 1970–1974 to a peak of 1.6 in 2000–2004, slightly decreasing to 1.5 in 2005–2009. This corresponds to an average absolute annual increase of 5.4 % in men and 4.9% in women, whereas the age-adjusted annual increase has been 4.2% and 2.9%, respectively (Fig. 1B).‘
Most patients with malignant pleural mesothelioma present with extensive disease, and receive palliative chemotherapy and/or radiotherapy. Less than 10% of these patients undergo surgery for treatment. During the last years, surgery for this disease has been centralized to the Department of Thoracic Surgery in Copenhagen, Denmark, where 25 Norwegian patients underwent surgery in the period 2004–2011. In 15 patients, extrapleural pneumonectomies were performed and in 10 decortication was done. In Norway, five pneumonectomies and one decortication were performed in the period 2003–2010, according to the national registry for thoracic surgery. In addition, presumably, a very small number of patients might have on their own expense undergone surgical procedures outside of Norway or Denmark.
Radiotherapy is often used as palliative treatment for this patient group in Norway, but doses delivered are very seldom more than 50 Gy. Less than 50% of the patients receive this modality, and there has been no trend in increased use of radiation therapy (data not shown).
After introduction of pemetrexed in the treatment of mesothelioma in Norway in February 2003, patients with malignant pleural mesothelioma have been treated with this drug mainly in combination with cisplatin or carboplatin. The first 2 years, 65 mesothelioma patients were treated with pemetrexed, corresponding to approximately 40% of the diagnosed cases (Fig. 2).
The 1-year survival increased significantly during 1970–2009 in both sexes, from 10% to 20% in the early 1970s, fluctuating between 30% and 35% through the 1980s and 1990s and reaching 44.0% (p = 0.0014) and 41.3% (p = 0.029) in men and women, respectively in the last period (Fig. 3). The 3-year survival has been below 10% throughout the period (nonsignificant change).
The median survival increased during the 1970s, seeming to reach a plateau of approximately 7 months in the 1980s and 1990s. During the last decade, there has been an increase in median survival, being 9.3 months in men in the last period of study (Fig. 4). The increase throughout the study period was statistically significant in both sexes (p = 0.0016 in men, and p = 0.05 in women).
This study confirms the increase in incidence of malignant pleural mesothelioma over the last 40 years, as observed elsewhere.9,15 The incidence in men has remained substantially higher than in women, but the increase rate in women has been almost as high as in men. It has been estimated that the incidence of this diagnosis will increase with a predicted peak in 2015–2020 in Europe.8 Our data indicate that the incidence-peak in men has been reached in Norway, with a slight decline in adjusted rate per 1,00,000 during the last 5-year period. This might be explained by the fact that restrictions on asbestos usage were implemented in 1974 in Norway, as one of the first nations. A general ban on import and use was established from 1984 and further restricted in 1991. In most other Western countries similar restrictions were implemented later, notably in Germany from 1993, France from 1996, and Great Britain from 1999.16
The 1-year survival has increased from approximately 20% in the 1970s, to well over 40% in the later years. This may have been because of several causes. The diagnostics have improved since 1970, with computed tomography being available from the mid 1970s, and it is likely that in general, the disease has been diagnosed in earlier stages in the recent years. Few surgeons seem enthusiastic regarding extensive surgery for these patients. The effect of extrapleural pneumonectomy has been reported to be of no positive and possible harmful effect regarding survival in these patients.17 However, the facts that 12 hospitals were engaged, and only 16 of 24 patients randomized to surgery were operated with a somewhat high 30-day mortality indicate that a firm conclusion regarding the place of surgery cannot be drawn. With the exception of a very small subset of patients, it is assumed that radical surgery in terms of an R0 resection cannot be achieved in patients with malignant pleural mesothelioma. Furthermore, radiotherapy is given in palliative doses only, and there does not seem to be a trend of increasing doses or increased frequency of this modality. Other studies have not shown any significant survival effect of radiotherapy for mesothelioma.18 Therefore, the advent of chemotherapy, especially the introduction of pemetrexed from 2003, most probably has contributed to the increased median and 1-year survival observed in the later years.19 Our data are consistent with this view, as we see an increase in median survival through the 1970s, reaching a plateau in the 1980s and 1990s. This is presumably because of earlier diagnosis caused by increased and improved computed tomography-based diagnostic, but no significant advance in treatment. However, over the last 10-year period, a significant improvement in median survival, from approximately 7 months (6.8 months in 1995–1999), to more than 9 months (9.3 months in 2004–2009) was observed, pointing to a substantial contribution from chemotherapy also on a population level. This is in concordance with recent results from The Netherlands, which also showed a coincidence of improved survival and introduction of pemetrexed for mesothelioma.20 Even though we have no data on pemetrexed usage in the mesothelioma group selectively after 2004, there are no indications that the patient group has been chemotherapy treated to a lesser extent than during the first years. Before the introduction of pemetrexed, a number of different chemotherapy regimens were tried for mesothelioma patients. These included metothrexate, cisplatin and trofosphamide, either in combination or as monotherapies. None of these were regarded as standard treatment, and were probably used in a minority of patients only.
The incidence of malignant pleural mesothelioma may be declining in several Western countries. Nevertheless, it will take several decades—if ever—before the disease has returned to an incidence rate so low that it could be neglected by the medical community. In the mean time, effort should be made to increase survival for one of the hitherto most fatal of all malignancies.
This study was financially supported by the South-Eastern Norway Regional Health Authority. Data on surgery and radiotherapy rates are provided by Jesper Ravn, Rigshospitalet, Copenhagen and Tor O. Green, The Norwegian Radium Hospital, Oslo, respectively. Data on pemetrexed usage are provided by Lars Petter Strand, Eli Lilly & Co. The study has used data from the Cancer Registry of Norway.
1. McDonald JC, McDonald AD. The epidemiology of mesothelioma in historical context. Eur Respir J. 1996;9:1932–1942
2. Park EK, Takahashi K, Hoshuyama T, et al. Global magnitude of reported and unreported mesothelioma. Environ Health Perspect. 2011;119:514–518
3. Driscoll T, Nelson DI, Steenland K, et al. The global burden of disease due to occupational carcinogens. Am J Ind Med. 2005;48:419–431
4. Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591–1603
5. Nagai H, Okazaki Y, Chew SH, et al. Diameter and rigidity of multiwalled carbon nanotubes are critical factors in mesothelial injury and carcinogenesis. Proc Natl Acad Sci USA. 2011;108:E1330–E1338
6. Hodgson DC, Gilbert ES, Dores GM, et al. Long-term solid cancer risk among 5-year survivors of Hodgkin’s lymphoma. J Clin Oncol. 2007;25:1489–1497
7. Marinaccio A, Binazzi A, Cauzillo G, et al.Italian Mesothelioma Register (ReNaM) Working Group. Analysis of latency time and its determinants in asbestos related malignant mesothelioma cases of the Italian register. Eur J Cancer. 2007;43:2722–2728
8. van Meerbeeck JP, Damhuis R. Facts, rumours and speculations about the mesothelioma epidemic. Respirology. 2011;16:1018–1019
9. Milano MT, Zhang H. Malignant pleural mesothelioma: a population-based study of survival. J Thorac Oncol. 2010;5:1841–1848
10. Montanaro F, Rosato R, Gangemi M, et al. Survival of pleural malignant mesothelioma in Italy: a population-based study. Int J Cancer. 2009;124:201–207
11. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–2644
12. Larsen IK, Småstuen M, Johannesen TB, et al. Data quality at the Cancer Registry of Norway: an overview of comparability, completeness, validity and timeliness. Eur J Cancer. 2009;45:1218–1231
14. Hakulinen T. Cancer survival corrected for heterogeneity in patient withdrawal. Biometrics. 1982;38:933–942
15. Ulvestad B, Kjaerheim K, Møller B, Andersen A. Incidence trends of mesothelioma in Norway, 1965-1999. Int J Cancer. 2003;107:94–98
17. Treasure T, Lang-Lazdunski L, Waller D, et al.MARS trialists. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011;12:763–772
18. Waite K, Gilligan D. The role of radiotherapy in the treatment of malignant pleural mesothelioma. Clin Oncol (R Coll Radiol). 2007;19:182–187
19. Fennell DA, Gaudino G, O’Byrne KJ, Mutti L, van Meerbeeck J. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008;5:136–147
20. Damhuis RA, Schroten C, Burgers JA. Population-based survival for malignant mesothelioma after introduction of novel chemotherapy. Eur Respir J. 2012;40:185–189
Mesothelioma; Survival; Prognostic factors; Population-based study; Pemetrexed