- Email: [email protected]
Interferon plus chemotherapy for primary treatment of ovarian cancer
COMMENTARY
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response against glutamic acid decarboylase. Nat Med 1996; 2: 148–53. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322: 1555–60. Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 1999; 42: 3–14. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of ␥-aminobutyric acid. Ann Intern Med 1999; 131: 522–30. Dinkel K, Meinck H-M, Jury KM, Karges W, Richter W. Inhibition of ␥-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998; 44: 194–201.
Interferon plus chemotherapy for primary treatment of ovarian cancer Ovarian epithelial cancer responds to many chemotherapeutic agents, but despite improvements in chemotherapy and in surgery, the 5-year survival rate remains at about 20–30% for advanced disease.1 Because the disease is so difficult to detect early, most patients present at a late stage—hence the search for new pharmaceutical and innovative approaches to the control of metastatic residual epithelial ovarian cancer. Interferon-␣ and interferon-␥ are active against ovarian cancer both in vitro and in vivo.2–5 The earliest clinical trials of interferon-␣ given intraperitoneally were conducted in women with persistent ovarian cancer as found at second-look laparotomy.6–8 In several confirmatory trials of interferon-␣ in second-line regimens in women with minimum residual disease, the response rates as assessed at surgery were 30–50%.9–13 Such results were similar to those for interferon-␥ given intraperitoneally in second-line regimens,14–16 with surgically confirmed responses of 30–45% in patients with minimum residual disease. Despite in-vitro evidence that interferon-␥ can increase the sensitivity of cancer cells to cisplatin,3 second-line regimens of intraperitoneal interferon-␣ plus cisplatin do not seem to offer any advantage over interferon alone in minimum residual disease.9–11 Side-effects such as lethargy, fatigue, and influenza-like symptoms are common with the interferons. Although interferon as second-line therapy yields response rates similar to those for cytotoxic chemotherapeutic agents, the use of interferon in the treatment of ovarian cancer has been limited to clinical trials. Now G H Windbichler and colleagues17 have reported the findings of a randomised phase III trial of interferon-␥ given subcutaneously to women receiving first-line platinum-based chemotherapy after surgery for FIGO stages Ic-IIIc ovarian cancer. The interferon was well tolerated although, as expected, the proportion of patients developing fever and an influenza-like syndrome was higher than that among the controls. However, there was no appreciable increase in gastrointestinal, neurological, or haematological side-effects. Importantly, the complete response rate was higher (68% vs 56%) and the diseasefree and progression-free survival rate was longer (66% vs 53%) in the interferon than in the control group. Progression-free survival was improved both in optimally resected patients (maximum diameter of residual tumour less than 2 cm) and in patients with bulky residual disease (greater than 2 cm). This effect in patients with bulky residual disease was not found in past studies of interferon regionally administered as second-line therapy, when benefit was found only with minimum residual disease (ie, maximum tumour diameter not more than 5 mm). In the 6
randomised trial reported by Windbichler and colleagues, the interferon-␥ was given as primary treatment, presumably before the development of drug resistance. Although the findings of this trial are for a new use (ie, for first-line therapy) and important, a limitation of the trial is that the chemotherapy used was a combination of cisplatin and cyclophosphamide, a regimen now supplanted by more effective and less toxic ones (ie, combinations of carboplatin and paclitaxel). That issue notwithstanding, the addition of interferon-␥ to highly effective combination chemotherapy in women with metastatic ovarian epithelial cancer seems to be acceptable in terms of toxicity and is associated with a clear benefit. Why does interferon increase the response rate and survival in patients with ovarian cancer? Windbichler and colleagues speculate that interferon inhibits the expression of dysregulated oncogenes (such as HER-2/neu), thus improving the response of cisplatin-resistant cells. Evidence for this proposal is mixed.18–20 Cytokine administration intraperitoneally was thought to be necessary to augment the action of local and cytotoxic effector cells at the site where presumably most of the residual cancer was located. However, Windbichler and colleagues have shown that systemic administration confers a survival benefit. Probably this effect is due to modulation by interferon-␥ of cells of the immune system—eg, by stimulation of NK cells and macrophages, both of which have antitumour properties.8 The induction of macrophages and other cytotoxic effector T-cells may also have a non-specific immunomodulatory effect that enhances responsiveness to chemotherapy. Interferon-␥ has not only an antiproliferative effect but also an anti-angiogenic one.21 Theoretically, the effects are likely to be greatest in women who are also receiving chemotherapy for treatment for their disease because of the non-specific immunomodulatory effect. The combination of anti-angiogenic agents with cytotoxic therapy is a new opportunity for the development of innovative pharmacological agents in solid tumours. The results reported by Widbichler and colleagues are reason for exploring the value of the combination of interferon and other related compounds with cytotoxic therapy in phase II and III trials in patients with ovarian epithelial cancer. Jonathan S Berek Division of Gynecologic Oncology, UCLA School of Medicine, Los Angeles, CA 90095-1740, USA 1
2
3
4
5
6
Berek JS. Epithelial ovarian cancer. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology, 3rd ed. Philadelphia: Lippincott, Williams & Wilkins, 2000: 457–522. Allavena P, Peccatori F, Maggioni D, et al. Intraperitoneal recombinant g-interferon in patients with recurrent ascitic ovarian carcinoma: modulation of cytotoxicity and cytokine production in tumor-associated effectors and of major histocompatibility antigen expression on tumor cells. Cancer Res 1990; 50: 7318–23. Nehme A, Julia AM, Jozan S, Chevreau C, Bugat R, Canal P. Modulation of cisplatin cytotoxicity by human recombinant interferon-gamma in human ovarian cancer cell lines. Eur J Cancer 1994; 30A: 550–75. Saito T, Berens ME, Welander CE. Direct and indirect effects of human recombinant gamma-interferon on tumor cells in a clonogenic assay. Cancer Res 1986; 46: 1142–47. Markman M, Berek JS. Intraperitoneal administration of the biologic agents tumor necrosis factor, gamma-interferon and interleukin-2. Int J Gynecol Cancer 1992; 2 (suppl 1): 30–34. Berek JS, Hacker NF, Lichtenstein A, et al. Intraperitoneal recombinant ␣-interferon for ‘salvage’ immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Cancer Res 1985; 45: 4447–53.
THE LANCET • Vol 356 • July 1, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY 7 8 9
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Berek JS. Intraperitoneal adoptive immunotherapy for peritoneal cancer. J Clin Oncol 1990; 10: 1610–12. Berek JS. Intraperitoneal immunotherapy for ovarian cancer with alpha interferon. Eur J Cancer 1992; 28A: 719–21. Berek JS, Welander C, Schink JC, Grossberg H, Montz FJ, Zigelboim J. A phase I-II trial of intraperitoneal cisplatin and ␣-interferon in patients with persistent epithelial ovarian cancer. Gynecol Oncol 1991; 40: 237–43. Berek JS, Markman M, Blessing JA, et al. Intraperitoneal ␣-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group Study. Gynecol Oncol 1999; 74: 48–52. Berek JS, Markman M, Stonebraker B, et al. Intraperitoneal interferon-␣ in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study. Gynecol Oncol 1999; 75: 10–14. Nardi M, Cognetti F, Pollera CF. Intraperitoneal recombinant alpha 2-interferon alternating with cisplatin as salvage therapy for minimal residual disease ovarian cancer: a phase II study. J Clin Oncol 1991; 8: 1036–41. Willemse PHB, deVries EGE, Mulder NH. Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer. Eur J Clin Oncol 1991; 26: 353–58. D’Acquisto R, Markman M, Hakes T, Rubin S, Hoskins W, Lewis JL. A phase I trial of intraperitoneal recombinant gamma-interferon in advanced ovarian carcinoma. J Clin Oncol 1988; 6: 689–95. Pujade-Lauraine E, Guastalla JP, Colombo N, et al. Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second look laparotomy. J Clin Oncol 1996; 14: 343–50. Colombo N, Peccatori F, Paganin C, et al. Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int J Cancer 1992; 51: 42–46. Windbichler G, Hausmaninger H, Stummvoll W, et al. Interferongamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 2000; 82: 1138–44. Marth C, Muller-Holzner E, Greiter E, et al. ␥-interferon reduces expression of the protooncogen c-erbB-2 in human ovarian carcinoma cells. Cancer Res 1990; 50: 7037–41. Marth C, Zeimet AG, Herold M, et al. Different effects of interferons, interleukin-1b and tumor necrosis factor-a in normal (OSE) and malignant human ovarian epithelial cells. Int J Cancer 1996; 67: 826–30. Marth C, Widschwendter M, Kaern J, et al. Cisplatin resistance is associated with reduced interferon-g-sensitivity and incrased HER-2 expression in cultured ovarian cancer cells. Br J Cancer 1997; 76: 1328–32. Duda DG, Sunamura M, Lozonschi L, et al. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res 2000; 60: 1111–16.
Challenge of reducing drug-related deaths The public-health attention given to deaths caused by illicit drug use in general, and by drug overdose in particular, should be commensurate with their contribution to premature death. For too long these deaths have been regarded as an unavoidable hazard of illicit drug use, their neglect abetted by the implicit view that the lives of illicit drug users are less deserving of being saved than those of others. In its report published this week,1 the UK Advisory Council on the Misuse of Drugs (ACMD) has rejected these implicit assumptions. Its view is that “drug-related deaths can, will and must in the near future be radically reduced in number”. It points out that the effort that society expends on preventing premature deaths “ should apply no less to drug misusers than it does to other classes of people”.1 One factor that obscures the public-health impact of drug-related deaths is the poor quality of statistical data on these events. As the ACMD shows, in England and Wales coroners vary arbitrarily in whether they do toxicological analyses in suspicious deaths and in how they classify causes of death in such cases. Hence the ACMD can only estimate that there were somewhere between 1076 and 2997 drug-related deaths in England and Wales in 1998. Despite these problems, the ACMD is in no doubt that
THE LANCET • Vol 356 • July 1, 2000
the rate of drug-related deaths in England and Wales has substantially increased since 1980. These deaths now account for 5% of life-years lost, a contribution to premature deaths that is beginning to rival that of motorvehicle accidents. The same trend has happened in Australia where opioid overdoses accounted for 9% of deaths, and for more deaths than alcohol-related motorvehicle accidents, among young adults in 1997.2 In the UK, as in many developed countries,3 heroin is the illicit drug that contributes to most overdose deaths, commonly in combination with alcohol and benzodiazepines.4 In the UK, so too does diverted methadone, a long-acting oral opioid that is widely prescribed to treat opioid dependence. Methadone contributes to 50% of opioid-overdose deaths in England and Wales,5 compared with 20% of such deaths in Australia, where there are more patients in methadone treatment per head.6 The ACMD accepts that methadone treatment is an effective treatment for opioid dependence7 but argues that action to prevent methadone deaths must be a priority. It is critical of the amount of methadone diversion that is tolerated in the UK and of the methadone prescribers’ lack of concern about methadone-related deaths. It endorses UK Department of Health guidelines8 that recommend that the consumption of methadone should be supervised early in treatment to reduce diversion. It also recommends that prescribers, patients, and drug users be educated about the risks of methadone overdose. The ACMD report highlights the contribution that hepatitis B (HBV) and C (HCV) are likely to make to drug-related deaths in Britain in the next decade. As many as 50-60% of the estimated 152 000 to 228 000 injecting drug users in Britain are infected with HBV or HCV. Chronic hepatitis, cirrhosis, and liver cancer may affect 10–20% of those who are infected. The ACMD recommends that drug, outreach, and public-health services should make a concerted effort to persuade injectors to stop injecting and to prevent noninjectors from starting to inject. This recommendation deserves strong support because of the evidence that injecting substantially increases the risk of drug overdose as well as transmission of blood-borne viruses. The public-health challenge will be to reconcile a campaign to discourage injection with the imperative to provide clean injecting equipment to drug users who continue to inject. The call to make the reduction of drug-related death a public-health priority needs to be heeded by governments in Europe, North America, and other parts of the world,3 all of which have had substantial increases in drug-related deaths over the past two decades. Without a concerted public-health campaign to reduce them, these deaths will continue to increase. *Wayne Hall, Deborah Zador *National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052, Australia; and Drugs North West, Mental Health Services of Salford, Prestwich Manchester, UK. 1 2 3 4 5
Advisory Council on the Misuse of Drugs. Reducing drug related d deaths. London: Stationery Office, 2000. Hall W, Degenhardt L, Lynskey M. Opioid overdose mortality in Australia, 1964-97: birth cohort trends. Med J Aust 1999; 171: 34–37. Donoghoe M, Hall W, Lopez A, Ball A. Opioid overdose: trends, risk factors, interventions and priorities for action. Geneva: WHO, 1998. Darke S, Zador D. Fatal heroin “overdose”: a review. Addiction 1996; 91: 1765–72. Neeleman J, Farrell M. Fatal methadone and heroin overdoses: time trends in England and Wales. J Epidemiol Commun Health 1997; 51: 435–37.
7
For personal use only. Not to be reproduced without permission of The Lancet.
5
6 7
8
response against glutamic acid decarboylase. Nat Med 1996; 2: 148–53. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322: 1555–60. Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in type I (insulin-dependent) diabetes. Diabetologia 1999; 42: 3–14. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of ␥-aminobutyric acid. Ann Intern Med 1999; 131: 522–30. Dinkel K, Meinck H-M, Jury KM, Karges W, Richter W. Inhibition of ␥-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998; 44: 194–201.
Interferon plus chemotherapy for primary treatment of ovarian cancer Ovarian epithelial cancer responds to many chemotherapeutic agents, but despite improvements in chemotherapy and in surgery, the 5-year survival rate remains at about 20–30% for advanced disease.1 Because the disease is so difficult to detect early, most patients present at a late stage—hence the search for new pharmaceutical and innovative approaches to the control of metastatic residual epithelial ovarian cancer. Interferon-␣ and interferon-␥ are active against ovarian cancer both in vitro and in vivo.2–5 The earliest clinical trials of interferon-␣ given intraperitoneally were conducted in women with persistent ovarian cancer as found at second-look laparotomy.6–8 In several confirmatory trials of interferon-␣ in second-line regimens in women with minimum residual disease, the response rates as assessed at surgery were 30–50%.9–13 Such results were similar to those for interferon-␥ given intraperitoneally in second-line regimens,14–16 with surgically confirmed responses of 30–45% in patients with minimum residual disease. Despite in-vitro evidence that interferon-␥ can increase the sensitivity of cancer cells to cisplatin,3 second-line regimens of intraperitoneal interferon-␣ plus cisplatin do not seem to offer any advantage over interferon alone in minimum residual disease.9–11 Side-effects such as lethargy, fatigue, and influenza-like symptoms are common with the interferons. Although interferon as second-line therapy yields response rates similar to those for cytotoxic chemotherapeutic agents, the use of interferon in the treatment of ovarian cancer has been limited to clinical trials. Now G H Windbichler and colleagues17 have reported the findings of a randomised phase III trial of interferon-␥ given subcutaneously to women receiving first-line platinum-based chemotherapy after surgery for FIGO stages Ic-IIIc ovarian cancer. The interferon was well tolerated although, as expected, the proportion of patients developing fever and an influenza-like syndrome was higher than that among the controls. However, there was no appreciable increase in gastrointestinal, neurological, or haematological side-effects. Importantly, the complete response rate was higher (68% vs 56%) and the diseasefree and progression-free survival rate was longer (66% vs 53%) in the interferon than in the control group. Progression-free survival was improved both in optimally resected patients (maximum diameter of residual tumour less than 2 cm) and in patients with bulky residual disease (greater than 2 cm). This effect in patients with bulky residual disease was not found in past studies of interferon regionally administered as second-line therapy, when benefit was found only with minimum residual disease (ie, maximum tumour diameter not more than 5 mm). In the 6
randomised trial reported by Windbichler and colleagues, the interferon-␥ was given as primary treatment, presumably before the development of drug resistance. Although the findings of this trial are for a new use (ie, for first-line therapy) and important, a limitation of the trial is that the chemotherapy used was a combination of cisplatin and cyclophosphamide, a regimen now supplanted by more effective and less toxic ones (ie, combinations of carboplatin and paclitaxel). That issue notwithstanding, the addition of interferon-␥ to highly effective combination chemotherapy in women with metastatic ovarian epithelial cancer seems to be acceptable in terms of toxicity and is associated with a clear benefit. Why does interferon increase the response rate and survival in patients with ovarian cancer? Windbichler and colleagues speculate that interferon inhibits the expression of dysregulated oncogenes (such as HER-2/neu), thus improving the response of cisplatin-resistant cells. Evidence for this proposal is mixed.18–20 Cytokine administration intraperitoneally was thought to be necessary to augment the action of local and cytotoxic effector cells at the site where presumably most of the residual cancer was located. However, Windbichler and colleagues have shown that systemic administration confers a survival benefit. Probably this effect is due to modulation by interferon-␥ of cells of the immune system—eg, by stimulation of NK cells and macrophages, both of which have antitumour properties.8 The induction of macrophages and other cytotoxic effector T-cells may also have a non-specific immunomodulatory effect that enhances responsiveness to chemotherapy. Interferon-␥ has not only an antiproliferative effect but also an anti-angiogenic one.21 Theoretically, the effects are likely to be greatest in women who are also receiving chemotherapy for treatment for their disease because of the non-specific immunomodulatory effect. The combination of anti-angiogenic agents with cytotoxic therapy is a new opportunity for the development of innovative pharmacological agents in solid tumours. The results reported by Widbichler and colleagues are reason for exploring the value of the combination of interferon and other related compounds with cytotoxic therapy in phase II and III trials in patients with ovarian epithelial cancer. Jonathan S Berek Division of Gynecologic Oncology, UCLA School of Medicine, Los Angeles, CA 90095-1740, USA 1
2
3
4
5
6
Berek JS. Epithelial ovarian cancer. In: Berek JS, Hacker NF, eds. Practical gynecologic oncology, 3rd ed. Philadelphia: Lippincott, Williams & Wilkins, 2000: 457–522. Allavena P, Peccatori F, Maggioni D, et al. Intraperitoneal recombinant g-interferon in patients with recurrent ascitic ovarian carcinoma: modulation of cytotoxicity and cytokine production in tumor-associated effectors and of major histocompatibility antigen expression on tumor cells. Cancer Res 1990; 50: 7318–23. Nehme A, Julia AM, Jozan S, Chevreau C, Bugat R, Canal P. Modulation of cisplatin cytotoxicity by human recombinant interferon-gamma in human ovarian cancer cell lines. Eur J Cancer 1994; 30A: 550–75. Saito T, Berens ME, Welander CE. Direct and indirect effects of human recombinant gamma-interferon on tumor cells in a clonogenic assay. Cancer Res 1986; 46: 1142–47. Markman M, Berek JS. Intraperitoneal administration of the biologic agents tumor necrosis factor, gamma-interferon and interleukin-2. Int J Gynecol Cancer 1992; 2 (suppl 1): 30–34. Berek JS, Hacker NF, Lichtenstein A, et al. Intraperitoneal recombinant ␣-interferon for ‘salvage’ immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Cancer Res 1985; 45: 4447–53.
THE LANCET • Vol 356 • July 1, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY 7 8 9
10
11
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14
15
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20
21
Berek JS. Intraperitoneal adoptive immunotherapy for peritoneal cancer. J Clin Oncol 1990; 10: 1610–12. Berek JS. Intraperitoneal immunotherapy for ovarian cancer with alpha interferon. Eur J Cancer 1992; 28A: 719–21. Berek JS, Welander C, Schink JC, Grossberg H, Montz FJ, Zigelboim J. A phase I-II trial of intraperitoneal cisplatin and ␣-interferon in patients with persistent epithelial ovarian cancer. Gynecol Oncol 1991; 40: 237–43. Berek JS, Markman M, Blessing JA, et al. Intraperitoneal ␣-interferon alternating with cisplatin in residual ovarian carcinoma: a phase II Gynecologic Oncology Group Study. Gynecol Oncol 1999; 74: 48–52. Berek JS, Markman M, Stonebraker B, et al. Intraperitoneal interferon-␣ in residual ovarian carcinoma: a phase II Gynecologic Oncology Group study. Gynecol Oncol 1999; 75: 10–14. Nardi M, Cognetti F, Pollera CF. Intraperitoneal recombinant alpha 2-interferon alternating with cisplatin as salvage therapy for minimal residual disease ovarian cancer: a phase II study. J Clin Oncol 1991; 8: 1036–41. Willemse PHB, deVries EGE, Mulder NH. Intraperitoneal human recombinant interferon alpha-2b in minimal residual ovarian cancer. Eur J Clin Oncol 1991; 26: 353–58. D’Acquisto R, Markman M, Hakes T, Rubin S, Hoskins W, Lewis JL. A phase I trial of intraperitoneal recombinant gamma-interferon in advanced ovarian carcinoma. J Clin Oncol 1988; 6: 689–95. Pujade-Lauraine E, Guastalla JP, Colombo N, et al. Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second look laparotomy. J Clin Oncol 1996; 14: 343–50. Colombo N, Peccatori F, Paganin C, et al. Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int J Cancer 1992; 51: 42–46. Windbichler G, Hausmaninger H, Stummvoll W, et al. Interferongamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer 2000; 82: 1138–44. Marth C, Muller-Holzner E, Greiter E, et al. ␥-interferon reduces expression of the protooncogen c-erbB-2 in human ovarian carcinoma cells. Cancer Res 1990; 50: 7037–41. Marth C, Zeimet AG, Herold M, et al. Different effects of interferons, interleukin-1b and tumor necrosis factor-a in normal (OSE) and malignant human ovarian epithelial cells. Int J Cancer 1996; 67: 826–30. Marth C, Widschwendter M, Kaern J, et al. Cisplatin resistance is associated with reduced interferon-g-sensitivity and incrased HER-2 expression in cultured ovarian cancer cells. Br J Cancer 1997; 76: 1328–32. Duda DG, Sunamura M, Lozonschi L, et al. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res 2000; 60: 1111–16.
Challenge of reducing drug-related deaths The public-health attention given to deaths caused by illicit drug use in general, and by drug overdose in particular, should be commensurate with their contribution to premature death. For too long these deaths have been regarded as an unavoidable hazard of illicit drug use, their neglect abetted by the implicit view that the lives of illicit drug users are less deserving of being saved than those of others. In its report published this week,1 the UK Advisory Council on the Misuse of Drugs (ACMD) has rejected these implicit assumptions. Its view is that “drug-related deaths can, will and must in the near future be radically reduced in number”. It points out that the effort that society expends on preventing premature deaths “ should apply no less to drug misusers than it does to other classes of people”.1 One factor that obscures the public-health impact of drug-related deaths is the poor quality of statistical data on these events. As the ACMD shows, in England and Wales coroners vary arbitrarily in whether they do toxicological analyses in suspicious deaths and in how they classify causes of death in such cases. Hence the ACMD can only estimate that there were somewhere between 1076 and 2997 drug-related deaths in England and Wales in 1998. Despite these problems, the ACMD is in no doubt that
THE LANCET • Vol 356 • July 1, 2000
the rate of drug-related deaths in England and Wales has substantially increased since 1980. These deaths now account for 5% of life-years lost, a contribution to premature deaths that is beginning to rival that of motorvehicle accidents. The same trend has happened in Australia where opioid overdoses accounted for 9% of deaths, and for more deaths than alcohol-related motorvehicle accidents, among young adults in 1997.2 In the UK, as in many developed countries,3 heroin is the illicit drug that contributes to most overdose deaths, commonly in combination with alcohol and benzodiazepines.4 In the UK, so too does diverted methadone, a long-acting oral opioid that is widely prescribed to treat opioid dependence. Methadone contributes to 50% of opioid-overdose deaths in England and Wales,5 compared with 20% of such deaths in Australia, where there are more patients in methadone treatment per head.6 The ACMD accepts that methadone treatment is an effective treatment for opioid dependence7 but argues that action to prevent methadone deaths must be a priority. It is critical of the amount of methadone diversion that is tolerated in the UK and of the methadone prescribers’ lack of concern about methadone-related deaths. It endorses UK Department of Health guidelines8 that recommend that the consumption of methadone should be supervised early in treatment to reduce diversion. It also recommends that prescribers, patients, and drug users be educated about the risks of methadone overdose. The ACMD report highlights the contribution that hepatitis B (HBV) and C (HCV) are likely to make to drug-related deaths in Britain in the next decade. As many as 50-60% of the estimated 152 000 to 228 000 injecting drug users in Britain are infected with HBV or HCV. Chronic hepatitis, cirrhosis, and liver cancer may affect 10–20% of those who are infected. The ACMD recommends that drug, outreach, and public-health services should make a concerted effort to persuade injectors to stop injecting and to prevent noninjectors from starting to inject. This recommendation deserves strong support because of the evidence that injecting substantially increases the risk of drug overdose as well as transmission of blood-borne viruses. The public-health challenge will be to reconcile a campaign to discourage injection with the imperative to provide clean injecting equipment to drug users who continue to inject. The call to make the reduction of drug-related death a public-health priority needs to be heeded by governments in Europe, North America, and other parts of the world,3 all of which have had substantial increases in drug-related deaths over the past two decades. Without a concerted public-health campaign to reduce them, these deaths will continue to increase. *Wayne Hall, Deborah Zador *National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052, Australia; and Drugs North West, Mental Health Services of Salford, Prestwich Manchester, UK. 1 2 3 4 5
Advisory Council on the Misuse of Drugs. Reducing drug related d deaths. London: Stationery Office, 2000. Hall W, Degenhardt L, Lynskey M. Opioid overdose mortality in Australia, 1964-97: birth cohort trends. Med J Aust 1999; 171: 34–37. Donoghoe M, Hall W, Lopez A, Ball A. Opioid overdose: trends, risk factors, interventions and priorities for action. Geneva: WHO, 1998. Darke S, Zador D. Fatal heroin “overdose”: a review. Addiction 1996; 91: 1765–72. Neeleman J, Farrell M. Fatal methadone and heroin overdoses: time trends in England and Wales. J Epidemiol Commun Health 1997; 51: 435–37.
7
For personal use only. Not to be reproduced without permission of The Lancet.