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TREATMENT OF EARLY BREAST CANCER
1193
theophylline, only 7 (12%) were related to the skin or allergic responses. This difference in adverse reaction profiles probably represents ethylenediamine sensitivity. The lower incidence of reported reactions with oral than ’with intravenous aminophylline may reflect the poor absorption of ethylenediamine from the gut.6 The of systemic most common manifestation ethylenediamine allergy is a rash, ranging from non-specific erythematous maculopapular’,to generalised exfoliative dermatitis9,1Q and urticaria." Indeed, ethylenediamine sensitivity should be suspected in any patient with an acute dermatitis or a flare-up of a more chronic condition whilst on aminophylline. Fever, lymphadenopathy, acute confusional states and even bronchospasm, 12,13 arising between 24 and 48 hours after administration, have also been described. Unless the clinician is aware of potential ethylenediamine sensitivity these effects may be attributed either to the primary disease state or to concomitant antibiotic therapy. Once suspected, ethylenediamine sensitivity should be confirmed by a 48-hour skin patch test to 107o solutions of aminophylline, and ethylenediamine, theophylline. (In typical aminophylline sensitivity skin patch tests are positive with aminophylline and ethylenediamine but not with anhydrous False-negative skin patch tests have been reported and in such cases it may be necessary to rechallenge with systemic aminophylline and theophylline to establish the diagnosis.14 The fact that a history of contact is not obtainable does not eliminate the possibility of previous exposure to ethylenediamine, either industrially or
theophylline.)
medicinally.2,s The mechanism of ethylenediamine sensitivity is poorly understood. Suggestions include individual variation in aminophylline metabolism and development of both immunoglobulin-dependent and cell-mediated hypersensitivity. We now know that N-acetylation is one of the main metabolic pathways of ethylenediamine, IS so acetylator status should ideally be determined in patients with allergic reactions to aminophylline. IgE-mediated hypersensitivity has been reported in three subjects with urticaria and angio-oedema.l’,’4 In most people the allergic manifestations develop 24-48 hours after exposure, favouring a cellmediated hypersensitivity reaction. Nevertheless, in 7 of 8 subjects rechallenged with systemic aminophylline symptoms developed within 6-8 hours,6,7 which suggests either an accelerated form of cell-mediated immunity ora recruitment of humoral mechanisms. Such modifications of the classic immunological responses have been described in other hypersensitivity reactions. 16,17 Sequential skin biopsies of developing lesions would help clarify the mechanism of
hypersensitivity. 6. 7
Caldwell J, Cotgreave IA Metabolism of ethylenediamine in the rat. Br J Pharmacol 1983; 78: suppl 62P. Hardy C, Schofield O, George CF. Allergy to aminophylline Br Med J 1983; 286: 2051-52.
8 9
Thompson PJ, Gibb WRG, Cole P, Citron KM Generalised allergic reactions to aminophylline. Thorax 1984, 39: 600-03. Petrozzi JW, Shore RM. Generalised exfoliative dematitis from ethylenediamine. Arch Dermatol 1976; 112: 525-26. RD, Stevenson HC. Generalised dermatitis
10. De Shazo
to
aminophylline
Ann
Allergy
1981, 46: 152-55. 11. Wong D, Lopapa AF, Haddad ZH. Immediate hypersensitivity reaction to aminophylline. J Allergy Clin Immunol 1971, 48: 165-70 12. Tas J, Weissberg D. Allergy to aminophylline report of a case. Acta Allergol 1958; 12:
What does this all mean to the physician and patient? Need asthmatic subjects with aminophylline hypersensitivity be deprived of the potential benefits of xanthine therapy? In most instances it is the ethylenediamine moiety of aminophylline rather than anhydrous theophylline that is the Thus of hypersensitivity reactions. causal agent can such be circumvented treating hypersensitivity by patients with oral anhydrous theophylline preparations not containing ethylenediamine. In acute asthma either the analogue dihydroxypropyl theophyllinel° or the salt lysine theophyllinel8may be given intravenously, preparations having a pharmacokinetic profile similar to that of parenteral aminophylline with a mean plasma half-life of 8 hours.
TREATMENT OF EARLY BREAST CANCER WHEN important therapeutic questions arise, dozens of independent clinical trials may be initiated around the world them. If many different trials address related there may be a period of several years during which each separate study might be inconclusive even though an overview of all the interim results would yield clear evidence as to whether or not the treatments save lives. In October, a meeting in London was attended by representatives of almost all randomised trials in early breast cancer that have compared tamoxifen with control (fortythree trials on a total of 16 000 women) or cytotoxic chemotherapy with control (thirty-seven trials on a total of over 10 000 women) (see p 1205). An overview of the eighty separate interim mortality differences, few of which were individually significant, produced evidence that, for postmenopausal women, a year or two oftamoxifen treatment reduced the number of early deaths by about one-sixth and that, for premenopausal women, cytotoxic regimens such as "CMF" reduced early mortality by about one-third. If these differences in early mortality are real, they may influence the choice of treatment of many tens ofthousands of women with stage-II disease, and if they carry over into differences oflong-term survival then some thousands oflives may be saved each year-indeed, in countries such as the United States, where breast cancer is common, perhaps 1% of all cancer deaths may be avoided. But, although there is no specific reason to doubt these claimed reductions in early mortality, more of the actual data should be published. Will the short-term and long-term sideeffects of cytotoxic treatment outweigh the benefits of stage-II disease? Which of the trial results are really unbiased? Exactly what treatments were supposed to be given, for how long, with what side-effects, and with what degree of compliance? What types of patient were studied? The best way to judge the meaning and reliability of an overview of many trials is to see a proper description of the methods and findings of each separate trial. Although the reporting of inconclusive trial results is not normally desirable, in this instance the individual trialists might do well to provide brief reports for
to answer
questions,
public scrutiny. 16. Polak
39-42. 13. Lam S, Chan-Yeung M. Ethylenediamine induced asthma Am Rev Respir Dis 1980; 121: 151-55. 14. Kradjan WA, Lakshminarayan S. Allergy to aminophylline: lack of predictability by skin testing. Am J Hosp Pharm 1981; 38: 1031-33. 15 Caldwell J, Cotgreave IA. Comparative disposition of theophylline and ethylenediamine given as aminophylline to human volunteers. Br J Clin Pharmacol 1982, 14: 610.
L, Turk JL. Studies
on
the effect of systemic administration of sensitisers
in
guinea pigs with contact hypersensitivity to inorganic metal compounds. The flareup of previous test sites of contact sensitivity and the development of a generalised
Exp Immunol 1968, 3: 253 ME, Cohen S, Dvorak HF Lymphokines as inflammatory mediators. In Cohen E, Pick E, Oppenheim JJ, eds Biology of Lymphokines. New York Academic Press, 1979; 13 Johnston A, Aldhous ME, Hedges A, Weersiriya K, Freeman A, Turner P. The pharmacokinetics of lysine theophylline, a new soluble theophylline in human volunteers Postgrad Med J 1983; 89: 86-87. rash. Clin
17. Adelman NC. Hammond
18
theophylline, only 7 (12%) were related to the skin or allergic responses. This difference in adverse reaction profiles probably represents ethylenediamine sensitivity. The lower incidence of reported reactions with oral than ’with intravenous aminophylline may reflect the poor absorption of ethylenediamine from the gut.6 The of systemic most common manifestation ethylenediamine allergy is a rash, ranging from non-specific erythematous maculopapular’,to generalised exfoliative dermatitis9,1Q and urticaria." Indeed, ethylenediamine sensitivity should be suspected in any patient with an acute dermatitis or a flare-up of a more chronic condition whilst on aminophylline. Fever, lymphadenopathy, acute confusional states and even bronchospasm, 12,13 arising between 24 and 48 hours after administration, have also been described. Unless the clinician is aware of potential ethylenediamine sensitivity these effects may be attributed either to the primary disease state or to concomitant antibiotic therapy. Once suspected, ethylenediamine sensitivity should be confirmed by a 48-hour skin patch test to 107o solutions of aminophylline, and ethylenediamine, theophylline. (In typical aminophylline sensitivity skin patch tests are positive with aminophylline and ethylenediamine but not with anhydrous False-negative skin patch tests have been reported and in such cases it may be necessary to rechallenge with systemic aminophylline and theophylline to establish the diagnosis.14 The fact that a history of contact is not obtainable does not eliminate the possibility of previous exposure to ethylenediamine, either industrially or
theophylline.)
medicinally.2,s The mechanism of ethylenediamine sensitivity is poorly understood. Suggestions include individual variation in aminophylline metabolism and development of both immunoglobulin-dependent and cell-mediated hypersensitivity. We now know that N-acetylation is one of the main metabolic pathways of ethylenediamine, IS so acetylator status should ideally be determined in patients with allergic reactions to aminophylline. IgE-mediated hypersensitivity has been reported in three subjects with urticaria and angio-oedema.l’,’4 In most people the allergic manifestations develop 24-48 hours after exposure, favouring a cellmediated hypersensitivity reaction. Nevertheless, in 7 of 8 subjects rechallenged with systemic aminophylline symptoms developed within 6-8 hours,6,7 which suggests either an accelerated form of cell-mediated immunity ora recruitment of humoral mechanisms. Such modifications of the classic immunological responses have been described in other hypersensitivity reactions. 16,17 Sequential skin biopsies of developing lesions would help clarify the mechanism of
hypersensitivity. 6. 7
Caldwell J, Cotgreave IA Metabolism of ethylenediamine in the rat. Br J Pharmacol 1983; 78: suppl 62P. Hardy C, Schofield O, George CF. Allergy to aminophylline Br Med J 1983; 286: 2051-52.
8 9
Thompson PJ, Gibb WRG, Cole P, Citron KM Generalised allergic reactions to aminophylline. Thorax 1984, 39: 600-03. Petrozzi JW, Shore RM. Generalised exfoliative dematitis from ethylenediamine. Arch Dermatol 1976; 112: 525-26. RD, Stevenson HC. Generalised dermatitis
10. De Shazo
to
aminophylline
Ann
Allergy
1981, 46: 152-55. 11. Wong D, Lopapa AF, Haddad ZH. Immediate hypersensitivity reaction to aminophylline. J Allergy Clin Immunol 1971, 48: 165-70 12. Tas J, Weissberg D. Allergy to aminophylline report of a case. Acta Allergol 1958; 12:
What does this all mean to the physician and patient? Need asthmatic subjects with aminophylline hypersensitivity be deprived of the potential benefits of xanthine therapy? In most instances it is the ethylenediamine moiety of aminophylline rather than anhydrous theophylline that is the Thus of hypersensitivity reactions. causal agent can such be circumvented treating hypersensitivity by patients with oral anhydrous theophylline preparations not containing ethylenediamine. In acute asthma either the analogue dihydroxypropyl theophyllinel° or the salt lysine theophyllinel8may be given intravenously, preparations having a pharmacokinetic profile similar to that of parenteral aminophylline with a mean plasma half-life of 8 hours.
TREATMENT OF EARLY BREAST CANCER WHEN important therapeutic questions arise, dozens of independent clinical trials may be initiated around the world them. If many different trials address related there may be a period of several years during which each separate study might be inconclusive even though an overview of all the interim results would yield clear evidence as to whether or not the treatments save lives. In October, a meeting in London was attended by representatives of almost all randomised trials in early breast cancer that have compared tamoxifen with control (fortythree trials on a total of 16 000 women) or cytotoxic chemotherapy with control (thirty-seven trials on a total of over 10 000 women) (see p 1205). An overview of the eighty separate interim mortality differences, few of which were individually significant, produced evidence that, for postmenopausal women, a year or two oftamoxifen treatment reduced the number of early deaths by about one-sixth and that, for premenopausal women, cytotoxic regimens such as "CMF" reduced early mortality by about one-third. If these differences in early mortality are real, they may influence the choice of treatment of many tens ofthousands of women with stage-II disease, and if they carry over into differences oflong-term survival then some thousands oflives may be saved each year-indeed, in countries such as the United States, where breast cancer is common, perhaps 1% of all cancer deaths may be avoided. But, although there is no specific reason to doubt these claimed reductions in early mortality, more of the actual data should be published. Will the short-term and long-term sideeffects of cytotoxic treatment outweigh the benefits of stage-II disease? Which of the trial results are really unbiased? Exactly what treatments were supposed to be given, for how long, with what side-effects, and with what degree of compliance? What types of patient were studied? The best way to judge the meaning and reliability of an overview of many trials is to see a proper description of the methods and findings of each separate trial. Although the reporting of inconclusive trial results is not normally desirable, in this instance the individual trialists might do well to provide brief reports for
to answer
questions,
public scrutiny. 16. Polak
39-42. 13. Lam S, Chan-Yeung M. Ethylenediamine induced asthma Am Rev Respir Dis 1980; 121: 151-55. 14. Kradjan WA, Lakshminarayan S. Allergy to aminophylline: lack of predictability by skin testing. Am J Hosp Pharm 1981; 38: 1031-33. 15 Caldwell J, Cotgreave IA. Comparative disposition of theophylline and ethylenediamine given as aminophylline to human volunteers. Br J Clin Pharmacol 1982, 14: 610.
L, Turk JL. Studies
on
the effect of systemic administration of sensitisers
in
guinea pigs with contact hypersensitivity to inorganic metal compounds. The flareup of previous test sites of contact sensitivity and the development of a generalised
Exp Immunol 1968, 3: 253 ME, Cohen S, Dvorak HF Lymphokines as inflammatory mediators. In Cohen E, Pick E, Oppenheim JJ, eds Biology of Lymphokines. New York Academic Press, 1979; 13 Johnston A, Aldhous ME, Hedges A, Weersiriya K, Freeman A, Turner P. The pharmacokinetics of lysine theophylline, a new soluble theophylline in human volunteers Postgrad Med J 1983; 89: 86-87. rash. Clin
17. Adelman NC. Hammond
18