- Email: [email protected]
Deferiprone for thalassaemia
CORRESPONDENCE
process and population density minimises the need to ship organs long distances. A possible exception might be for non-European white patients when HLA matching is difficult to achieve given that HLA specificity frequencies differ between racial groups and nearly all cadaver organ donors are from white Europeans. If the outcome of kidney transplantation is judged on transplant survival rates at 1 year, 3 years, and 5 years then it is unlikely that any change in HLA matching policies in the USA or in Europe will lead to significant benefit. However, if patients with kidney failure are seen to have a career of treatment that lasts several decades then repeat transplantation must be planned since about 30% of kidney transplants fail within 5 years. Successful repeat transplantation with survival rates equivalent to those for first transplants can only be achieved if donor HLA specific sensitisation is avoided by preventing HLA specificity mismatches at the time of the first transplant. A policy of HLA CREG matching for first transplants will only be of marginal benefit and will not be as advantageous as avoiding HLA private specificity mismatches. *Philip A Dyer, Chas Newstead, Craig J Taylor *Transplantation Laboratory, Manchester Royal Infirmary, Manchester M13 9WL, UK; Department of Renal Medicine, St James’s University Hospital, Leeds; and Tissue Typing Laboratory, Addenbrooke’s Hospital, Cambridge (e-mail: [email protected]) 1
McKenna RM, Takemoto SK. Improving HLA matching for kidney transplantation by use of CREGs. Lancet 2000; 355: 1842–43.
Psychotropic drugs, HERG, and the heart Sir—J G Reilly and colleagues1 linked psychotropic drugs to lengthening of the rate-corrected QT interval (QTc) and raised important questions regarding the mechanisms underlying the observed electrocardiogram (ECG) changes. A key issue is whether or not the cellular basis for QTc prolongation is shared by different psychotropic agents. Reilly and colleagues commented that the QT lengthening observed with the antipsychotic agent thioridazine probably results from inhibition of the cardiac delayed rectifier potassium channel. In fact, net delayed rectifier K current (IK) in the heart is comprised of two subtypes and thioridazine
428
produces a preferential blockade of the rapidly activating subtype (IKr). Drolet and colleagues2 showed this effect in experiments on isolated heart cells, and in cells transfected with HERG (human-ether-a-go-go-related gene; the gene known to underlie IKr). HERG encoded IKr plays an important part in the repolarisation of the cardiac action potential. Pharmacological inhibition of either heterologously expressed HERG or native IKr would thus be expected to correlate with ventricular action potential prolongation and associated prolongation of the QTc interval on ECG. Indeed, when HERG was originally reported to encode IKr channels, this was suggested to provide a mechanistic link between certain forms of inherited and acquired long QT syndrome.3 Reilly and colleagues also found an association between therapeutic doses of tricyclic antidepressants (TCAs) and QT interval lengthening. Imipramine has been observed to inhibit native cardiac IKr4 and, last year, inhibition of HERG channels by clinically relevant concentrations of the TCAs imipramine and amitriptyline was reported,5 with more recent work extending the observations with amitriptyline (Jo S-H, et al. Br J Pharmacol 2000; 129: 1474–80). Thus, it appears that TCAs and thioridazine share a similar cellular effect consistent with QTc interval prolongation at clinically relevant drug concentrations. Correspondence from H Tie and colleagues (May 20, p 1825) has provided additional, confirmatory evidence for HERG/IKr block as the cellular basis for QT prolongation by thioridazine and amitriptyline, as well as reporting an inhibitory effect of chlorpromazine. Clearly, other factors additional to in-vitro channel blockade, including drug metabolism and binding to plasma proteins will determine in-vivo activity. However, the collective evidence points to IKr inhibition as a likely candidate underlying QT-interval prolonging effects of at least some psychotropic drugs. If this is the case, then one of the variables which Reilly and colleagues commented upon as not being measured in their study may be of particular importance: serum potassium. HERG current is highly sensitive to external potassium concentrations,3 and repolarisation abnormalities, both in patients with HERG-linked inherited long QT syndrome (LQTS) and with quinidineinduced acquired LQTS, have been corrected by raising serum potassium. If the potency of particular psychotropic drugs as HERG blockers
can be reduced by raising external potassium (as observed in-vitro with amitriptyline), then modulating serum potassium concentrations may also offer a means of mitigating QTc prolongation associated with TCAs or anti-psychotic drugs. Further research to investigate this possibility is warranted. *J C Hancox, H J Witchel Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, Bristol BS8 1TD, UK (e-mail: [email protected]) 1
2
3
4
5
Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52. Drolet B, Vincent F, Rail J, et al. Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current. J Pharmacol Exp Ther 1999; 288: 1261–68. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia. HERG encodes the IKr potassium channel. Cell 1995; 81: 299–307. Valenzuela C, Sanchez-Chapula J, Delpon E, Elizalde A, Perez O, Tamargo J. Imipramine blocks rapidly activating and delays slowly activating K+ current activation in guinea pig ventricular myocytes. Circ Res 1994; 74: 687–99. Teschemacher AG, Seward EP, Hancox JC, Witchel HJ. Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol 1999; 128: 479–85.
Deferiprone for thalassaemia Sir—Deferiprone should be used in patients with thalassaemia and other patients with iron overload, who cannot receive effective or sufficient deferoxamine therapy. This was the recommendation issued following the 10th International Conference on Oral Chelation, March 22–26, 2000, Limassol, Cyprus.1 At least one third of patients with thalassaemia in countries in which deferoxamine is available have serum ferritin in excess of 2500 g/L and in general a higher morbidity and mortality rate than those with a target serum ferritin below 2500 g/L. This reflects the low compliance with subcutaneous deferoxamine. Whereas, more than 80% of patients with thalassaemia are born in Asia and Middle Eastern countries, only 10% of those transfused are adequately chelated. For these parts of the world deferoxamine is too costly to offer patients. The remainder are at risk of irreversible organ damage and death resulting from iron overload. Deferiprone in these countries could be supplied at an eighth of the price of deferoxamine. More than 6000 patients
THE LANCET • Vol 356 • July 29, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
in 40 countries have received deferiprone since 1986.1,2 In India, where deferiprone has been a registered drug since 1994, there are more patients taking deferiprone than deferoxamine. Deferiprone has also been registered in Europe in 1999, following the recommendation by the European Community authorities that its use be restricted to patients who cannot tolerate deferoxamine and that patients on the drug be closely monitored for toxicity. Iron excretion in response to deferiprone appears to depend on the iron load and rate of iron loading of patients, the dose, frequency of administration, and metabolism of the drug.1–3 In about 70% of patients with thalassaemia treated with deferiprone (75–120 mg/kg/day) for more than 2 years, serum ferritin decreased and remained below 2500 g/L.1 In the 30% of patients who were treated with a dose of 75 mg/kg/day or less and who failed to reach negative iron balance or experienced toxicity with deferiprone or deferoxamine, a combination of these two drugs appears to be more effective and less toxic than using either drug alone. No new toxic side effects of deferiprone have been identified and all those known are reversible, controlable, and manageable. Agranulocytosis, which is the most serious, affects less than 0·6% of patients on the drug and is satisfactorily monitored with weekly blood counts. Joint and musculoskeletal pains affect up to 15%, gastrointestinal complaints up to 10%, and zinc deficiency up to 1% of the treated patients. Contrary to the claim that deferiprone initiates or increases the progression of liver fibrosis,4,5 no other investigators have substantiated these findings nor have they observed significant differences by comparison to patients receiving deferoxamine.1 This observation was made in groups of patients who had been taking deferiprone daily for over 10 years in India and Switzerland.1,3 New oral chelators, if successful, will certainly not be available at least in the next 5 years. New protocols aimed at improving deferiprone therapy are also being developed. Deferiprone remains the drug of choice for those patients who cannot afford the high cost of deferoxamine, cannot comply with its subcutaneous infusion, or cannot overcome its toxicity. The prognosis of patients taking deferiprone is much better than that of patients experiencing iron overload toxicity because of lack of chelation therapy or ineffective or insufficient chelation therapy with deferoxamine. We thank C Politis, V A Berdoukas, A Maggio,
THE LANCET • Vol 356 • July 29, 2000
P Nielsen, and P Tondury for helpful comments.
*G J Kontoghiorghes, M B Agarwal, R W Grady, A Kolnagou, J J Marx *Postgraduate Research Institute, CY-3021 Limassol, Cyprus; Department of Haematology, LTMG Hospital and LTM Medical College, Mumbai, India; Cornell University Medical Centre, New York, USA; Thalassaemia Unit, Paphos General Hospital, Paphos, Cyprus; and Department of Internal Medicine, University Medical Centre, Utrecht, The Netherlands (e-mail: [email protected]) 1
2
3
4
5
10th International Conference on Oral Chelation in the Treatment of Thalassaemia and other Diseases (ICOC), Limassol, Cyprus, March 22–26, 2000, 1–56. Oral chelation in the treatment of thalassaemia and other diseases [suppl]. Kontoghiorghes GJ, ed. Drugs of Today 1992; 28 (A): 1–187. Tondury P, Zimmerman A, Nielsen P, Hirt A. Liver iron fibrosis during long-term treatment with deferiprone in Swiss thalssaemic patients. Br J Haematol 1998; 101: 413–15. Olivieri NF, Brittenham GM, Mclaren C, et al. Long term safety and effectiveness of iron chelation therapy with deferiprone for thalassaemia major. N Engl J Med 1998; 339: 417–23. Kowdly KV, Kaplan MM. Iron chelation therapy with oral deferiprone—toxicity or lack of efficacy. N Engl J Med 1998; 339: 468–69.
Treatment of endometriotic cysts Sir—The report by Spyros Mesogitis and colleagues (April 1, p 1160)1 on the use of methotrexate as a treatment for endometriotic cysts raises important questions about side effects, mode of treatment, balance of risk and benefit, effectiveness, and safety. Local treatments are associated with a small amount of systemic absorption, which are associated with side effects.2 A quarter of patients with ectopic pregnancy receiving methotrexate have been found3 to experience side effects at similar doses, so we were surprised at the absence of side effects in the series described by Mesogitis and colleagues. This absence is probably a result of small sample size. The use of percutaneous needle aspiration of cystic contents is not usual practice in the UK and carries a significant risk of bowel or bloodvessel perforation because ultrasound cannot define the hazards of adhesions or small ovarian vessels. Surely it would be prudent to advocate antibiotic prophylaxis when this technique is used. The additional risks of introducing a chemotherapeutic agent into a cyst cavity resulting in a communication with the abdominal cavity invites local complications,
which may not have been apparent in this small series. Consequently, the benefits of this approach do not appear to outweigh the risks. Laparoscopic ovarian cystotomy and fenestration is probably the optimum procedure, where the aim is to reduce cyst volume and conserve the ovarian cortex. The proposed treatment might damage the ovarian cortex and reduce its complement of primordial follicles. Furthermore, a large proportion of patients underwent repeat aspiration and treatment with methotrexate, thus doubling their exposure to the associated risks. The conclusion that this technique is a safe and effective treatment is unsound without a prospective randomised controlled trial. Such a trial should have appropriate primary endpoints, namely symptom relief and subsequent pregnancy, rather than a subgroup analysis of a series of ovarian cysts with cyst resolution. The safety of a highly toxic chemotherapeutic agent introduced into gonadal tissue, namely the ovary, as an effective treatment for endometriotic and benign ovarian cysts, is not adequately shown. The issue of methotrexate treatment of endometriotic cysts in infertile women was not addressed and neither is future fertility in women yet to plan a family. Likewise, there is no comment on the subsequent menstrual pattern of women following this treatment. Recurrence at 6 months is not comparable with larger studies done over 5 years. Further long-term studies incorporating these outcome measures need to be done before transabdominal drainage and local methotrexate administration can be declared a safe and effective technique. Guy Fender, *Andrew Prentice Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, The Rosie Hospital, University of Cambridge, Cambridge CB2 2SW, UK (e-mail: [email protected]) 1
2
3
4
Mesogitis S, Antsaklis A, Daskalakis G, Papantoniou N, Michalas S. Combined ultrasonographically guided drainage and methotrexate administration for treatment of endometriotic cysts. Lancet 2000; 355: 1160. Lecru F, Robin F, Taurell R, Bernard JP, Vilde F. Effect of methotrexate on tubal epithelium: a report of three cases. J Reprod Med 1999; 44: 46–48. Parker J, Bitsits A, Proietto AM. A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy. Aust N Z J Obstet Gynaecol 1998; 38: 145–50. Sutton C, Hill D. Laser laparoscopy in the treatment of endometriosis: a five year study. Br J Obstet Gynaecol 1990; 97: 181–85.
429
For personal use only. Not to be reproduced without permission of The Lancet.
process and population density minimises the need to ship organs long distances. A possible exception might be for non-European white patients when HLA matching is difficult to achieve given that HLA specificity frequencies differ between racial groups and nearly all cadaver organ donors are from white Europeans. If the outcome of kidney transplantation is judged on transplant survival rates at 1 year, 3 years, and 5 years then it is unlikely that any change in HLA matching policies in the USA or in Europe will lead to significant benefit. However, if patients with kidney failure are seen to have a career of treatment that lasts several decades then repeat transplantation must be planned since about 30% of kidney transplants fail within 5 years. Successful repeat transplantation with survival rates equivalent to those for first transplants can only be achieved if donor HLA specific sensitisation is avoided by preventing HLA specificity mismatches at the time of the first transplant. A policy of HLA CREG matching for first transplants will only be of marginal benefit and will not be as advantageous as avoiding HLA private specificity mismatches. *Philip A Dyer, Chas Newstead, Craig J Taylor *Transplantation Laboratory, Manchester Royal Infirmary, Manchester M13 9WL, UK; Department of Renal Medicine, St James’s University Hospital, Leeds; and Tissue Typing Laboratory, Addenbrooke’s Hospital, Cambridge (e-mail: [email protected]) 1
McKenna RM, Takemoto SK. Improving HLA matching for kidney transplantation by use of CREGs. Lancet 2000; 355: 1842–43.
Psychotropic drugs, HERG, and the heart Sir—J G Reilly and colleagues1 linked psychotropic drugs to lengthening of the rate-corrected QT interval (QTc) and raised important questions regarding the mechanisms underlying the observed electrocardiogram (ECG) changes. A key issue is whether or not the cellular basis for QTc prolongation is shared by different psychotropic agents. Reilly and colleagues commented that the QT lengthening observed with the antipsychotic agent thioridazine probably results from inhibition of the cardiac delayed rectifier potassium channel. In fact, net delayed rectifier K current (IK) in the heart is comprised of two subtypes and thioridazine
428
produces a preferential blockade of the rapidly activating subtype (IKr). Drolet and colleagues2 showed this effect in experiments on isolated heart cells, and in cells transfected with HERG (human-ether-a-go-go-related gene; the gene known to underlie IKr). HERG encoded IKr plays an important part in the repolarisation of the cardiac action potential. Pharmacological inhibition of either heterologously expressed HERG or native IKr would thus be expected to correlate with ventricular action potential prolongation and associated prolongation of the QTc interval on ECG. Indeed, when HERG was originally reported to encode IKr channels, this was suggested to provide a mechanistic link between certain forms of inherited and acquired long QT syndrome.3 Reilly and colleagues also found an association between therapeutic doses of tricyclic antidepressants (TCAs) and QT interval lengthening. Imipramine has been observed to inhibit native cardiac IKr4 and, last year, inhibition of HERG channels by clinically relevant concentrations of the TCAs imipramine and amitriptyline was reported,5 with more recent work extending the observations with amitriptyline (Jo S-H, et al. Br J Pharmacol 2000; 129: 1474–80). Thus, it appears that TCAs and thioridazine share a similar cellular effect consistent with QTc interval prolongation at clinically relevant drug concentrations. Correspondence from H Tie and colleagues (May 20, p 1825) has provided additional, confirmatory evidence for HERG/IKr block as the cellular basis for QT prolongation by thioridazine and amitriptyline, as well as reporting an inhibitory effect of chlorpromazine. Clearly, other factors additional to in-vitro channel blockade, including drug metabolism and binding to plasma proteins will determine in-vivo activity. However, the collective evidence points to IKr inhibition as a likely candidate underlying QT-interval prolonging effects of at least some psychotropic drugs. If this is the case, then one of the variables which Reilly and colleagues commented upon as not being measured in their study may be of particular importance: serum potassium. HERG current is highly sensitive to external potassium concentrations,3 and repolarisation abnormalities, both in patients with HERG-linked inherited long QT syndrome (LQTS) and with quinidineinduced acquired LQTS, have been corrected by raising serum potassium. If the potency of particular psychotropic drugs as HERG blockers
can be reduced by raising external potassium (as observed in-vitro with amitriptyline), then modulating serum potassium concentrations may also offer a means of mitigating QTc prolongation associated with TCAs or anti-psychotic drugs. Further research to investigate this possibility is warranted. *J C Hancox, H J Witchel Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, Bristol BS8 1TD, UK (e-mail: [email protected]) 1
2
3
4
5
Reilly JG, Ayis SA, Ferrier IN, Jones SJ, Thomas SHL. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52. Drolet B, Vincent F, Rail J, et al. Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current. J Pharmacol Exp Ther 1999; 288: 1261–68. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia. HERG encodes the IKr potassium channel. Cell 1995; 81: 299–307. Valenzuela C, Sanchez-Chapula J, Delpon E, Elizalde A, Perez O, Tamargo J. Imipramine blocks rapidly activating and delays slowly activating K+ current activation in guinea pig ventricular myocytes. Circ Res 1994; 74: 687–99. Teschemacher AG, Seward EP, Hancox JC, Witchel HJ. Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol 1999; 128: 479–85.
Deferiprone for thalassaemia Sir—Deferiprone should be used in patients with thalassaemia and other patients with iron overload, who cannot receive effective or sufficient deferoxamine therapy. This was the recommendation issued following the 10th International Conference on Oral Chelation, March 22–26, 2000, Limassol, Cyprus.1 At least one third of patients with thalassaemia in countries in which deferoxamine is available have serum ferritin in excess of 2500 g/L and in general a higher morbidity and mortality rate than those with a target serum ferritin below 2500 g/L. This reflects the low compliance with subcutaneous deferoxamine. Whereas, more than 80% of patients with thalassaemia are born in Asia and Middle Eastern countries, only 10% of those transfused are adequately chelated. For these parts of the world deferoxamine is too costly to offer patients. The remainder are at risk of irreversible organ damage and death resulting from iron overload. Deferiprone in these countries could be supplied at an eighth of the price of deferoxamine. More than 6000 patients
THE LANCET • Vol 356 • July 29, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
CORRESPONDENCE
in 40 countries have received deferiprone since 1986.1,2 In India, where deferiprone has been a registered drug since 1994, there are more patients taking deferiprone than deferoxamine. Deferiprone has also been registered in Europe in 1999, following the recommendation by the European Community authorities that its use be restricted to patients who cannot tolerate deferoxamine and that patients on the drug be closely monitored for toxicity. Iron excretion in response to deferiprone appears to depend on the iron load and rate of iron loading of patients, the dose, frequency of administration, and metabolism of the drug.1–3 In about 70% of patients with thalassaemia treated with deferiprone (75–120 mg/kg/day) for more than 2 years, serum ferritin decreased and remained below 2500 g/L.1 In the 30% of patients who were treated with a dose of 75 mg/kg/day or less and who failed to reach negative iron balance or experienced toxicity with deferiprone or deferoxamine, a combination of these two drugs appears to be more effective and less toxic than using either drug alone. No new toxic side effects of deferiprone have been identified and all those known are reversible, controlable, and manageable. Agranulocytosis, which is the most serious, affects less than 0·6% of patients on the drug and is satisfactorily monitored with weekly blood counts. Joint and musculoskeletal pains affect up to 15%, gastrointestinal complaints up to 10%, and zinc deficiency up to 1% of the treated patients. Contrary to the claim that deferiprone initiates or increases the progression of liver fibrosis,4,5 no other investigators have substantiated these findings nor have they observed significant differences by comparison to patients receiving deferoxamine.1 This observation was made in groups of patients who had been taking deferiprone daily for over 10 years in India and Switzerland.1,3 New oral chelators, if successful, will certainly not be available at least in the next 5 years. New protocols aimed at improving deferiprone therapy are also being developed. Deferiprone remains the drug of choice for those patients who cannot afford the high cost of deferoxamine, cannot comply with its subcutaneous infusion, or cannot overcome its toxicity. The prognosis of patients taking deferiprone is much better than that of patients experiencing iron overload toxicity because of lack of chelation therapy or ineffective or insufficient chelation therapy with deferoxamine. We thank C Politis, V A Berdoukas, A Maggio,
THE LANCET • Vol 356 • July 29, 2000
P Nielsen, and P Tondury for helpful comments.
*G J Kontoghiorghes, M B Agarwal, R W Grady, A Kolnagou, J J Marx *Postgraduate Research Institute, CY-3021 Limassol, Cyprus; Department of Haematology, LTMG Hospital and LTM Medical College, Mumbai, India; Cornell University Medical Centre, New York, USA; Thalassaemia Unit, Paphos General Hospital, Paphos, Cyprus; and Department of Internal Medicine, University Medical Centre, Utrecht, The Netherlands (e-mail: [email protected]) 1
2
3
4
5
10th International Conference on Oral Chelation in the Treatment of Thalassaemia and other Diseases (ICOC), Limassol, Cyprus, March 22–26, 2000, 1–56. Oral chelation in the treatment of thalassaemia and other diseases [suppl]. Kontoghiorghes GJ, ed. Drugs of Today 1992; 28 (A): 1–187. Tondury P, Zimmerman A, Nielsen P, Hirt A. Liver iron fibrosis during long-term treatment with deferiprone in Swiss thalssaemic patients. Br J Haematol 1998; 101: 413–15. Olivieri NF, Brittenham GM, Mclaren C, et al. Long term safety and effectiveness of iron chelation therapy with deferiprone for thalassaemia major. N Engl J Med 1998; 339: 417–23. Kowdly KV, Kaplan MM. Iron chelation therapy with oral deferiprone—toxicity or lack of efficacy. N Engl J Med 1998; 339: 468–69.
Treatment of endometriotic cysts Sir—The report by Spyros Mesogitis and colleagues (April 1, p 1160)1 on the use of methotrexate as a treatment for endometriotic cysts raises important questions about side effects, mode of treatment, balance of risk and benefit, effectiveness, and safety. Local treatments are associated with a small amount of systemic absorption, which are associated with side effects.2 A quarter of patients with ectopic pregnancy receiving methotrexate have been found3 to experience side effects at similar doses, so we were surprised at the absence of side effects in the series described by Mesogitis and colleagues. This absence is probably a result of small sample size. The use of percutaneous needle aspiration of cystic contents is not usual practice in the UK and carries a significant risk of bowel or bloodvessel perforation because ultrasound cannot define the hazards of adhesions or small ovarian vessels. Surely it would be prudent to advocate antibiotic prophylaxis when this technique is used. The additional risks of introducing a chemotherapeutic agent into a cyst cavity resulting in a communication with the abdominal cavity invites local complications,
which may not have been apparent in this small series. Consequently, the benefits of this approach do not appear to outweigh the risks. Laparoscopic ovarian cystotomy and fenestration is probably the optimum procedure, where the aim is to reduce cyst volume and conserve the ovarian cortex. The proposed treatment might damage the ovarian cortex and reduce its complement of primordial follicles. Furthermore, a large proportion of patients underwent repeat aspiration and treatment with methotrexate, thus doubling their exposure to the associated risks. The conclusion that this technique is a safe and effective treatment is unsound without a prospective randomised controlled trial. Such a trial should have appropriate primary endpoints, namely symptom relief and subsequent pregnancy, rather than a subgroup analysis of a series of ovarian cysts with cyst resolution. The safety of a highly toxic chemotherapeutic agent introduced into gonadal tissue, namely the ovary, as an effective treatment for endometriotic and benign ovarian cysts, is not adequately shown. The issue of methotrexate treatment of endometriotic cysts in infertile women was not addressed and neither is future fertility in women yet to plan a family. Likewise, there is no comment on the subsequent menstrual pattern of women following this treatment. Recurrence at 6 months is not comparable with larger studies done over 5 years. Further long-term studies incorporating these outcome measures need to be done before transabdominal drainage and local methotrexate administration can be declared a safe and effective technique. Guy Fender, *Andrew Prentice Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, The Rosie Hospital, University of Cambridge, Cambridge CB2 2SW, UK (e-mail: [email protected]) 1
2
3
4
Mesogitis S, Antsaklis A, Daskalakis G, Papantoniou N, Michalas S. Combined ultrasonographically guided drainage and methotrexate administration for treatment of endometriotic cysts. Lancet 2000; 355: 1160. Lecru F, Robin F, Taurell R, Bernard JP, Vilde F. Effect of methotrexate on tubal epithelium: a report of three cases. J Reprod Med 1999; 44: 46–48. Parker J, Bitsits A, Proietto AM. A systematic review of single-dose intramuscular methotrexate for the treatment of ectopic pregnancy. Aust N Z J Obstet Gynaecol 1998; 38: 145–50. Sutton C, Hill D. Laser laparoscopy in the treatment of endometriosis: a five year study. Br J Obstet Gynaecol 1990; 97: 181–85.
429
For personal use only. Not to be reproduced without permission of The Lancet.