- Email: [email protected]
Interferon as adjuvant treatment for melanoma
CORRESPONDENCE
Tea: not immoral, illegal, or fattening, but is it innocuous? Sir—J Finsterer’s report (April 27, p 1484)1 of intoxication with Earl Grey tea coincides with a report on tea intoxication in the Netherlands involving 63 people, of whom 22 needed admission.2 In Finsterer’s case, the toxic component was bergapten contained in the bergamot oil flavouring. The tea was consumed in large quantities of up to 4 L daily, and led to symptoms of muscle cramps, paraesthesiae, and blurred vision after 1 week. He deems the mechanism to be due to a largely selective axolemmal potassium-channel blocker, reducing potassium permeability at the nodes of Ranvier. In the Netherlands report, herbal tea probably contained the Japanese star anise (Illicium anisatum L) instead of the Chinese star anise (Illicium verum L). The Japanese star anise contains anisatin, which is a non-competitive GABAA-receptor antagonist. In in-vitro studies, anisatin may cause long-term inhibition of the response to GABA once the receptor is blocked. The reported patients developed nausea, vomiting, auditory hallucinations, and epileptic attacks within hours of ingestion. More than 3 billion kg of tea made from the leaves of the plant Camellia sinenis is consumed worldwide yearly, and has been drunk since at least 2737 BC. Of this, 78% is black tea, most of which is consumed in European countries and the USA. The leaves are allowed to wither before being broken to allow oxidisation or fermentation. Green tea, for which the withered leaves are steamed and rolled before drying to stop fermentation, accounts for 20% of consumption and is commonly drunk in Asian countries. The other 2% of consumption is of Oolong tea, produced by partial fermentation and consumed mainly in Southern China. More than 2000 varieties of tea are produced, including spiced and flavoured varieties. Tea from the leaves of the plant Camellia sinenis has been associated with some health benefits attributed to its antioxidant activity.3 However, toxicity has been extensively reported in components of herbal teas containing such diverse ingredients as fir club moss, angel’s trumpet, nerium oleander, mabi bark, and foxglove. Tea is a comfort without which normal daily life for many would be much more stressful. Finsterer’s and the Netherlands’ cases destroy our life-long belief that tea is one little pleasure that,
878
to quote Alexander Woollcott is not “immoral, illegal or fattening”.4 Anne Marie Oudesluys-Murphy, Niall Oudesluys Department of Paediatrics, Medisch Centrum Rijnmond-Zuid, locatie Zuider, Groene Hilledijk 315, 3075 EA Rotterdam, Netherlands (e-mail: [email protected]) 1 2
3
4
Finsterer J. Earl Grey tea intoxication. Lancet 2002; 359: 1484. Johanns ESD, van der Kolk LE, van Gemert HMA, Sijben AEJ, Peters PWJ, de Vries I. An epidemic of epileptic seizures after consumption of herbal tea. Ned Tijdschr Geneeskd 2002; 146: 813–16. Yang CS, Landau JM. Effects of tea consumption on nutrition and health. J Nutr 2000; 130: 2409–12. Drennan RE (ed). The Algonquin wits. Secaucas: Citadel, 1968.
Interferon as adjuvant treatment for melanoma Sir—The role of interferon as adjuvant treatment for high-risk melanoma remains controversial and there has been much heated debate on the subject. John Kirkwood and colleagues (March 16, p 978)1 state that the benefits of high-dose interferon are unrivalled by any other adjuvant treatment and that it is the standard of care for high-risk resected melanoma patients. On the other hand, Punt and Eggermont2 conclude that the standard use of adjuvant high-dose interferon alfa cannot be recommended. That such eminent people in this specialty as Kirkwood and Eggermont can disagree to such an extent on the interpretation of the evidence suggests that the data are not sufficiently definitive to produce incontrovertible conclusions. There is a danger that people might quote evidence selectively to emphasise their prior beliefs. For example, Kirkwood and colleagues criticise Cascinelli and colleagues3 for failing to mention the positive E1694 trial (in which interferon was compared with vaccine, not with control), but they completely omit to mention the negative E1690 trial of high-dose interferon.4 Hypotheses can be put forward in an attempt to explain results that are inconsistent with a particular view—eg, that salvage with interferon after recurrence in the control group might explain the lack of a survival difference in E1690. However, and perhaps many clinicians will find this surprising, the survival results of the first, and positive, E1684 trial (hazard ratio 0·74 [95% CI 0·55–0·99], p=0·05) and the subsequent, and negative, E1690 trial (hazard ratio 1·00 [0·75–1·33], p=1·0) are actually statistically compatible
with each other (test for interaction: p=0·2), and the apparent differences could simply be due to chance. Thus, to avoid bias, all the available evidence should be assessed. We have reported the preliminary results of such an assessment done with quantitative meta-analysis methods.5. We show that interferon significantly reduces the risk of recurrence (hazard ratio 0·84 [0·77–0·92], p=0·0001), with no good evidence that high-dose is more effective than low-dose (test for interaction: p=0·2). The evidence for a survival benefit is less clear (hazard ratio 0·90 [0·81–0·99], p=0·05), and the CIs are compatible with both a very small and not clinically meaningful benefit, and with a moderate, but worthwhile, benefit. Again, there is no good evidence of a difference in survival between high-dose and low-dose interferon (test for interaction: p=0·6). There are limitations to the use of published data and we encourage all the groups that have done trials of adjuvant interferon in melanoma to collaborate on a meta-analysis of individual patients’ data. This approach will permit a more reliable assessment of the true role of interferon overall and in specific subgroups, whether related to treatment (eg, dose), disease (eg, stage), or patients (eg, age). KW received an honorarium from Schering-Plough for presenting results of a meta-analysis at a meeting on high-dose interferon. MG has received honoraria from Schering-Plough and Roche for lectures and contributions to advisory boards.
*Keith Wheatley, Natalie Ives, Barry Hancock, Martin Gore *Clinical Trials Unit, University of Birmingham, Birmingham B15 2RR, UK; Department of Clinical Oncology, University of Sheffield, Sheffield; and Department of Medicine, Royal Marsden Hospital, London (e-mail: [email protected]) 1
2
3
4
5
Kirkwood JM, Ibrahim JG, Sondak VK, Ernstoff MS, Ross M. Interferon alfa-2a for melanoma metastases. Lancet 2002; 359: 978–79. Punt CJA, Eggermont AMM. Adjuvant interferon-alpha for melanoma revisited: news from old and new studies. Ann Oncol 2001; 12: 1663–66. Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001; 358: 866–69. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18: 2444–58. Wheatley K, Hancock B, Gore M, Suciu S, Eggermont A. Interferon-alpha as adjuvant therapy for melanoma: a meta-analysis of the randomised trials. Proc Am Soc Clin Oncol 2001; 20: 1394.
THE LANCET • Vol 360 • September 14, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Tea: not immoral, illegal, or fattening, but is it innocuous? Sir—J Finsterer’s report (April 27, p 1484)1 of intoxication with Earl Grey tea coincides with a report on tea intoxication in the Netherlands involving 63 people, of whom 22 needed admission.2 In Finsterer’s case, the toxic component was bergapten contained in the bergamot oil flavouring. The tea was consumed in large quantities of up to 4 L daily, and led to symptoms of muscle cramps, paraesthesiae, and blurred vision after 1 week. He deems the mechanism to be due to a largely selective axolemmal potassium-channel blocker, reducing potassium permeability at the nodes of Ranvier. In the Netherlands report, herbal tea probably contained the Japanese star anise (Illicium anisatum L) instead of the Chinese star anise (Illicium verum L). The Japanese star anise contains anisatin, which is a non-competitive GABAA-receptor antagonist. In in-vitro studies, anisatin may cause long-term inhibition of the response to GABA once the receptor is blocked. The reported patients developed nausea, vomiting, auditory hallucinations, and epileptic attacks within hours of ingestion. More than 3 billion kg of tea made from the leaves of the plant Camellia sinenis is consumed worldwide yearly, and has been drunk since at least 2737 BC. Of this, 78% is black tea, most of which is consumed in European countries and the USA. The leaves are allowed to wither before being broken to allow oxidisation or fermentation. Green tea, for which the withered leaves are steamed and rolled before drying to stop fermentation, accounts for 20% of consumption and is commonly drunk in Asian countries. The other 2% of consumption is of Oolong tea, produced by partial fermentation and consumed mainly in Southern China. More than 2000 varieties of tea are produced, including spiced and flavoured varieties. Tea from the leaves of the plant Camellia sinenis has been associated with some health benefits attributed to its antioxidant activity.3 However, toxicity has been extensively reported in components of herbal teas containing such diverse ingredients as fir club moss, angel’s trumpet, nerium oleander, mabi bark, and foxglove. Tea is a comfort without which normal daily life for many would be much more stressful. Finsterer’s and the Netherlands’ cases destroy our life-long belief that tea is one little pleasure that,
878
to quote Alexander Woollcott is not “immoral, illegal or fattening”.4 Anne Marie Oudesluys-Murphy, Niall Oudesluys Department of Paediatrics, Medisch Centrum Rijnmond-Zuid, locatie Zuider, Groene Hilledijk 315, 3075 EA Rotterdam, Netherlands (e-mail: [email protected]) 1 2
3
4
Finsterer J. Earl Grey tea intoxication. Lancet 2002; 359: 1484. Johanns ESD, van der Kolk LE, van Gemert HMA, Sijben AEJ, Peters PWJ, de Vries I. An epidemic of epileptic seizures after consumption of herbal tea. Ned Tijdschr Geneeskd 2002; 146: 813–16. Yang CS, Landau JM. Effects of tea consumption on nutrition and health. J Nutr 2000; 130: 2409–12. Drennan RE (ed). The Algonquin wits. Secaucas: Citadel, 1968.
Interferon as adjuvant treatment for melanoma Sir—The role of interferon as adjuvant treatment for high-risk melanoma remains controversial and there has been much heated debate on the subject. John Kirkwood and colleagues (March 16, p 978)1 state that the benefits of high-dose interferon are unrivalled by any other adjuvant treatment and that it is the standard of care for high-risk resected melanoma patients. On the other hand, Punt and Eggermont2 conclude that the standard use of adjuvant high-dose interferon alfa cannot be recommended. That such eminent people in this specialty as Kirkwood and Eggermont can disagree to such an extent on the interpretation of the evidence suggests that the data are not sufficiently definitive to produce incontrovertible conclusions. There is a danger that people might quote evidence selectively to emphasise their prior beliefs. For example, Kirkwood and colleagues criticise Cascinelli and colleagues3 for failing to mention the positive E1694 trial (in which interferon was compared with vaccine, not with control), but they completely omit to mention the negative E1690 trial of high-dose interferon.4 Hypotheses can be put forward in an attempt to explain results that are inconsistent with a particular view—eg, that salvage with interferon after recurrence in the control group might explain the lack of a survival difference in E1690. However, and perhaps many clinicians will find this surprising, the survival results of the first, and positive, E1684 trial (hazard ratio 0·74 [95% CI 0·55–0·99], p=0·05) and the subsequent, and negative, E1690 trial (hazard ratio 1·00 [0·75–1·33], p=1·0) are actually statistically compatible
with each other (test for interaction: p=0·2), and the apparent differences could simply be due to chance. Thus, to avoid bias, all the available evidence should be assessed. We have reported the preliminary results of such an assessment done with quantitative meta-analysis methods.5. We show that interferon significantly reduces the risk of recurrence (hazard ratio 0·84 [0·77–0·92], p=0·0001), with no good evidence that high-dose is more effective than low-dose (test for interaction: p=0·2). The evidence for a survival benefit is less clear (hazard ratio 0·90 [0·81–0·99], p=0·05), and the CIs are compatible with both a very small and not clinically meaningful benefit, and with a moderate, but worthwhile, benefit. Again, there is no good evidence of a difference in survival between high-dose and low-dose interferon (test for interaction: p=0·6). There are limitations to the use of published data and we encourage all the groups that have done trials of adjuvant interferon in melanoma to collaborate on a meta-analysis of individual patients’ data. This approach will permit a more reliable assessment of the true role of interferon overall and in specific subgroups, whether related to treatment (eg, dose), disease (eg, stage), or patients (eg, age). KW received an honorarium from Schering-Plough for presenting results of a meta-analysis at a meeting on high-dose interferon. MG has received honoraria from Schering-Plough and Roche for lectures and contributions to advisory boards.
*Keith Wheatley, Natalie Ives, Barry Hancock, Martin Gore *Clinical Trials Unit, University of Birmingham, Birmingham B15 2RR, UK; Department of Clinical Oncology, University of Sheffield, Sheffield; and Department of Medicine, Royal Marsden Hospital, London (e-mail: [email protected]) 1
2
3
4
5
Kirkwood JM, Ibrahim JG, Sondak VK, Ernstoff MS, Ross M. Interferon alfa-2a for melanoma metastases. Lancet 2002; 359: 978–79. Punt CJA, Eggermont AMM. Adjuvant interferon-alpha for melanoma revisited: news from old and new studies. Ann Oncol 2001; 12: 1663–66. Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001; 358: 866–69. Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18: 2444–58. Wheatley K, Hancock B, Gore M, Suciu S, Eggermont A. Interferon-alpha as adjuvant therapy for melanoma: a meta-analysis of the randomised trials. Proc Am Soc Clin Oncol 2001; 20: 1394.
THE LANCET • Vol 360 • September 14, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.