- Email: [email protected]
Toxicity and reconstitution of recombinant interleukin-2 with albumin
1464
through a second wound without causing substantial additional damage.3 No special instruments are required and one feels rewarded when the relieved angler returns to his fishing with his favourite fish-hook in one piece. out
I thank Dr L.
Palmer, Dr A. Hunt, and Mrs E. Rosenfeld for their help.
The Queen Elizabeth Adelaide 5011, South Australia
1. Hulme J. How to
Hospital,
SURESH S. DAVID
Nursing Mirror 1977; 145: 23. string Med J Aust 1961; 48: 3. Rose JD. Removing the embedded fish hook. Aust Fam Phys 1981; 10: 33. remove
fish-hooks.
2. Cooke T. How to remove fish-hooks with a bit of
815-16.
Toxicity and reconstitution of recombinant interleukin-2 with albumin SIR,-We have reported that failure
to reconstitute some interleukin-2 of recombinant (rIL-2) intended for preparations 2 infusion may lead to reduced bioavailability. The toxicity of rIL-2 given by infusion might therefore have been underestimated. If a carrier protein is not included when IL-2 is reconstituted, cytokine adherence to the plastic of the giving set might cause this reduction. We have tested this hypothesis in a patient by giving initially IL-2 reconstituted with glucose alone and on the second infusion with glucose and albumin. A 47-year-old woman was referred for treatment of metastatic malignant melanoma. 8 years earlier she had undergone wide excision of melanoma on the right forearm. 6 years later she presented with a mass in the right axilla and block dissection revealed metastatic melanoma. Biopsy of a right supraclavicular node five months later again showed melanoma. Following radiotherapy to the right side of the neck left-sided cervical lymphadenopathy developed. Despite treatment with interferon-oc further cervical adenopathy developed and para-aortic and iliac lymphadenopathy was detected by ultrasonography. The patient was otherwise symptom-free with no other notable medical history. She was entered into a multicentre phase-2 study of dacarbazine and interleukin-2 (EuroCetus). She was given dacarbazine 250 mg/m2 intravenously by infusion on five consecutive days, and subsequently rIL-2 18 million IU/m2 daily. During the first five-day infusion IL-2 was reconstituted with 5% glucose alone. A vygon lectro-cath giving set was used with a Becton Dickinson 50 ml syringe. She tolerated the treatment well despite pyrexia of up to 38.5C. Blood pressure fell by 20 mm Hg and she gained 1 kg. During the second infusion, albumin was added for the reconstitution of rIL-2. Within 48 h blood pressure fell by 50 mm Hg (figure). rIL-2 was discontinued and plasma expanders were given. Blood pressure recovered rapidly and IL-2 was recommenced at half the original dose. Substantial hypotension developed and treatment was stopped; rigors and weight gain of 6 kg were noted. Blood samples were analysed for tumour necrosis factor
(TNF, Medgenix IRMA), interferon-gamma (IFN-y, Medgenix IRMA), and neopterin (Henning, Berlin, RIA). TNF concentrations remained low during the first infusion of IL-2 (figure). IFN-y values remained below the level of detection and plasma neopterin was slightly high at 32 nmol/1. After addition of albumin during the second infusion, plasma TNF concentrations rose strikingly, coinciding with the fall in blood pressure. Neopterin (121 nmol/1) and IFN-y values also rose during this
period. The dose limiting toxic reactions of rIL-2 are hypotension and vascular leak syndrome.2These side-effects are probably mediated by other cytokines induced by rIL-2 such as TNF, IFN-y, and IL-1 .3 Other markers of monocyte activation such as neopterin have also been noted.4 IFN-y and neopterin in our patient remained low. Because toxicity worsened after addition of albumin, and was associated with raised TNF, IFN-y, and neopterin, the increase in bioavailability of IL-2 after the addition of albumin1 probably accounts for this increase in toxicity. Although toxicity of IL-2 is related to duration of treatment’’ the temporal relation between the addition of albumin, the induction of TNF, and the occurrence of hypotension supports this contention. We have since routinely reconstituted rIL-2 with albumin and all patients have shown
Changes
in blood pressure and TNF
during
IL-2 treatment.
Rx=treatment, BP=blood pressure, A=albumin. TNF upper limit of normal= 6
pg/ml.
increases in plasma TNF and neopterin during both infusion periods. The albumin used for reconstitution might contain a small amount of endotoxin and its administration might lead to induction of TNF and its associated side-effects.s However, since only 50 ml of a 1 % solution of albumin is infused per 24 h, endotoxin contamination is most unlikely to be the cause of the observed toxicity and increase in plasma TNF. Thus the true toxicity of this preparation of rIL-2 may have been underestimated when given by infusion without albumin. ICRF Clinical Oncology Unit, Guy’s Hospital, London SE1 9RT, UK, Department of Medical Homerton Hospital,
Oncology,
London, and Biological Therapies Laboratory, Imperial Cancer Research Fund,
London WC2
D. W. MILES S. J. LONGHURST P. G. HARPER F. R. BALKWILL
1. Miles
DW, Bird CR, Whadwa M, et al Interleukin-2 for infusion should be reconstituted with albumin. Lancet 1990; 336: 1602-03. 2. Lotze MT, Matory YL, Ettinghausen SE, et al. In vivo administration of purified interleukin-2 II, half life, immunological effects and expansion of peripheral lymphoid cells in vivo with recombinant interleukin-2. J Immunol 1985; 135: 2865-75. 3. Heberman RB. Interleukin-2 therapy of human cancer. potential benefits versus toxicity. J Clin Oncol 1989; 7: 1-4 4. Brown RR, Lee CM, Kohler PC, Hank JA, Storer BE, Sondel PM. Altered tryptophan and neopterin metabolism in cancer patients treated with interleukin-2. Cancer Res 1989; 49: 4941-44. 5. Poole S, Thorpe R, Meager A, Hubbard AH, Gearing AJH. Detection of pyrogen by cytokine release. Lancet 1988; i: 130.
Can
meta-analyses
be trusted?
SIR,—The question posed in the title of Mr Thompson and Professor Pocock’s article (Nov 2, p 1127) is very important. It is disappointing, therefore, that they chose to "focus on statistical issues" relating to meta-analyses of randomised trials. As Pocock himself shows in his excellent book on clinical trials,l these issues should not be contentious because they are generally the same as those that have already been considered widely for analysing the results of multicentre trials. Instead, Thompson and Pocock should have assessed the trustworthiness of meta-analysis by considering more explicitly the principles upon which it is based and by analysing the substantial amount of empirical evidence now available to help to assess the validity of the approach. Are the formal and more explicit methods used by people conducting meta-analyses preferable, in principle, to the informal and usually implicit methods used by those preparing traditional reviews? PillemerZ has identified the factors that should influence an answer to this question. The usual, informal review is "subjective, relying on idiosyncratic judgments about such key issues as which studies to include and how to draw overall conclusions. Studies are considered one at a time, with strengths and weaknesses selectively identified and casually discussed. Since the process is informal, it is
through a second wound without causing substantial additional damage.3 No special instruments are required and one feels rewarded when the relieved angler returns to his fishing with his favourite fish-hook in one piece. out
I thank Dr L.
Palmer, Dr A. Hunt, and Mrs E. Rosenfeld for their help.
The Queen Elizabeth Adelaide 5011, South Australia
1. Hulme J. How to
Hospital,
SURESH S. DAVID
Nursing Mirror 1977; 145: 23. string Med J Aust 1961; 48: 3. Rose JD. Removing the embedded fish hook. Aust Fam Phys 1981; 10: 33. remove
fish-hooks.
2. Cooke T. How to remove fish-hooks with a bit of
815-16.
Toxicity and reconstitution of recombinant interleukin-2 with albumin SIR,-We have reported that failure
to reconstitute some interleukin-2 of recombinant (rIL-2) intended for preparations 2 infusion may lead to reduced bioavailability. The toxicity of rIL-2 given by infusion might therefore have been underestimated. If a carrier protein is not included when IL-2 is reconstituted, cytokine adherence to the plastic of the giving set might cause this reduction. We have tested this hypothesis in a patient by giving initially IL-2 reconstituted with glucose alone and on the second infusion with glucose and albumin. A 47-year-old woman was referred for treatment of metastatic malignant melanoma. 8 years earlier she had undergone wide excision of melanoma on the right forearm. 6 years later she presented with a mass in the right axilla and block dissection revealed metastatic melanoma. Biopsy of a right supraclavicular node five months later again showed melanoma. Following radiotherapy to the right side of the neck left-sided cervical lymphadenopathy developed. Despite treatment with interferon-oc further cervical adenopathy developed and para-aortic and iliac lymphadenopathy was detected by ultrasonography. The patient was otherwise symptom-free with no other notable medical history. She was entered into a multicentre phase-2 study of dacarbazine and interleukin-2 (EuroCetus). She was given dacarbazine 250 mg/m2 intravenously by infusion on five consecutive days, and subsequently rIL-2 18 million IU/m2 daily. During the first five-day infusion IL-2 was reconstituted with 5% glucose alone. A vygon lectro-cath giving set was used with a Becton Dickinson 50 ml syringe. She tolerated the treatment well despite pyrexia of up to 38.5C. Blood pressure fell by 20 mm Hg and she gained 1 kg. During the second infusion, albumin was added for the reconstitution of rIL-2. Within 48 h blood pressure fell by 50 mm Hg (figure). rIL-2 was discontinued and plasma expanders were given. Blood pressure recovered rapidly and IL-2 was recommenced at half the original dose. Substantial hypotension developed and treatment was stopped; rigors and weight gain of 6 kg were noted. Blood samples were analysed for tumour necrosis factor
(TNF, Medgenix IRMA), interferon-gamma (IFN-y, Medgenix IRMA), and neopterin (Henning, Berlin, RIA). TNF concentrations remained low during the first infusion of IL-2 (figure). IFN-y values remained below the level of detection and plasma neopterin was slightly high at 32 nmol/1. After addition of albumin during the second infusion, plasma TNF concentrations rose strikingly, coinciding with the fall in blood pressure. Neopterin (121 nmol/1) and IFN-y values also rose during this
period. The dose limiting toxic reactions of rIL-2 are hypotension and vascular leak syndrome.2These side-effects are probably mediated by other cytokines induced by rIL-2 such as TNF, IFN-y, and IL-1 .3 Other markers of monocyte activation such as neopterin have also been noted.4 IFN-y and neopterin in our patient remained low. Because toxicity worsened after addition of albumin, and was associated with raised TNF, IFN-y, and neopterin, the increase in bioavailability of IL-2 after the addition of albumin1 probably accounts for this increase in toxicity. Although toxicity of IL-2 is related to duration of treatment’’ the temporal relation between the addition of albumin, the induction of TNF, and the occurrence of hypotension supports this contention. We have since routinely reconstituted rIL-2 with albumin and all patients have shown
Changes
in blood pressure and TNF
during
IL-2 treatment.
Rx=treatment, BP=blood pressure, A=albumin. TNF upper limit of normal= 6
pg/ml.
increases in plasma TNF and neopterin during both infusion periods. The albumin used for reconstitution might contain a small amount of endotoxin and its administration might lead to induction of TNF and its associated side-effects.s However, since only 50 ml of a 1 % solution of albumin is infused per 24 h, endotoxin contamination is most unlikely to be the cause of the observed toxicity and increase in plasma TNF. Thus the true toxicity of this preparation of rIL-2 may have been underestimated when given by infusion without albumin. ICRF Clinical Oncology Unit, Guy’s Hospital, London SE1 9RT, UK, Department of Medical Homerton Hospital,
Oncology,
London, and Biological Therapies Laboratory, Imperial Cancer Research Fund,
London WC2
D. W. MILES S. J. LONGHURST P. G. HARPER F. R. BALKWILL
1. Miles
DW, Bird CR, Whadwa M, et al Interleukin-2 for infusion should be reconstituted with albumin. Lancet 1990; 336: 1602-03. 2. Lotze MT, Matory YL, Ettinghausen SE, et al. In vivo administration of purified interleukin-2 II, half life, immunological effects and expansion of peripheral lymphoid cells in vivo with recombinant interleukin-2. J Immunol 1985; 135: 2865-75. 3. Heberman RB. Interleukin-2 therapy of human cancer. potential benefits versus toxicity. J Clin Oncol 1989; 7: 1-4 4. Brown RR, Lee CM, Kohler PC, Hank JA, Storer BE, Sondel PM. Altered tryptophan and neopterin metabolism in cancer patients treated with interleukin-2. Cancer Res 1989; 49: 4941-44. 5. Poole S, Thorpe R, Meager A, Hubbard AH, Gearing AJH. Detection of pyrogen by cytokine release. Lancet 1988; i: 130.
Can
meta-analyses
be trusted?
SIR,—The question posed in the title of Mr Thompson and Professor Pocock’s article (Nov 2, p 1127) is very important. It is disappointing, therefore, that they chose to "focus on statistical issues" relating to meta-analyses of randomised trials. As Pocock himself shows in his excellent book on clinical trials,l these issues should not be contentious because they are generally the same as those that have already been considered widely for analysing the results of multicentre trials. Instead, Thompson and Pocock should have assessed the trustworthiness of meta-analysis by considering more explicitly the principles upon which it is based and by analysing the substantial amount of empirical evidence now available to help to assess the validity of the approach. Are the formal and more explicit methods used by people conducting meta-analyses preferable, in principle, to the informal and usually implicit methods used by those preparing traditional reviews? PillemerZ has identified the factors that should influence an answer to this question. The usual, informal review is "subjective, relying on idiosyncratic judgments about such key issues as which studies to include and how to draw overall conclusions. Studies are considered one at a time, with strengths and weaknesses selectively identified and casually discussed. Since the process is informal, it is