- Email: [email protected]
Testicular cancer: the challenge for cancer control
Personal view
Mortality from testicular cancer
Testicular cancer: the challenge for cancer control Peter Boyle
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
© Robert Harding Picture Library
The effect of the discovery of a curative treatment regimen for testicular cancer is apparent in countries with declining national mortality rates. The introduction of centralised treatment in Slovakia has been maintained, and the decline seen in the former country referred to as East Germany after rapid economic change is also clear and continuing. However, mortality remains higher in all countries of central and eastern Europe, compared with western European countries. Testicular cancer could almost be eliminated as a cause of death worldwide if the political will, adequate finance, and the necessary training and logistics to deliver appropriate treatment were implemented. The resources required to eliminate death from testicular cancer are resource-based, rather than dependent on the outcome of further research. The aim of all cancer research is to benefit the patient with cancer or those who are at risk of developing the disease. Testicular cancer control would be the finest illustration of this process and, simultaneously, would be a model for implementation as new, successful therpaeutic modalities for other cancers are developed. Lancet Oncol 2003; 5: 56–61
Chemotherapy has long been used in the treatment of testicular cancer (figure 1). In the 1960s, Li and colleagues1 used chlorambucil, dactinomycin, and methotrexate to obtain seven of 23 patient responses: three patients remained well for 9 to 18 months. MacKenzie2 reported that among 154 patients with advanced testicular cancer, dactinomycin was the most active single agent for the treatment of teratomas. Other studies from the same era showed that other agents were also useful (eg, vinblastine sulphate, plicamycin, bleomycin sulphate, dacarbazine, and doxorubicin hydrochloride). The role of chemotherapy in the treatment of testicular tumours up until the early 1970s has been reviewed in detail by Smithers.3 Tim McElwain, summarising the current state of knowledge for the treatment of testicular cancer in 1976, concluded that chemotherapy had little place in the management of seminoma—a tumour so radiosensitive that it can usually be controlled by radiotherapy.4 However, chemotherapy became more important in the treatment of teratomas because over half of patients with widespread metastases (or who later develop them) and associated tumours are considerably less radiosensitive than patients with seminomas. He did acknowledge that: “responses to chemotherapy are often transitory and it is doubtful if life is always prolonged in responders”. Remarkable progress has been made since then: survival has increased from around 10% in the 1970s to 90% in the
56
Figure 1. Combination chemotherapy has substantially improved treatment outcome for patients with testicular cancer.
1990s.5,6 Much of this improvement is attributable to the development of chemotherapy regimens based on cisplatin7 as well as a realisation of the importance of combined management of patients.8 Current best-practice dictates that stage I, IIA, and IIB seminoma is generally treated with 25–30 Gy radiation, and stages IIC and III of disease are treated with cisplatin-based polychemotherapy. Stage I nonseminoma is treated with either surveillance or elective nerve-preserving retroperitoneal lymph-node dissection, stages IIA and IIB with retroperiotineal lymph-node dissection, and all other stages are treated with cisplatinbased polychemotherapy and eventually adjuvant surgical resection of residual disease.
Observations on population outcome Incidence and mortality data up to 1983 showed a decline in mortality from testicular cancer in Scotland, UK. They also PB is Director of the Division of Epidemiology and Biostatistics at the European Institute of Oncology, Milan, Italy. Correspondence: Prof Peter Boyle, Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39 02 5748 9815. Fax: +39 02 5748 9922. Email: [email protected]
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Mortality from testicular cancer
Events/100 000
showed that in 1977, despite a 8 background of increasing incidence of Incidence testicular cancer, therapy for the 7 disease was effective.9 Since then, the 6 incidence of testicular cancer has continued to increase in Scotland, 5 while mortality has continued to 4 decline (figure 2). Similar patterns have been recorded in several other 3 countries including Denmark10, 2 Poland11, England, and Wales.12 The decline in mortality from Mortality 1 testicular cancer was quickly evident in 0 nearly all countries between 1975 (precisplatin) and 1985 (post-cisplatin), 60 963 966 969 972 975 978 981 984 987 990 993 996 999 with large decreases in the relative risk 1 1 1 1 1 1 1 1 1 1 1 1 1 19 of death apparent almost everywhere Year (table). Kaye and Boyle13 concluded that: Figure 2 Average annual (World Standard Population) incidence and mortality of testicular cancer in “it is widely appreciated that the Scotland, 1960–1999. Data are for all ages and are age standardised. application of chemotherapy in the treatment of germ-cell may die of their disease. This situation is unlikely to be tumours exemplifies the best results to be expected from this caused by fundamental differences in biological behaviour. approach to solid tumours, since the majority of patients A more likely explanation is that the differences in mortality treated are now cured”. 80–90% of patients with testicular relate to the delivery of curative chemotherapy—including cancer could be cured of their disease and in most countries cisplatin—or to deficiencies in patient referral patterns.14 In west Scotland, a clinical audit was done on 440 of 454 this seemed to be so. However, this was not the case in central and eastern Europe, where around 1 in 2 patients (97%) men diagnosed with non-seminomatous germ-cell 9
Mortality from testicular cancer worldwide in 1975 and 1985 Numbers of deaths
Age-adjusted death rates
Country
1975
1985
1975
1985
Austria Australia Belgium Bulgaria Canada Czechoslovakia Denmark East Germany England and Wales Finland France Hungary Ireland Italy Japan Netherlands New Zealand Northern Ireland Norway Poland Romania Scotland Spain Sweden West Germany Yugoslavia
40 62 24 45 83 86 50 139 241 18 233 58 13 221 196 65 14 10 23 86 45 32 65 45 424 56
26 29 18 59 46 102 22 162 112 7 193 76 13 165 149 31 8 0 14 126 58 12 58 15 317 70
1·11 0·85 0·44 0·88 0·68 1·10 1·84 1·58 0·94 0·69 0·80 1·04 0·83 0·71 0·33 0·88 0·95 1·31 1·03 0·55 0·39 1·28 0·36 0·90 1·26 0·49
0·60 0·31 0·30 1·22 0·31 1·20 0·66 1·70 0·40 0·29 0·61 1·27 0·75 0·50 0·20 0·36 0·42 0·00 0·53 0·63 0·50 0·43 0·29 0·25 0·87 0·58
Relative Risk*
0·54 0·36 0·68 1·39 0·46 1·10 0·36 1·08 0·43 0·42 0·76 1·22 0·90 0·70 0·69 0·41 0·44 ·· 0·51 1·15 1·28 0·33 0·80 0·28 0·69 1·18
*calculated as the ratio of the death rates in 1985 relative to 1975.
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Mortality from testicular cancer
established a specialist treatment centre for non-seminomatous testiIncidence cular cancer in the Department of 7 Urology, Bratislava School of 6 Medicine. This centre initially used a multidisciplinary approach to treat 5 about 50 new patients a year. As a 4 result, similar specialist units in the largest hospitals in central and eastern 3 Slovakia have been set up.16 2 Plesko and colleagues17 showed Mortality that although the incidence of 1 testicular cancer gradually increased 0 between 1968 and 1990, the mortality rate declined slightly from the mid8 7 0 1 9 2 8 3 5 4 6 9 6 7 9 9 7 8 8 7 8 8 9 9 9 9 9 9 9 9 9 9 9 1980s to 1990 (after an initial increase 1 1 1 1 1 1 1 1 1 1 1 between 1968 and 1980). The gap Year between incidence and mortality is Figure 3. Average annual (World Standard Population) incidence and mortality of testicular cancer in increasing—an indication of the Slovakia, 1968–1999. Data are for all ages and are age standardised. increasingly efficacious therapy that is given to patients with testicular cancer tumours between 1975 and 1989.15 Independent prognostic in Slovakia. The authors concluded that this gap is likely to factors identified for 5-year survival were: extent of tumour at grow as more recent data becomes available, and this has diagnosis (p<0·001), 5-year period of diagnosis (p<0·001), been the case (figure 3). and treatment unit (the largest treatment unit compared with The economic development that is occurring in four others, p<0·001). This particular hospital department Slovakia—which coincides with establishment of specialist treated most of the patients (53%), and also handled most treatment centres—seems to have contributed to the cases in the worst prognosis group (70% were classed as poor improved outcome of testicular cancer in Slovakia. prognosis: metastatic disease). In this unit, 97% of men The most rapid economic change for a European received treatment according to the national protocol, country occurred in East Germany. Mortality data from East compared with 61% elsewhere (p<0·0001). When analysis Germany has been available since 1980. In the former was restricted to those men who received protocol country referred to as West Germany, mortality from treatment—after adjustment for other prognostic factors— testicular cancer peaked around the mid-1970s. By 1995 men treated in other units had a relative risk of death of 2·8 mortality (0·4 per 100 000) was a third less than it had been (95% CI 1·53–5·19) compared with the largest referral unit in 1977 (1·4 per 100 000), when details of treatment (relative risk of 1·0). This unit is characterised by the assessment of men 2·0 at a joint multidisciplinary clinic. 1·8 East Germany These findings contain a clear message that specialisation and centralisation of 1·6 treatment for non-seminomatous germ-cell tumours improves outcome, 1·4 and the benefit is over and above the 1·2 advantage conferred from protocol treatment. 1·0 Boyle and Kaye13 speculated that the poor outcome from testicular 0·8 cancer could be related to a lack of 0·6 financial resources to purchase the expensive drugs necessary to treat 0·4 disseminated disease. The economic West Germany 0·2 situation in many European countries has been changing rapidly. For 0 example, in Slovakia there has been an effective population-based cancer registry for many years that enables Year comparisons between incidence and mortality from testicular cancer to be Figure 4. Average annual (World Standard Population) mortality of testicular cancer in East and West made. Interestingly in 1982, Slovakia Germany, 1955–2000. Data are for all ages and are age standardised. Events/100 000
8
9
6
19 9
3
19 9
0
19 9
7
19 9
4
19 8
1
19 8
6
19 8
0
19 7
4
19 7
8
19 6
19 5
19 5
5
Mortality/100 000
17
18
58
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Mortality from testicular cancer
(1·5 per 100 000) occurred even earlier (in the late 1960s), and testicular 1·6 cancer mortality has since declined by two-thirds in adults aged 20 to 44, 1·4 stabilising at just 0·5 per 100 000 for 1·2 men aged 20 to 44 in 1995–97. In Japan, testicular cancer mortality has 1 been much lower than in other 0·8 areas. There were, however, substantial 0·6 declines during the late 1970s, to 0·3 per 100 000 for men aged between 0·4 20 and 44 (figure 5). 0·2 Between 1975 and 1979, the highest 0 mortality for all ages in Europe were recorded in Denmark (1·7 per 100 000), Switzerland (1·5 per 100 000), Norway (1·3 per 100 000), Austria, and the Czech Republic (1·2 per 100 000).19 Year Subsequently, a decline in mortality of Figure 5. Average annual (World Standard Population) mortality of testicular cancer in the European between 55% and 70% occurred in Union (yellow), central and eastern Europe (red), USA (green), and Japan (blue), 1960–1999 for men most western European countries aged 20–44. Data are for all ages and are age standardised. (except of Spain and Greece). The advances were published. In East Germany, mortality decline in mortality was comparatively smaller (25–30%) in remained stable until its border was opened in the Czech Republic, Hungary, and Poland. Mortality 1989 (1·5 per 100 000) and has declined by over 50% in increased in Bulgaria and Romania. Consequently, in the late subsequent years (figure 4). The most recent mortality data 1990s, the highest number of deaths from testicular cancer shows that deaths from testicular A cancer are now only a little higher in 2·00 Austria the territories of East Germany (0·7 per 1·80 Belgium 100 000) than in West Germany (0·4 Finland 1·60 per 100 000). France 1·40 Germany The decline in mortality from East Germany 1·20 testicular cancer in East Germany has West Germany Greece 1·00 paralleled the economic changes Ireland resulting from German reunification. 0·80 Italy This provides further support to the Netherlands 0·60 Norway hypothesis that economic considerPortugal 0·40 ations have previously limited the Spain 0·20 Sweden implementation of new treatments for United kingdom this curable cancer. Unfortunately, this 0 has caused at least 1000 avoidable B 2·00 deaths to occur since 1977 in this Albania 1·80 Bosnia and Herzegovina population.18 Bulgaria 1·60 Levi and colleagues have systemaCroatia Czechoslovakia 1·40 tically reviewed mortality rates from Czech Republic testicular cancer in Europe, the USA, Estonia 1·20 Georgia Japan, and in separate geographic areas West Germany 1·00 Hungary and countries within Europe.19 0·80 Kazakhstan In the European Union (EU), the Latvia 0·60 Lithuania peak mortality (1·6 per 100 000 at age Poland Year 0·40 20 to 44) was reached in the early Republic of Moldova Romania 0·20 1970s, and has since decreased by 75%. Slovak Republic In the six countries of central and Slovenia 0 Turkmenistan eastern European that provided data to Yugoslavia the World Health Organisation Mortality Database, the peak (1·7 per Year 100 000) was reached in the late 1970s, Figure 6. Average annual all-ages, age-standardised (World Standard Population) mortality for but the decline has been much smaller testicular cancer in the European Union and central and eastern Europe, 1955–2000. (a) Western since—just 35%. In the USA, the peak European countries. (b) Eastern European countries. 99
8–
97
19 9
5–
94
19 9
0–
89
19 9
5–
84
19 8
0–
79
19 8
5–
74
19 7
0–
69
19 7
5–
19 6
19 6
0–
64
Relative incidence
1·8
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0
5
20 0
0
19 9
5
19 9
0
19 8
19 8
5
0
19 7
5
19 7
19 6
0
19 6
19 5
5
Incidence/100 000
Incidence/100 000
19
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Personal view
Mortality from testicular cancer
for all ages in Europe were in Bulgaria (1·0 per 100 000), the Czech Republic (0·9 per 100 000), Hungary (0·8 per 100 000), and Poland (0·7 per 100 000). The overall decline was 75% (from 0·8 per 100 000 to 0·2 per 100 000) in the EU as a whole. Resultingly, mortality is now considerably higher in all countries in central and eastern Europe, compared with countries in the EU (figure 6). In recent years, mortality from testicular cancer in the USA and Japan have stabilised. In the EU, some decline has been noted as recently as the late 1990s, where mortality has now almost approached the level seen in the USA. Mortality still continues to fall in central and eastern Europe, but is still about twice that of the EU. In the six countries that constitute central and eastern Europe, this corresponds to over 100 deaths each year.19
Discussion The incidence of testicular cancer is increasing in most countries but reasons for this are not entirely clear. For example, testicular-cancer incidence increased ten-fold in young men in Connecticut (USA) over a 60-year period.20 It can be complicated to study hypotheses, and exposure assessment is also difficult. For a form of cancer that is increasing so much, there is some degree of complacency in pursuing studies to determine the causes of testicular cancer. One main contributory reason is the potential complacency caused by a low and declining mortality. Observations on the outcome of testicular cancer in the general population highlight several clear messages. First, although cisplatin-based chemotherapy has been available since the 1970s, the fall in testicular cancer mortality has not been the same in different areas of the world. This is likely to be a result of delays in the implementation of new treatment protocols both within different countries and within different centres in each country. Such delays—and the lack of centralised and specialised treatment centres—have almost certainly contibuted to some avoidable deaths from testicular cancer. Thus, the importance of centralised treatment facilities and their effect on improved outcome has been apparent. Second, there is some suggestion of a stabilisation in the decline of mortality over the past few years in the European Union, the USA, and Japan. This decline started earlier in the USA compared with the EU—an observation that is consistent with more rapid implementation of new curative regimens. Within the EU, the decline was proportionally smaller in Mediterranean countries, although absolute rates in the late 1990s were comparable with other European areas. Presently, the number of deaths from testicular cancer in the EU, USA, and Japan are very low. There has, however, been a considerably delayed decrease in testicular cancer mortality in central and eastern Europe, although a 20–30% fall occurred during the 1990s. In any case, for a largely curable disease, many avoidable deaths still occur in central Europe. Although national mortality data cannot directly address issues of equity, they indicate that in central and eastern Europe inadequacies in adopting adequate treatments remain widespread and substantial, and require urgent action. A major challenge today in cancer control is to implement the
60
Search strategy and selection criteria Data for this article were identified by searches of PubMed with the search terms “testicular cancer” and “epidemiology”. Only papers published in English were included and no limits were placed on year of publication. References were also obtained from the author’s personal collection.
knowledge that is currently available about effective ways to prevent deaths from cancer. Thus, the causes of the anomalous situation of testicular cancer mortality in central and eastern Europe need to be identified, otherwise there shall continue to be several hundred preventable deaths occurring in the male population every year. When the National Cancer Act was signed into law in the USA on Dec 23, 1971, what became widely known as the “War Against Cancer” was launched. At that time, testicular cancer was almost invariably fatal; whereas today, testicular cancer is almost always curable in most developed countries. This has been a major achievement for cancer control in the USA and other countries. Testicular cancer could become a very rare cause of death around the world if the knowledge currently available could be implemented worldwide. It is clear that when the economic situation enables acquisition of the necessary drugs, large reductions in mortality can occur quite rapidly. It is also clear than when treatment is centralised, the outcome of disease also improves. To deliver the most appropriate treatment, political will, adequate finance, and appropriate training and logistics must be introduced. This change will require mobilisation of resources rather than relying on further, unnecessary research. Highly efficacious treatment regimens for testicular cancer are expensive, particularly for countries with limited resources. A concerted effort between pharmaceutical companies and the developed world is now needed to ensure adequate care is provided for men with testicular cancer in developing countries. Specifically, provision of specialist training for central and eastern Europe by the EU and USA would improve the long-term provision of adequate healthcare in these regions. Although eradication of death from testicular cancer will not have a large effect on overall cancer mortality, it will provide an example of what can be done when an achievable target is identified and all the necessary resources—both financial and logistical—are provided in an organised way. All cancer research should aim to benefit the patient, or those who are at risk of developing the disease. The implementation of research to bring about control of testicular cancer would be a fine illustration of this process and could become an example model to be used in cancer therapy in the years to come. Conflicts of interest
None declared. Acknowledgments
This work was supported by the Italian Association for Cancer Research (Associazone Italiana per la Ricerca sul Cancro). I also thank Stefan Dittrich (Statistisches Bundesamt, Bonn) for information on East and West Germany, and Patrick Maisonneuve for data on mortality in Europe. I also extend my thanks to Stan Kaye, Carlo La Vecchia, Fabio Levi, Nikolas Becker, and Ivan Plesko for their valuable contributions.
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References
1 Li MC, Whitmore WF, Golbey R, Grabstald H. Effects of combined drug therapy on metastatic cancer of the testis. JAMA 1960; 174: 1291–98. 2 MacKenzie AR. Chemotherapy for metastatic testicular tumours. Cancer 1966; 19: 1369–76. 3 Smithers DW. Chemotherapy for metastatic teratomas of the testis. Br J Urol 1972; 44: 217–26. 4 McElwain TJ. Cancer Chemotherapy: General Clinical Aspects. In: Symington T and Carter RL, (Eds). Scientific Foundations of Oncology. London: William Heinemann Medical Books, 1976. 5 Sternberg CN. Cancers of the Genitourinary Tract. In: Cavalli F, Hansen HH, and Kaye SB. Textbook of Medical Oncology. London: Martin Dunitz, 1977. 6 Dearnaley DP, Huddart RA, Horwich A. Clinical Review: Managing Testicular Cancer. BMJ 2001; 322: 1583–88. 7 Einhorn LH, Donohue JP. Cis-diamminedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 1997; 87: 293–99. 8 Peckham MJ, Barret A, McElwain TJ, et al. Combined management of malignant teratoma of the testis. Lancet 1979; 2: 267–70. 9 Boyle P, Kaye SB, Robertson AG. Changes in testicular cancer in Scotland. Eur J Cancer Clin Oncol 1987; 23: 827–30. 10 Osterlind A. Diverging trends in incidence and mortality of testicular cancer in Denmark, 1943–1982. Br J Cancer 1986; 53: 501–05.
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11 Jeziorski KG, Tyczynski J, Zatonski W. [Epidemiological analysis of testicular malignant neoplasm incidence and mortality in Poland, 1963–1986]. Pol Tyg Lek 1990; 45: 661–64. 12 Power DA, Brown RS, Brock CS, et al. Trends in testicular carcinoma in England and Wales, 1971–99. BJU Int 2002; 87: 361–65. 13 Kaye SB, Boyle P. The Impact of Chemotherapy in Germ-cell Tumours. Cancer Surveys 1990; 8: 631–46. 14 Boyle P, Maisonneuve P, Kaye SB. Testicular cancer in Central Europe. Lancet 1990; 335: 1033. 15 Harding MJ, Paul J, Gillis CR, Kaye SB. Management of malignant malignant teratoma: does referral to a specialist unit matter? Lancet 1993; 341: 999–1002. 16 Ondrus D, Hornal M, Matoska J. Chemotherapy of testicular cancer: 10-year experience. Neoplasma 1993; 40: 247–53. 17 Plesko I, Ondrus D, Boyle P. Evolution of testicular cancer incidence and mortality in Slovakia, 1968–1990. Lancet 1996; 347: 900–01. 18 Becker N, Boyle P. Decline in mortality from testicular cancer in West Germany after reunification. Lancet 1997; 350: 744. 19 Levi F, Lucchini F, Boyle P, et al Testicular Cancer Mortality in Eastern Europe. Int J Cancer 2003; 105: 574. 20 Zheng T, Holford TR, Ma Z, et al. Continuing increase in incidence of germ-cell testis cancer in young adults: experience from Connecticut, USA, 1935–1992. Int J Cancer 1996; 65: 723–29.
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Mortality from testicular cancer
Testicular cancer: the challenge for cancer control Peter Boyle
Rights were not granted to include this image in electronic media. Please refer to the printed journal.
© Robert Harding Picture Library
The effect of the discovery of a curative treatment regimen for testicular cancer is apparent in countries with declining national mortality rates. The introduction of centralised treatment in Slovakia has been maintained, and the decline seen in the former country referred to as East Germany after rapid economic change is also clear and continuing. However, mortality remains higher in all countries of central and eastern Europe, compared with western European countries. Testicular cancer could almost be eliminated as a cause of death worldwide if the political will, adequate finance, and the necessary training and logistics to deliver appropriate treatment were implemented. The resources required to eliminate death from testicular cancer are resource-based, rather than dependent on the outcome of further research. The aim of all cancer research is to benefit the patient with cancer or those who are at risk of developing the disease. Testicular cancer control would be the finest illustration of this process and, simultaneously, would be a model for implementation as new, successful therpaeutic modalities for other cancers are developed. Lancet Oncol 2003; 5: 56–61
Chemotherapy has long been used in the treatment of testicular cancer (figure 1). In the 1960s, Li and colleagues1 used chlorambucil, dactinomycin, and methotrexate to obtain seven of 23 patient responses: three patients remained well for 9 to 18 months. MacKenzie2 reported that among 154 patients with advanced testicular cancer, dactinomycin was the most active single agent for the treatment of teratomas. Other studies from the same era showed that other agents were also useful (eg, vinblastine sulphate, plicamycin, bleomycin sulphate, dacarbazine, and doxorubicin hydrochloride). The role of chemotherapy in the treatment of testicular tumours up until the early 1970s has been reviewed in detail by Smithers.3 Tim McElwain, summarising the current state of knowledge for the treatment of testicular cancer in 1976, concluded that chemotherapy had little place in the management of seminoma—a tumour so radiosensitive that it can usually be controlled by radiotherapy.4 However, chemotherapy became more important in the treatment of teratomas because over half of patients with widespread metastases (or who later develop them) and associated tumours are considerably less radiosensitive than patients with seminomas. He did acknowledge that: “responses to chemotherapy are often transitory and it is doubtful if life is always prolonged in responders”. Remarkable progress has been made since then: survival has increased from around 10% in the 1970s to 90% in the
56
Figure 1. Combination chemotherapy has substantially improved treatment outcome for patients with testicular cancer.
1990s.5,6 Much of this improvement is attributable to the development of chemotherapy regimens based on cisplatin7 as well as a realisation of the importance of combined management of patients.8 Current best-practice dictates that stage I, IIA, and IIB seminoma is generally treated with 25–30 Gy radiation, and stages IIC and III of disease are treated with cisplatin-based polychemotherapy. Stage I nonseminoma is treated with either surveillance or elective nerve-preserving retroperitoneal lymph-node dissection, stages IIA and IIB with retroperiotineal lymph-node dissection, and all other stages are treated with cisplatinbased polychemotherapy and eventually adjuvant surgical resection of residual disease.
Observations on population outcome Incidence and mortality data up to 1983 showed a decline in mortality from testicular cancer in Scotland, UK. They also PB is Director of the Division of Epidemiology and Biostatistics at the European Institute of Oncology, Milan, Italy. Correspondence: Prof Peter Boyle, Division of Epidemiology and Biostatistics, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Tel: +39 02 5748 9815. Fax: +39 02 5748 9922. Email: [email protected]
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Personal view
Mortality from testicular cancer
Events/100 000
showed that in 1977, despite a 8 background of increasing incidence of Incidence testicular cancer, therapy for the 7 disease was effective.9 Since then, the 6 incidence of testicular cancer has continued to increase in Scotland, 5 while mortality has continued to 4 decline (figure 2). Similar patterns have been recorded in several other 3 countries including Denmark10, 2 Poland11, England, and Wales.12 The decline in mortality from Mortality 1 testicular cancer was quickly evident in 0 nearly all countries between 1975 (precisplatin) and 1985 (post-cisplatin), 60 963 966 969 972 975 978 981 984 987 990 993 996 999 with large decreases in the relative risk 1 1 1 1 1 1 1 1 1 1 1 1 1 19 of death apparent almost everywhere Year (table). Kaye and Boyle13 concluded that: Figure 2 Average annual (World Standard Population) incidence and mortality of testicular cancer in “it is widely appreciated that the Scotland, 1960–1999. Data are for all ages and are age standardised. application of chemotherapy in the treatment of germ-cell may die of their disease. This situation is unlikely to be tumours exemplifies the best results to be expected from this caused by fundamental differences in biological behaviour. approach to solid tumours, since the majority of patients A more likely explanation is that the differences in mortality treated are now cured”. 80–90% of patients with testicular relate to the delivery of curative chemotherapy—including cancer could be cured of their disease and in most countries cisplatin—or to deficiencies in patient referral patterns.14 In west Scotland, a clinical audit was done on 440 of 454 this seemed to be so. However, this was not the case in central and eastern Europe, where around 1 in 2 patients (97%) men diagnosed with non-seminomatous germ-cell 9
Mortality from testicular cancer worldwide in 1975 and 1985 Numbers of deaths
Age-adjusted death rates
Country
1975
1985
1975
1985
Austria Australia Belgium Bulgaria Canada Czechoslovakia Denmark East Germany England and Wales Finland France Hungary Ireland Italy Japan Netherlands New Zealand Northern Ireland Norway Poland Romania Scotland Spain Sweden West Germany Yugoslavia
40 62 24 45 83 86 50 139 241 18 233 58 13 221 196 65 14 10 23 86 45 32 65 45 424 56
26 29 18 59 46 102 22 162 112 7 193 76 13 165 149 31 8 0 14 126 58 12 58 15 317 70
1·11 0·85 0·44 0·88 0·68 1·10 1·84 1·58 0·94 0·69 0·80 1·04 0·83 0·71 0·33 0·88 0·95 1·31 1·03 0·55 0·39 1·28 0·36 0·90 1·26 0·49
0·60 0·31 0·30 1·22 0·31 1·20 0·66 1·70 0·40 0·29 0·61 1·27 0·75 0·50 0·20 0·36 0·42 0·00 0·53 0·63 0·50 0·43 0·29 0·25 0·87 0·58
Relative Risk*
0·54 0·36 0·68 1·39 0·46 1·10 0·36 1·08 0·43 0·42 0·76 1·22 0·90 0·70 0·69 0·41 0·44 ·· 0·51 1·15 1·28 0·33 0·80 0·28 0·69 1·18
*calculated as the ratio of the death rates in 1985 relative to 1975.
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Mortality from testicular cancer
established a specialist treatment centre for non-seminomatous testiIncidence cular cancer in the Department of 7 Urology, Bratislava School of 6 Medicine. This centre initially used a multidisciplinary approach to treat 5 about 50 new patients a year. As a 4 result, similar specialist units in the largest hospitals in central and eastern 3 Slovakia have been set up.16 2 Plesko and colleagues17 showed Mortality that although the incidence of 1 testicular cancer gradually increased 0 between 1968 and 1990, the mortality rate declined slightly from the mid8 7 0 1 9 2 8 3 5 4 6 9 6 7 9 9 7 8 8 7 8 8 9 9 9 9 9 9 9 9 9 9 9 1980s to 1990 (after an initial increase 1 1 1 1 1 1 1 1 1 1 1 between 1968 and 1980). The gap Year between incidence and mortality is Figure 3. Average annual (World Standard Population) incidence and mortality of testicular cancer in increasing—an indication of the Slovakia, 1968–1999. Data are for all ages and are age standardised. increasingly efficacious therapy that is given to patients with testicular cancer tumours between 1975 and 1989.15 Independent prognostic in Slovakia. The authors concluded that this gap is likely to factors identified for 5-year survival were: extent of tumour at grow as more recent data becomes available, and this has diagnosis (p<0·001), 5-year period of diagnosis (p<0·001), been the case (figure 3). and treatment unit (the largest treatment unit compared with The economic development that is occurring in four others, p<0·001). This particular hospital department Slovakia—which coincides with establishment of specialist treated most of the patients (53%), and also handled most treatment centres—seems to have contributed to the cases in the worst prognosis group (70% were classed as poor improved outcome of testicular cancer in Slovakia. prognosis: metastatic disease). In this unit, 97% of men The most rapid economic change for a European received treatment according to the national protocol, country occurred in East Germany. Mortality data from East compared with 61% elsewhere (p<0·0001). When analysis Germany has been available since 1980. In the former was restricted to those men who received protocol country referred to as West Germany, mortality from treatment—after adjustment for other prognostic factors— testicular cancer peaked around the mid-1970s. By 1995 men treated in other units had a relative risk of death of 2·8 mortality (0·4 per 100 000) was a third less than it had been (95% CI 1·53–5·19) compared with the largest referral unit in 1977 (1·4 per 100 000), when details of treatment (relative risk of 1·0). This unit is characterised by the assessment of men 2·0 at a joint multidisciplinary clinic. 1·8 East Germany These findings contain a clear message that specialisation and centralisation of 1·6 treatment for non-seminomatous germ-cell tumours improves outcome, 1·4 and the benefit is over and above the 1·2 advantage conferred from protocol treatment. 1·0 Boyle and Kaye13 speculated that the poor outcome from testicular 0·8 cancer could be related to a lack of 0·6 financial resources to purchase the expensive drugs necessary to treat 0·4 disseminated disease. The economic West Germany 0·2 situation in many European countries has been changing rapidly. For 0 example, in Slovakia there has been an effective population-based cancer registry for many years that enables Year comparisons between incidence and mortality from testicular cancer to be Figure 4. Average annual (World Standard Population) mortality of testicular cancer in East and West made. Interestingly in 1982, Slovakia Germany, 1955–2000. Data are for all ages and are age standardised. Events/100 000
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19 9
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19 9
0
19 9
7
19 9
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19 8
1
19 8
6
19 8
0
19 7
4
19 7
8
19 6
19 5
19 5
5
Mortality/100 000
17
18
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(1·5 per 100 000) occurred even earlier (in the late 1960s), and testicular 1·6 cancer mortality has since declined by two-thirds in adults aged 20 to 44, 1·4 stabilising at just 0·5 per 100 000 for 1·2 men aged 20 to 44 in 1995–97. In Japan, testicular cancer mortality has 1 been much lower than in other 0·8 areas. There were, however, substantial 0·6 declines during the late 1970s, to 0·3 per 100 000 for men aged between 0·4 20 and 44 (figure 5). 0·2 Between 1975 and 1979, the highest 0 mortality for all ages in Europe were recorded in Denmark (1·7 per 100 000), Switzerland (1·5 per 100 000), Norway (1·3 per 100 000), Austria, and the Czech Republic (1·2 per 100 000).19 Year Subsequently, a decline in mortality of Figure 5. Average annual (World Standard Population) mortality of testicular cancer in the European between 55% and 70% occurred in Union (yellow), central and eastern Europe (red), USA (green), and Japan (blue), 1960–1999 for men most western European countries aged 20–44. Data are for all ages and are age standardised. (except of Spain and Greece). The advances were published. In East Germany, mortality decline in mortality was comparatively smaller (25–30%) in remained stable until its border was opened in the Czech Republic, Hungary, and Poland. Mortality 1989 (1·5 per 100 000) and has declined by over 50% in increased in Bulgaria and Romania. Consequently, in the late subsequent years (figure 4). The most recent mortality data 1990s, the highest number of deaths from testicular cancer shows that deaths from testicular A cancer are now only a little higher in 2·00 Austria the territories of East Germany (0·7 per 1·80 Belgium 100 000) than in West Germany (0·4 Finland 1·60 per 100 000). France 1·40 Germany The decline in mortality from East Germany 1·20 testicular cancer in East Germany has West Germany Greece 1·00 paralleled the economic changes Ireland resulting from German reunification. 0·80 Italy This provides further support to the Netherlands 0·60 Norway hypothesis that economic considerPortugal 0·40 ations have previously limited the Spain 0·20 Sweden implementation of new treatments for United kingdom this curable cancer. Unfortunately, this 0 has caused at least 1000 avoidable B 2·00 deaths to occur since 1977 in this Albania 1·80 Bosnia and Herzegovina population.18 Bulgaria 1·60 Levi and colleagues have systemaCroatia Czechoslovakia 1·40 tically reviewed mortality rates from Czech Republic testicular cancer in Europe, the USA, Estonia 1·20 Georgia Japan, and in separate geographic areas West Germany 1·00 Hungary and countries within Europe.19 0·80 Kazakhstan In the European Union (EU), the Latvia 0·60 Lithuania peak mortality (1·6 per 100 000 at age Poland Year 0·40 20 to 44) was reached in the early Republic of Moldova Romania 0·20 1970s, and has since decreased by 75%. Slovak Republic In the six countries of central and Slovenia 0 Turkmenistan eastern European that provided data to Yugoslavia the World Health Organisation Mortality Database, the peak (1·7 per Year 100 000) was reached in the late 1970s, Figure 6. Average annual all-ages, age-standardised (World Standard Population) mortality for but the decline has been much smaller testicular cancer in the European Union and central and eastern Europe, 1955–2000. (a) Western since—just 35%. In the USA, the peak European countries. (b) Eastern European countries. 99
8–
97
19 9
5–
94
19 9
0–
89
19 9
5–
84
19 8
0–
79
19 8
5–
74
19 7
0–
69
19 7
5–
19 6
19 6
0–
64
Relative incidence
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20 0
0
19 9
5
19 9
0
19 8
19 8
5
0
19 7
5
19 7
19 6
0
19 6
19 5
5
Incidence/100 000
Incidence/100 000
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Mortality from testicular cancer
for all ages in Europe were in Bulgaria (1·0 per 100 000), the Czech Republic (0·9 per 100 000), Hungary (0·8 per 100 000), and Poland (0·7 per 100 000). The overall decline was 75% (from 0·8 per 100 000 to 0·2 per 100 000) in the EU as a whole. Resultingly, mortality is now considerably higher in all countries in central and eastern Europe, compared with countries in the EU (figure 6). In recent years, mortality from testicular cancer in the USA and Japan have stabilised. In the EU, some decline has been noted as recently as the late 1990s, where mortality has now almost approached the level seen in the USA. Mortality still continues to fall in central and eastern Europe, but is still about twice that of the EU. In the six countries that constitute central and eastern Europe, this corresponds to over 100 deaths each year.19
Discussion The incidence of testicular cancer is increasing in most countries but reasons for this are not entirely clear. For example, testicular-cancer incidence increased ten-fold in young men in Connecticut (USA) over a 60-year period.20 It can be complicated to study hypotheses, and exposure assessment is also difficult. For a form of cancer that is increasing so much, there is some degree of complacency in pursuing studies to determine the causes of testicular cancer. One main contributory reason is the potential complacency caused by a low and declining mortality. Observations on the outcome of testicular cancer in the general population highlight several clear messages. First, although cisplatin-based chemotherapy has been available since the 1970s, the fall in testicular cancer mortality has not been the same in different areas of the world. This is likely to be a result of delays in the implementation of new treatment protocols both within different countries and within different centres in each country. Such delays—and the lack of centralised and specialised treatment centres—have almost certainly contibuted to some avoidable deaths from testicular cancer. Thus, the importance of centralised treatment facilities and their effect on improved outcome has been apparent. Second, there is some suggestion of a stabilisation in the decline of mortality over the past few years in the European Union, the USA, and Japan. This decline started earlier in the USA compared with the EU—an observation that is consistent with more rapid implementation of new curative regimens. Within the EU, the decline was proportionally smaller in Mediterranean countries, although absolute rates in the late 1990s were comparable with other European areas. Presently, the number of deaths from testicular cancer in the EU, USA, and Japan are very low. There has, however, been a considerably delayed decrease in testicular cancer mortality in central and eastern Europe, although a 20–30% fall occurred during the 1990s. In any case, for a largely curable disease, many avoidable deaths still occur in central Europe. Although national mortality data cannot directly address issues of equity, they indicate that in central and eastern Europe inadequacies in adopting adequate treatments remain widespread and substantial, and require urgent action. A major challenge today in cancer control is to implement the
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Search strategy and selection criteria Data for this article were identified by searches of PubMed with the search terms “testicular cancer” and “epidemiology”. Only papers published in English were included and no limits were placed on year of publication. References were also obtained from the author’s personal collection.
knowledge that is currently available about effective ways to prevent deaths from cancer. Thus, the causes of the anomalous situation of testicular cancer mortality in central and eastern Europe need to be identified, otherwise there shall continue to be several hundred preventable deaths occurring in the male population every year. When the National Cancer Act was signed into law in the USA on Dec 23, 1971, what became widely known as the “War Against Cancer” was launched. At that time, testicular cancer was almost invariably fatal; whereas today, testicular cancer is almost always curable in most developed countries. This has been a major achievement for cancer control in the USA and other countries. Testicular cancer could become a very rare cause of death around the world if the knowledge currently available could be implemented worldwide. It is clear that when the economic situation enables acquisition of the necessary drugs, large reductions in mortality can occur quite rapidly. It is also clear than when treatment is centralised, the outcome of disease also improves. To deliver the most appropriate treatment, political will, adequate finance, and appropriate training and logistics must be introduced. This change will require mobilisation of resources rather than relying on further, unnecessary research. Highly efficacious treatment regimens for testicular cancer are expensive, particularly for countries with limited resources. A concerted effort between pharmaceutical companies and the developed world is now needed to ensure adequate care is provided for men with testicular cancer in developing countries. Specifically, provision of specialist training for central and eastern Europe by the EU and USA would improve the long-term provision of adequate healthcare in these regions. Although eradication of death from testicular cancer will not have a large effect on overall cancer mortality, it will provide an example of what can be done when an achievable target is identified and all the necessary resources—both financial and logistical—are provided in an organised way. All cancer research should aim to benefit the patient, or those who are at risk of developing the disease. The implementation of research to bring about control of testicular cancer would be a fine illustration of this process and could become an example model to be used in cancer therapy in the years to come. Conflicts of interest
None declared. Acknowledgments
This work was supported by the Italian Association for Cancer Research (Associazone Italiana per la Ricerca sul Cancro). I also thank Stefan Dittrich (Statistisches Bundesamt, Bonn) for information on East and West Germany, and Patrick Maisonneuve for data on mortality in Europe. I also extend my thanks to Stan Kaye, Carlo La Vecchia, Fabio Levi, Nikolas Becker, and Ivan Plesko for their valuable contributions.
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References
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