- Email: [email protected]
Methods for lung cancer biopsy
CORRESPONDENCE
for a thymoma causing chest discomfort and dyspnoea, but was otherwise healthy and had not travelled to endemic areas for yellow fever. On presentation, his temperature was 38·8⬚C, heart rate 80 beats per min, and blood pressure 125/60 mm Hg. The physical examination was unremarkable. His white blood cell count was 4·4⫻109/L (9·5% bands, 72·5% neutrophils, 11% lymphocytes, and 5·5% monocytes), platelet count 63⫻109/L, haemoglobin concentration 140 g/L. His total bilirubin concentration was 24 µmol/L, aspartate aminotransferase concentration 47 U/L, alanine aminotransferase concentration 69 U/L, γ glutamyl transpeptidase concentration 306 U/L, alkaline phosphatase concentration 195 U/L, creatinine concentration 73 µmol/L, and C-reactive protein concentration 101 mg/L. Urine analysis showed leucocytes 25/µL, erythrocytes 10/µL, proteins 0·25 g/L, urobilinogen 68 µmol/L, and bilirubin 17 µmol/L. Findings were normal on chest radiography and chest and abdominal computerised tomography. Blood cultures did not grow microorganisms. Serologies for hepatitis A, B, C, cytomegalovirus, and EpsteinBarr virus showed no acute or active infection. Blood samples sent to the Unité des Arbovirus et Virus des Fièvres Hémorragiques, Institut Pasteur, Paris, France, were positive for IgM, but not IgG antibodies to yellow fever virus with increasing concentrations over the 3 days after admission. Yellow fever virus was isolated by the same laboratory (Vero cell culture) from blood drawn 13 days after vaccination. The patient was discharged 4 days after admission, after normalisation of his platelet count, aminotransferase concentrations, urine analysis, and a clear decrease of his γ glutamyl transpeptidase, alkaline phosphatase, and C-reactive protein concentrations. He remained, nevertheless, febrile for an additional week. T-cell subset counts were done 9 weeks after recovery. CD3 lymphocytes were 0·965⫻109/L (81%), CD4 lymphocytes 0·643⫻109/L (54%), and CD8 lymphocytes 0·250⫻109/L (21%). Irrespective of the results of the continuing sequencing of the yellow fever virus isolated from this patient’s blood, we think that the history of thymectomy and the resulting decrease in the proportion of circulating CD8 T-cells2 constitute host factors that might have impaired the immune response to a live attenuated vaccine,
THE LANCET • Vol 358 • December 1, 2001
and could, at least partly, have caused the adverse effects. *Nicolas Troillet, Francis Laurencet Central Institute of the Valais Hospitals, Sion, Switzerland (e-mail: [email protected]) 1
2
Marianneau P, Georges-Courbot MC, Deubel V. Rarity of adverse effects after 17D yellow-fever vaccination. Lancet 2001; 358: 84–85. Hoffacker V, Schulz A, Tiesinga JJ, et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 2000; 96: 3872–79.
Sir—Michael Martin and colleagues1 report on four cases of multisystem organ failure after yellow fever vaccination in elderly patients. We report a similar case. A man aged 71 years presented with inflammatory reaction that began 5 days after vaccination with yellow fever strain 17D. He had fever up to 39·8ºC, myalgia, and headache. Physical examination showed no abnormality. White blood cell count was 4·7⫻109/L (neutrophils 51%, lymphocytes 42%) and platelet count was 178⫻109/L. Aspartate aminotransferase was 14 U/L and alanine aminotransferase was 17 U/L. Alkaline phosphatase was 103 U/L, bilirubin 8·5 mol/L, and creatinine 88 mol/L. The patient had a history of sigmoid diverticulosis and had acquired a borreliosis 12 years previously, but was otherwise healthy. He came to hospital 10 days after yellow fever vaccination. Chest radiography and abdominal ultrasound showed no focus. We started empirical antibiotic treatment with a cephalosporin. The patient had a fever until 15 days after vaccination, but headache continued and, therefore, we did further investigations. Serum aspartate aminotransferase and alanine aminotransferase had risen to 35 U/L and 73 U/L, respectively. Cerebral computed tomography and assessment of cerebrospinal fluid were normal (9 cells/L, glucose concentration 3·5 mmol/L, protein concentration 0·38 g/L). Microscopy and cultures for bacteria in cerebrospinal fluid were negative, and no yellow fever antibodies and yellow fever virus were detected on reverse transcriptase (RT) PCR. However, blood serum showed an abnormally high concentration of yellow fever antibodies with a titre of 1:10 240, although RT-PCR was negative. We saw no evidence for recent infection with Epstein-Barr virus, coxsackie virus, cytomegalovirus, poliomyelitis virus, and Borrelia sp.
The patient left hospital 25 days after yellow fever vaccination, free from symptoms. Activity of aspartate and alanine aminotransferases had decreased. This case underlines the fact that in elderly patients yellow fever vaccination might cause severe and long-term side-effects. *Uwe Werfel, Walter Popp *Department of Internal Medicine, Kliniken Essen-Mitte, 45136 Essen, Germany; and Department of Hospital Hygiene, University of Essen 1
Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001; 358: 98–104.
Methods for lung cancer biopsy Sir—Rex Yung and Jonathan Orens, in their April 28 commentary1 about lung cancer emphasise the importance of accurate pretreatment staging. They correctly highlight the inadequacies of current non-invasive staging methods and contrast these with the potential morbidity of more invasive techniques, such as mediastinoscopy or mediastinotomy. Positron emission tomography scanning is discussed, and Yung and Orens point out it should not be used instead of tissue sampling. Although they refer to transbronchial methods of retrieving tissue, there is no discussion of endoscopic ultrasound-guided transoesophageal fine-needle aspiration (EUS-FNA) biopsy of mediastinal nodes. This procedure is simple, safe, non-invasive, and well tolerated. A fine needle is passed through the oesophageal wall into adjacent lymph nodes guided by endoluminal ultrasound. The merits of the technique have been discussed.2 In an early comparative study by Gress and colleagues,3 EUSFNA had a specificity of 96% for nodal involvement, compared with 49% for computed tomography. Serna and colleagues4 recorded that EUS-FNA had a sensitivity of 86% compared with 100% for mediastinoscopy but noted that each had a specificity and positive predictive value of 100%. Those workers concluded the techniques were complementary in the nodal stations they could sample—ie, mediastinoscopy can access the anterior mediastinum, whereas EUS-FNA can reliably reach the remainder. We have reported on our initial experience with EUS-FNA5 and have since done more than 60 transoesophageal biopsies. Our
1909
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
sensitivity for diagnosis of carcinoma in lymph nodes is more than 90% with no complications. We recommend this procedure to clinicians involved in the management of lung cancer. Anthony Ryan, John Banks, *S Ashley Roberts Departments of *Clinical Radiology and Respiratory Medicine, Singleton Hospital, Swansea NHS Trust, Swansea SA2 8QA, UK 1 2
3
4
5
Yung RC, Orens JB. Radicalism in therapy of lung cancer Lancet 2001; 357: 1306–07. Roberts SA. Obtaining tissue from the mediastinum: endoscopic ultrasound guided transoesophageal biopsy. Thorax 2000; 55: 983–85. Gress FG, Savides TJ, Sandier A, et al. Endoscopic ultrasonography, fine needle aspiration biopsy guided by endoscopic ultrasonography and computed tomography in the preoperative staging of non-small-cell lung cancer: a comparison study. Ann Intern Med 1997; 127: 604–12. Serna DL, Aryan HE, Chang KJ, et al. An early comparison between endoscopic ultrasound guided fine needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy. Am Surg 1998; 64: 1014–18. Roberts SA, Davies G, Howell S, Banks J. Endoscopic ultrasound guided biopsy of sub-carinal lymph nodes. Clin Radiol 2000; 55: 832–36.
influenza virus, about 33% of patients undergo amantadine treatment. We could detect six resistant viruses (3·4%) in 179 isolates from children before the treatment in the 1999/2000 season, but in neither the 1998/99 nor the 2000/01 season in Niigata, Japan. Therefore, circulation of drug-resistant viruses was not so high in the community even with excess use of amantadine. We support the fact that amantadine has an important part to play in the battle against an influenza pandemic. However, we request a monitoring system to survey resistant viruses, and to investigate their frequency, clinical importance, and likelihood of transmission. *Hiroshi Suzuki, Reiko Saito, Hitoshi Oshitani Department of Public Health, Niigata University School of Medicine, Niigata 951-8510, Japan (e-mail: [email protected]) 1 2
3
Excess amantadine use and resistant viruses Sir—Peter Tooley (Aug 25, p 670)1 argues about the misconceptions on the use of amantadine in a future pandemic of influenza because of its side-effects and the development of resistance. When the influenza emergency arises, the potential for the rapid emergence and dissemination of resistant viruses needs to be studied, especially in relation to strategies for antiviral use and spread to unprimed populations.2 The risk of adverse drug effects is an additional concern. However, their effects have been incompletely defined. About 1·54% of 1813 isolates in UK, and 0·8% of 2017 viruses collected in 43 countries and territories were drugresistant.3,4 This finding suggests that the circulation of drug-resistant viruses is actually quite rare. From 1993 to 1998, before the approval of amantadine for treatment of influenza virus infections, we could not identify any resistant virus among 55 isolates at 27 sentinel surveillance sites in Niigata, Japan.5 However, after the drug’s approval in 1998, 1·3, 2·2, and 0·7 million courses of treatment (100 mg daily for 5 days) were used for the 1998/99 to 2000/01 seasons in Japan. In the 1999/2000 season, 1·6% of the total Japanese population (around 126 million) was estimated to undergo amantadine treatment; when 5% of the total population of Japan is infected with
1910
4
5
Tooley P. Unprepared for an influenza pandemic. Lancet 2001; 358: 670–71. Monto A. Prospects for pandemic influenza control with currently available vaccines and antivirals. J Infect Dis 1997; 176 (suppl 1): 32–37. Dawson J. Neuraminidase inhibitor and amantadine. Lancet 2000; 355: 2254. Ziegler T, Hemphill ML, Ziegler ML, et al. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis 1999; 180: 935–39. Masuda H, Suzuki H, Oshitani H, et al. Incidence of Amantadine-resistant influenza A viruses in sentinel surveillance sites and nursing homes in Niigata, Japan. Microbiol Immunol 2000; 44: 833–39.
Oestrogen replacement therapy and ovarian cancer Sir—In their Aug 11 commentary, Noel Weiss and Mary Anne Rossing1 offer much needed advice to clinicians on the potential link between oestrogen replacement therapy and ovarian cancer. However, the potential for damage by Rodriguez and colleagues’ report,2 to which they refer, was highlighted by the fact that selected data from that publication were printed in the UK national lay press. Doctors were presented with confusing information, and women who were taking or considering hormone replacement therapy (HRT) were alarmed. Doctors and patients need detailed information to assess the potential risks and benefits of HRT. Weiss and Rossing make several valid points, but Rodriguez and colleagues’ report raises wider issues, which need to be addressed. Rodriguez and colleagues studied 211 581 fit, non-hysterectomised, postmenopausal US women. The women had taken oral oestrogen
replacement therapy after age 35 years (oestrogen only use was common in the USA for women with or without an intact uterus at that time). Treatment with oestrogen plus progestogen was not investigated. The women were followed up until 1996 (14 years). 944 died of ovarian cancer (0·45%). The researchers compared ovarian mortality with the effect of oestrogen replacement therapy among women who had never used treatment, those using treatment at baseline, and previous but not current users, and for total accumulated years of treatment use. Risk of ovarian cancer death was reported as higher in users at baseline and slightly higher for previous users than never users. A doubling of risk with duration of use of 10 years or more was suggested, but at beseline only 22% had ever used oestrogen replacement therapy (24% current, 76% previous users). The mean duration of therapy use was 6 years in users at baseline, and 4 years among previous users, which provides very small numbers for 10 or more years use data. Only 66 of 944 women who died of ovarian cancer had used HRT for 10 or more years. The mean relative risk was significant in previous users (1·59) and baseline users (2·2), compared with never users, but 95% CI for all groups were wide and numbers small. Most of these women took unopposed oestrogen in the 1970s and early 80s. Powerful synthetic oestrogens were commonly used. Rodriguez and colleagues acknowledge that the data might not, therefore, be relevant to current practice. However, the study is still seriously underpowered to make the conclusions it does. However, the media picked up one claim. The report states that the effects of oestrogen replacement therapy on ovarian cancer persist for up to 29 years after cessation of use; no data support this claim. The best that can be said about the Rodriguez and colleagues’ results is that long-term high-dose unopposed oestrogen replacement therapy might increase the risk of ovarian cancer. There is no evidence that modern lowdose oestrogen and progestogen combinations have this effect. This message must be conveyed to prescribing doctors, advising nurses, and enquiring patients. Stuart V Drew Old Postings, North Street, Rogate, Petersfield, Hants GU31 5HG, UK 1
2
Weiss NS, Rossing MA. Oestrogenreplacement therapy and risk of ovarian cancer. Lancet 2001; 358: 438. Rodriguez C, Patel AV, Calle EE, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285: 1460–65.
THE LANCET • Vol 358 • December 1, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
for a thymoma causing chest discomfort and dyspnoea, but was otherwise healthy and had not travelled to endemic areas for yellow fever. On presentation, his temperature was 38·8⬚C, heart rate 80 beats per min, and blood pressure 125/60 mm Hg. The physical examination was unremarkable. His white blood cell count was 4·4⫻109/L (9·5% bands, 72·5% neutrophils, 11% lymphocytes, and 5·5% monocytes), platelet count 63⫻109/L, haemoglobin concentration 140 g/L. His total bilirubin concentration was 24 µmol/L, aspartate aminotransferase concentration 47 U/L, alanine aminotransferase concentration 69 U/L, γ glutamyl transpeptidase concentration 306 U/L, alkaline phosphatase concentration 195 U/L, creatinine concentration 73 µmol/L, and C-reactive protein concentration 101 mg/L. Urine analysis showed leucocytes 25/µL, erythrocytes 10/µL, proteins 0·25 g/L, urobilinogen 68 µmol/L, and bilirubin 17 µmol/L. Findings were normal on chest radiography and chest and abdominal computerised tomography. Blood cultures did not grow microorganisms. Serologies for hepatitis A, B, C, cytomegalovirus, and EpsteinBarr virus showed no acute or active infection. Blood samples sent to the Unité des Arbovirus et Virus des Fièvres Hémorragiques, Institut Pasteur, Paris, France, were positive for IgM, but not IgG antibodies to yellow fever virus with increasing concentrations over the 3 days after admission. Yellow fever virus was isolated by the same laboratory (Vero cell culture) from blood drawn 13 days after vaccination. The patient was discharged 4 days after admission, after normalisation of his platelet count, aminotransferase concentrations, urine analysis, and a clear decrease of his γ glutamyl transpeptidase, alkaline phosphatase, and C-reactive protein concentrations. He remained, nevertheless, febrile for an additional week. T-cell subset counts were done 9 weeks after recovery. CD3 lymphocytes were 0·965⫻109/L (81%), CD4 lymphocytes 0·643⫻109/L (54%), and CD8 lymphocytes 0·250⫻109/L (21%). Irrespective of the results of the continuing sequencing of the yellow fever virus isolated from this patient’s blood, we think that the history of thymectomy and the resulting decrease in the proportion of circulating CD8 T-cells2 constitute host factors that might have impaired the immune response to a live attenuated vaccine,
THE LANCET • Vol 358 • December 1, 2001
and could, at least partly, have caused the adverse effects. *Nicolas Troillet, Francis Laurencet Central Institute of the Valais Hospitals, Sion, Switzerland (e-mail: [email protected]) 1
2
Marianneau P, Georges-Courbot MC, Deubel V. Rarity of adverse effects after 17D yellow-fever vaccination. Lancet 2001; 358: 84–85. Hoffacker V, Schulz A, Tiesinga JJ, et al. Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 2000; 96: 3872–79.
Sir—Michael Martin and colleagues1 report on four cases of multisystem organ failure after yellow fever vaccination in elderly patients. We report a similar case. A man aged 71 years presented with inflammatory reaction that began 5 days after vaccination with yellow fever strain 17D. He had fever up to 39·8ºC, myalgia, and headache. Physical examination showed no abnormality. White blood cell count was 4·7⫻109/L (neutrophils 51%, lymphocytes 42%) and platelet count was 178⫻109/L. Aspartate aminotransferase was 14 U/L and alanine aminotransferase was 17 U/L. Alkaline phosphatase was 103 U/L, bilirubin 8·5 mol/L, and creatinine 88 mol/L. The patient had a history of sigmoid diverticulosis and had acquired a borreliosis 12 years previously, but was otherwise healthy. He came to hospital 10 days after yellow fever vaccination. Chest radiography and abdominal ultrasound showed no focus. We started empirical antibiotic treatment with a cephalosporin. The patient had a fever until 15 days after vaccination, but headache continued and, therefore, we did further investigations. Serum aspartate aminotransferase and alanine aminotransferase had risen to 35 U/L and 73 U/L, respectively. Cerebral computed tomography and assessment of cerebrospinal fluid were normal (9 cells/L, glucose concentration 3·5 mmol/L, protein concentration 0·38 g/L). Microscopy and cultures for bacteria in cerebrospinal fluid were negative, and no yellow fever antibodies and yellow fever virus were detected on reverse transcriptase (RT) PCR. However, blood serum showed an abnormally high concentration of yellow fever antibodies with a titre of 1:10 240, although RT-PCR was negative. We saw no evidence for recent infection with Epstein-Barr virus, coxsackie virus, cytomegalovirus, poliomyelitis virus, and Borrelia sp.
The patient left hospital 25 days after yellow fever vaccination, free from symptoms. Activity of aspartate and alanine aminotransferases had decreased. This case underlines the fact that in elderly patients yellow fever vaccination might cause severe and long-term side-effects. *Uwe Werfel, Walter Popp *Department of Internal Medicine, Kliniken Essen-Mitte, 45136 Essen, Germany; and Department of Hospital Hygiene, University of Essen 1
Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet 2001; 358: 98–104.
Methods for lung cancer biopsy Sir—Rex Yung and Jonathan Orens, in their April 28 commentary1 about lung cancer emphasise the importance of accurate pretreatment staging. They correctly highlight the inadequacies of current non-invasive staging methods and contrast these with the potential morbidity of more invasive techniques, such as mediastinoscopy or mediastinotomy. Positron emission tomography scanning is discussed, and Yung and Orens point out it should not be used instead of tissue sampling. Although they refer to transbronchial methods of retrieving tissue, there is no discussion of endoscopic ultrasound-guided transoesophageal fine-needle aspiration (EUS-FNA) biopsy of mediastinal nodes. This procedure is simple, safe, non-invasive, and well tolerated. A fine needle is passed through the oesophageal wall into adjacent lymph nodes guided by endoluminal ultrasound. The merits of the technique have been discussed.2 In an early comparative study by Gress and colleagues,3 EUSFNA had a specificity of 96% for nodal involvement, compared with 49% for computed tomography. Serna and colleagues4 recorded that EUS-FNA had a sensitivity of 86% compared with 100% for mediastinoscopy but noted that each had a specificity and positive predictive value of 100%. Those workers concluded the techniques were complementary in the nodal stations they could sample—ie, mediastinoscopy can access the anterior mediastinum, whereas EUS-FNA can reliably reach the remainder. We have reported on our initial experience with EUS-FNA5 and have since done more than 60 transoesophageal biopsies. Our
1909
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
sensitivity for diagnosis of carcinoma in lymph nodes is more than 90% with no complications. We recommend this procedure to clinicians involved in the management of lung cancer. Anthony Ryan, John Banks, *S Ashley Roberts Departments of *Clinical Radiology and Respiratory Medicine, Singleton Hospital, Swansea NHS Trust, Swansea SA2 8QA, UK 1 2
3
4
5
Yung RC, Orens JB. Radicalism in therapy of lung cancer Lancet 2001; 357: 1306–07. Roberts SA. Obtaining tissue from the mediastinum: endoscopic ultrasound guided transoesophageal biopsy. Thorax 2000; 55: 983–85. Gress FG, Savides TJ, Sandier A, et al. Endoscopic ultrasonography, fine needle aspiration biopsy guided by endoscopic ultrasonography and computed tomography in the preoperative staging of non-small-cell lung cancer: a comparison study. Ann Intern Med 1997; 127: 604–12. Serna DL, Aryan HE, Chang KJ, et al. An early comparison between endoscopic ultrasound guided fine needle aspiration and mediastinoscopy for diagnosis of mediastinal malignancy. Am Surg 1998; 64: 1014–18. Roberts SA, Davies G, Howell S, Banks J. Endoscopic ultrasound guided biopsy of sub-carinal lymph nodes. Clin Radiol 2000; 55: 832–36.
influenza virus, about 33% of patients undergo amantadine treatment. We could detect six resistant viruses (3·4%) in 179 isolates from children before the treatment in the 1999/2000 season, but in neither the 1998/99 nor the 2000/01 season in Niigata, Japan. Therefore, circulation of drug-resistant viruses was not so high in the community even with excess use of amantadine. We support the fact that amantadine has an important part to play in the battle against an influenza pandemic. However, we request a monitoring system to survey resistant viruses, and to investigate their frequency, clinical importance, and likelihood of transmission. *Hiroshi Suzuki, Reiko Saito, Hitoshi Oshitani Department of Public Health, Niigata University School of Medicine, Niigata 951-8510, Japan (e-mail: [email protected]) 1 2
3
Excess amantadine use and resistant viruses Sir—Peter Tooley (Aug 25, p 670)1 argues about the misconceptions on the use of amantadine in a future pandemic of influenza because of its side-effects and the development of resistance. When the influenza emergency arises, the potential for the rapid emergence and dissemination of resistant viruses needs to be studied, especially in relation to strategies for antiviral use and spread to unprimed populations.2 The risk of adverse drug effects is an additional concern. However, their effects have been incompletely defined. About 1·54% of 1813 isolates in UK, and 0·8% of 2017 viruses collected in 43 countries and territories were drugresistant.3,4 This finding suggests that the circulation of drug-resistant viruses is actually quite rare. From 1993 to 1998, before the approval of amantadine for treatment of influenza virus infections, we could not identify any resistant virus among 55 isolates at 27 sentinel surveillance sites in Niigata, Japan.5 However, after the drug’s approval in 1998, 1·3, 2·2, and 0·7 million courses of treatment (100 mg daily for 5 days) were used for the 1998/99 to 2000/01 seasons in Japan. In the 1999/2000 season, 1·6% of the total Japanese population (around 126 million) was estimated to undergo amantadine treatment; when 5% of the total population of Japan is infected with
1910
4
5
Tooley P. Unprepared for an influenza pandemic. Lancet 2001; 358: 670–71. Monto A. Prospects for pandemic influenza control with currently available vaccines and antivirals. J Infect Dis 1997; 176 (suppl 1): 32–37. Dawson J. Neuraminidase inhibitor and amantadine. Lancet 2000; 355: 2254. Ziegler T, Hemphill ML, Ziegler ML, et al. Low incidence of rimantadine resistance in field isolates of influenza A viruses. J Infect Dis 1999; 180: 935–39. Masuda H, Suzuki H, Oshitani H, et al. Incidence of Amantadine-resistant influenza A viruses in sentinel surveillance sites and nursing homes in Niigata, Japan. Microbiol Immunol 2000; 44: 833–39.
Oestrogen replacement therapy and ovarian cancer Sir—In their Aug 11 commentary, Noel Weiss and Mary Anne Rossing1 offer much needed advice to clinicians on the potential link between oestrogen replacement therapy and ovarian cancer. However, the potential for damage by Rodriguez and colleagues’ report,2 to which they refer, was highlighted by the fact that selected data from that publication were printed in the UK national lay press. Doctors were presented with confusing information, and women who were taking or considering hormone replacement therapy (HRT) were alarmed. Doctors and patients need detailed information to assess the potential risks and benefits of HRT. Weiss and Rossing make several valid points, but Rodriguez and colleagues’ report raises wider issues, which need to be addressed. Rodriguez and colleagues studied 211 581 fit, non-hysterectomised, postmenopausal US women. The women had taken oral oestrogen
replacement therapy after age 35 years (oestrogen only use was common in the USA for women with or without an intact uterus at that time). Treatment with oestrogen plus progestogen was not investigated. The women were followed up until 1996 (14 years). 944 died of ovarian cancer (0·45%). The researchers compared ovarian mortality with the effect of oestrogen replacement therapy among women who had never used treatment, those using treatment at baseline, and previous but not current users, and for total accumulated years of treatment use. Risk of ovarian cancer death was reported as higher in users at baseline and slightly higher for previous users than never users. A doubling of risk with duration of use of 10 years or more was suggested, but at beseline only 22% had ever used oestrogen replacement therapy (24% current, 76% previous users). The mean duration of therapy use was 6 years in users at baseline, and 4 years among previous users, which provides very small numbers for 10 or more years use data. Only 66 of 944 women who died of ovarian cancer had used HRT for 10 or more years. The mean relative risk was significant in previous users (1·59) and baseline users (2·2), compared with never users, but 95% CI for all groups were wide and numbers small. Most of these women took unopposed oestrogen in the 1970s and early 80s. Powerful synthetic oestrogens were commonly used. Rodriguez and colleagues acknowledge that the data might not, therefore, be relevant to current practice. However, the study is still seriously underpowered to make the conclusions it does. However, the media picked up one claim. The report states that the effects of oestrogen replacement therapy on ovarian cancer persist for up to 29 years after cessation of use; no data support this claim. The best that can be said about the Rodriguez and colleagues’ results is that long-term high-dose unopposed oestrogen replacement therapy might increase the risk of ovarian cancer. There is no evidence that modern lowdose oestrogen and progestogen combinations have this effect. This message must be conveyed to prescribing doctors, advising nurses, and enquiring patients. Stuart V Drew Old Postings, North Street, Rogate, Petersfield, Hants GU31 5HG, UK 1
2
Weiss NS, Rossing MA. Oestrogenreplacement therapy and risk of ovarian cancer. Lancet 2001; 358: 438. Rodriguez C, Patel AV, Calle EE, et al. Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA 2001; 285: 1460–65.
THE LANCET • Vol 358 • December 1, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.