- Email: [email protected]
Methodological and ethical difficulties in clinical oncology studies
CORRESPONDENCE
results (Dean Erdman, personal communication, Centers for Disease Control and Prevention, Atlanta, USA). We believe that the description of the clinical findings in our report is appropriate. A paper on the serological findings with respect to non-retroviral porcine viruses which discusses the question of cross-reactivities is in preparation. Annika Tibell, *Walid Heneine, Thomas Folks, Louisa Chapman, Carl Groth Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Sweden; and *HIV and Retrovirology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 1
2
Butler D. Last chance to stop and think on risks of xenotranplants. Nature 1998; 391: 320–25. Correction. Nature 1998; 329: 646.
Malaysia and Taiwan over a period of 12 months may signal the re-emergence of neurovirulent strains of EV71 in Asia. We wish to emphasise that HFMD was not a consistent clinical finding. Two of our four children did not have cutaneous or mucosal exanthemata. The other two had scanty vesticular eruptions but their siblings had definite HFMD from whom EV71 was isolated. In the 1975 Bulgarian epidemic of EV71, there were no patients with HFMD.3 Physicians should be aware of these unusual manifestations so that appropriate preventive and management strategies can be implemented to control the outbreak. *Lucy C S Lum, K T Wong, S K Lam, K B Chua, A Y T Goh Departments of *Paediatrics, Pathology, and Medical Microbiology, University Malaya Medical Centre, Kuala Lumpur 50603, Malaysia. 1
Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis Sir—The enterovirus 71 (EV71) epidemic reported by Luan-Yin Chang and colleagues (Aug 1, p 367)1 was similar to an epidemic of hand-footmouth disease (HFMD) associated with EV71 that occurred in Kuala Lumpur, Malaysia, in 1997. Between April and October, a few thousand children with HFMD caused by EV71 were seen in several hospitals in the city. Our hospital admitted four fatal cases of EV71 brainstem encephalomyelitis.2 After a prodrome of 3–5 days of fever, all four presented with clinical features of pulmonary oedema that progressed rapidly to cardiopulmonary arrest. EV71 was isolated from the brainstem in three cases and in the brain of one. All four had evidence of viral encephalitis characterised by perivascular cuffing by inflammatory cells and neuronophagia in the brainstem and spinal cord, as described by Shindarov et al3 and Chang and colleagues. Despite the widespread and severe inflammation of the brainstem and spinal cord, there was an absence of overwhelming neurological signs and symptoms. Instead, the clinical picture was dominated by rapid and inexorable cardiopulmonary deterioration. The extent and distribution of brainstem inflammation in our cases seems identical to those described in cases of bulbar poliomyelitis with fatal pulmonary oedema.4 The occurrence of EV71 encephalomyelitis epidemics in
THE LANCET • Vol 352 • October 24, 1998
2
3
4
Chang LY, Huang YC, Lin TY, Fulminant neurogenic pulmonary oedema with hand, foot, mouth disease. Lancet 1998; 352: 367. Lum LCS, Wong KT, Lam SK, et al. Fatal Enterovirus 71 encephalomyelitis. J Pediatrics (in press). Shindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol 1979; 23: 284–95. Baker AB, Poliomyelitis. A study of pulmonary edema. Neurology 1957; 7: 743–51.
Methodological and ethical difficulties in clinical oncology studies Sir—In your Aug 8 news item (p 460)1 Bruno Simini reported the preliminary negative results of a clinical trial of a cancer treatment which has received much attention in the Italian mass media. The treatment involves a cocktail of somatostatin, melatonin, bromocriptine, vitamin A, vitamin E, and -carotene, as proposed by the physiologist L Di Bella. Some of these agents, which were studied both experimentally and clinically, are effective in reducing tumour growth.2,3 Bromocriptine is well known in the treatment of prolactinoma whereas vitamin A is implied in the enhancement of immunity. Because of public pressure a committee of oncologists has been commissioned by the Italian health minister to conduct a clinical trial on the effectiveness of Di Bella’s treatment. There are several basic imperatives of an adequate clinical trial: a preliminary, careful review (and perhaps a metaanalysis) of the evidence for the
effectiveness of the various drugs should provide a baseline; an initial doubleblind, treatment-control group pilot study based on histological diagnoses should be carried out; the clinical application and the doctor-patient relationship should be controlled and assessed by the trial physicians. Variables of the patients including personality and psychodynamic variables and coping3 mechanisms, need to be assessed and controlled for. Complete and appropriate multivariate statistical analyses and longitudinal study, and follow-up of the samples to assess any long term effects should be done. These basic conditions have not been met in the Italian state trial. Patients were selected on the criteria that their cancer has been resistant to therapies of known efficacy, excluding anyone under the age of 18 years and those who were not eligible for other innovative treatments (this is not defined in the protocol). There is no random assignment or control group, making it impossible to assess any eventual placebo effect. The failure to include assessment of personality and other personological variables greatly reduces the internal validity of any findings. Any psychological and biological interactions of the treatment cannot be assessed. This state clinical trial, unfortunately, appears poorly conceived and rushed probably because of continued public pressure and mass media exposure. We raise a number of ethical drawbacks: (1) selection of patients who have not responded to known conventional therapy; (2) the issue of the state unertaking a clinical trial solely as a consequence of public pressure without a pilot study; (3) the trial itself is poorly conceived and methodologically flawed; (4) preliminary results have been released in the mass media without careful peer review and appropriate evaluation; (5) early release of results from this state trial pronouncing the treatment ineffective. *Giuseppe R Brera, Claudio Violato *Department of Health and Medical Psychology, Ambrosiana University, 20133 Milan, Italy; and Psychometrica Unit Laboratory, University of Calgary, Canada (e-mail: [email protected]) 1
2
3
Simini B, Di Bella cancer regimen becomes much ado about nothing. Lancet 1998; 352: 460. Van Ejick CH, Slooter GD, Holland LJ, et al. Somatostatin receptor-dependent growth inhibition of liver metastases by octeotride. Br J Surg 1994; 9: 1333–37. Panzer A, Villyoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997; 4: 184–202.
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results (Dean Erdman, personal communication, Centers for Disease Control and Prevention, Atlanta, USA). We believe that the description of the clinical findings in our report is appropriate. A paper on the serological findings with respect to non-retroviral porcine viruses which discusses the question of cross-reactivities is in preparation. Annika Tibell, *Walid Heneine, Thomas Folks, Louisa Chapman, Carl Groth Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Sweden; and *HIV and Retrovirology Branch, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA 1
2
Butler D. Last chance to stop and think on risks of xenotranplants. Nature 1998; 391: 320–25. Correction. Nature 1998; 329: 646.
Malaysia and Taiwan over a period of 12 months may signal the re-emergence of neurovirulent strains of EV71 in Asia. We wish to emphasise that HFMD was not a consistent clinical finding. Two of our four children did not have cutaneous or mucosal exanthemata. The other two had scanty vesticular eruptions but their siblings had definite HFMD from whom EV71 was isolated. In the 1975 Bulgarian epidemic of EV71, there were no patients with HFMD.3 Physicians should be aware of these unusual manifestations so that appropriate preventive and management strategies can be implemented to control the outbreak. *Lucy C S Lum, K T Wong, S K Lam, K B Chua, A Y T Goh Departments of *Paediatrics, Pathology, and Medical Microbiology, University Malaya Medical Centre, Kuala Lumpur 50603, Malaysia. 1
Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis Sir—The enterovirus 71 (EV71) epidemic reported by Luan-Yin Chang and colleagues (Aug 1, p 367)1 was similar to an epidemic of hand-footmouth disease (HFMD) associated with EV71 that occurred in Kuala Lumpur, Malaysia, in 1997. Between April and October, a few thousand children with HFMD caused by EV71 were seen in several hospitals in the city. Our hospital admitted four fatal cases of EV71 brainstem encephalomyelitis.2 After a prodrome of 3–5 days of fever, all four presented with clinical features of pulmonary oedema that progressed rapidly to cardiopulmonary arrest. EV71 was isolated from the brainstem in three cases and in the brain of one. All four had evidence of viral encephalitis characterised by perivascular cuffing by inflammatory cells and neuronophagia in the brainstem and spinal cord, as described by Shindarov et al3 and Chang and colleagues. Despite the widespread and severe inflammation of the brainstem and spinal cord, there was an absence of overwhelming neurological signs and symptoms. Instead, the clinical picture was dominated by rapid and inexorable cardiopulmonary deterioration. The extent and distribution of brainstem inflammation in our cases seems identical to those described in cases of bulbar poliomyelitis with fatal pulmonary oedema.4 The occurrence of EV71 encephalomyelitis epidemics in
THE LANCET • Vol 352 • October 24, 1998
2
3
4
Chang LY, Huang YC, Lin TY, Fulminant neurogenic pulmonary oedema with hand, foot, mouth disease. Lancet 1998; 352: 367. Lum LCS, Wong KT, Lam SK, et al. Fatal Enterovirus 71 encephalomyelitis. J Pediatrics (in press). Shindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical and pathomorphological characteristics of epidemic poliomyelitis-like disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol 1979; 23: 284–95. Baker AB, Poliomyelitis. A study of pulmonary edema. Neurology 1957; 7: 743–51.
Methodological and ethical difficulties in clinical oncology studies Sir—In your Aug 8 news item (p 460)1 Bruno Simini reported the preliminary negative results of a clinical trial of a cancer treatment which has received much attention in the Italian mass media. The treatment involves a cocktail of somatostatin, melatonin, bromocriptine, vitamin A, vitamin E, and -carotene, as proposed by the physiologist L Di Bella. Some of these agents, which were studied both experimentally and clinically, are effective in reducing tumour growth.2,3 Bromocriptine is well known in the treatment of prolactinoma whereas vitamin A is implied in the enhancement of immunity. Because of public pressure a committee of oncologists has been commissioned by the Italian health minister to conduct a clinical trial on the effectiveness of Di Bella’s treatment. There are several basic imperatives of an adequate clinical trial: a preliminary, careful review (and perhaps a metaanalysis) of the evidence for the
effectiveness of the various drugs should provide a baseline; an initial doubleblind, treatment-control group pilot study based on histological diagnoses should be carried out; the clinical application and the doctor-patient relationship should be controlled and assessed by the trial physicians. Variables of the patients including personality and psychodynamic variables and coping3 mechanisms, need to be assessed and controlled for. Complete and appropriate multivariate statistical analyses and longitudinal study, and follow-up of the samples to assess any long term effects should be done. These basic conditions have not been met in the Italian state trial. Patients were selected on the criteria that their cancer has been resistant to therapies of known efficacy, excluding anyone under the age of 18 years and those who were not eligible for other innovative treatments (this is not defined in the protocol). There is no random assignment or control group, making it impossible to assess any eventual placebo effect. The failure to include assessment of personality and other personological variables greatly reduces the internal validity of any findings. Any psychological and biological interactions of the treatment cannot be assessed. This state clinical trial, unfortunately, appears poorly conceived and rushed probably because of continued public pressure and mass media exposure. We raise a number of ethical drawbacks: (1) selection of patients who have not responded to known conventional therapy; (2) the issue of the state unertaking a clinical trial solely as a consequence of public pressure without a pilot study; (3) the trial itself is poorly conceived and methodologically flawed; (4) preliminary results have been released in the mass media without careful peer review and appropriate evaluation; (5) early release of results from this state trial pronouncing the treatment ineffective. *Giuseppe R Brera, Claudio Violato *Department of Health and Medical Psychology, Ambrosiana University, 20133 Milan, Italy; and Psychometrica Unit Laboratory, University of Calgary, Canada (e-mail: [email protected]) 1
2
3
Simini B, Di Bella cancer regimen becomes much ado about nothing. Lancet 1998; 352: 460. Van Ejick CH, Slooter GD, Holland LJ, et al. Somatostatin receptor-dependent growth inhibition of liver metastases by octeotride. Br J Surg 1994; 9: 1333–37. Panzer A, Villyoen M. The validity of melatonin as an oncostatic agent. J Pineal Res 1997; 4: 184–202.
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