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HIV in the developing world
THE LANCET nations desperate for hard currency and threatens the health and safety o f their people.
Tdal
Regimens
No
Follow.,p (m0)
P A Stephenson centre for Public Health Research, S-651 82 Karlstad, Sweden
Ministry of Health of Romania, Institute for Mother and Child, Bucharest, United Nation's Children's Fund. Preventing maternal death in Romania: an analysisof maternity care and maternal mortality with recommendationsfor a Safe Motherhood programme. Bucharest: UNICEF, 1993.
Survival(%) Diseasefree
ECSG'
CA~/CMF
82-'7--
~2
SWOG'
FACM
28;
SS
S2
NSABP4
CMFVP AC
265 734 739
44
52 64 64
CMF
Overal~ 71 88 58 75 75
C = cyclophosphamide,A = doxorubicin (anthracycline), F= 541uorouracil,M = methotrexate, V = vincristine, P= prednisone.
Table: Randomlsed trials of adjuvant chemotherapy In breast cancer with or without anthracycllnes
HIV in the developing world SIR--Gilks (Oct 23, p 1037) rightly emphasises the importance o f moving away from a narrow focus on A I D S . But I believe he is not justified in speaking of an "absence o f an appropriate response or strategy" to cope with H I V infection in developing countries. T h e W H O Global Programme on A I D S has developed guidelines for the clinical management o f H I V infection in adults and children 1,2which uses.the approach Gilks describes. T h e s e guidelines focus on treatable conditions and, in the absence o f diagnostic resources, prescribe a symptomatic approach to clinical care; they do not mention A I D S as the entry criteria, but look at the broad spectrum of symptomatic H I V infection. T h e guidelines are presented as a flow-chart, which increases their use for training and facilitates local adaptation. T h e y are addressed to health centre, district, and hospital settings. T h e W H O clinical guidelines could be a model for the development o f individual countries or institution guidelines that would consider both clinical presentation and available resources. T h e methodology o f local adaptation was successfully field-tested in Burundi, Malawi, Thailand, Barbados, and Uganda, and in 15 countries in the Caribbean. s T o help countries to go through this process and to provide basic information on the use and procurement o f drugs for H I V care, W H O has developed additional background material. 4~ F r o m spring, 1994, software versions o f the clinical guidelines, in D O S and Macintosh, will further help improve clinical care in developing countries. R Wabitsch Health Care Support, Office of Intervention Develo0ment and Support, Global Programme on AIDS, World Health Organisation, 1211 Geneva 27, Switzerland
1 WHO. Guidelines for the clinicalmanagement of HIV infection in children. Geneva: WHO, 1991: WHO/GPA/IDS/HCS/91.6. 2 WHO. Guidelines for the clinicalmanagement of HIV infection in adults. Geneva: WHO, 1993: WHO/GPA[IDS/HCS[93.3. 3 Wabitsch R, van Praag E. WHO guidelines on the clinical management of HIV infection, evaluation of the process of national adaptation (PoB 3847). Presented at 8th International Conferenceon AIDS/3rd STD World Congress, 19-24 July 1992, Amsterdam, Netherlands. 4 WHO standardizing guidelines for the clinical management of HIV infection: a facilitatorguide. Geneva: WHO (in press). 5 WHO. Drugs used in HIV and associatedinfections. (Limited distribution.) Geneva: WHO, 1991. WHO/HQ. 6 Interim procedures for the provision of commonly used drugs for HIV/AIDS harougb,national aids programme medium-term plans. (Limited distribution.) Geneva: WHO, 1991. WHO/HQ.
Doxorubicin adjuvant combinations for breast cancer S I R - - F r o m May 1, 1993, the International Breast Cancer Study G r o u p (IBCSG) with participating centres in eleven countries activated protocols 11-14 for the adjuvant treatment of node-positive breast cancer. Every patient up to the age o f 70, regardless of risk factors, will be given either doxorubicin
1550
(60 m g / m a intravenously) or epirubicin (90 m g / m 2) plus intravenous cyclophosphamide (600 m g / m 2) every 21 days for four cycles (AC). I question the decision to administer an anthracycline to all such patients. Adjuvant chemotherapy trials with cyclophosphamide, methotrexate, and 5-fluorouracil ( C M F ) produced an increase in Survival in patients with a minimal axillary l y m p h - n o d e involvement (less than four) but not of patients with more nodes affected. 1 Randomised trials comparing doxorubicincontaining combinations with C M F were started about 10 years ago (table) 2-4 but none revealed an advantage for doxorubicin with respect to disease-free and overall survival. T h e 1993 update o f the NSABP-15 trial confirms (B Fisher, personal communication), at 59 m o n t h s ' median time on study, the results published in 1990; 4 and in that trial the dose and schedule o f AC was the same as that in the new I B C S G protocols. Is 240 m g / m 2 (the total dose of doxorubicin in the new I B C S G trials) irrelevant to the myocardium? T h a t is the crucial question since the superiority o f doxorubicincontaining combinations has not been demonstrated, at least for patients with fewer t h a n four positive l y m p h nodes. Morphological and functional studies show that 200-300 m g / m 2 may harm the myocardium. Endomyocardial biopsy revealed doxorubicin-associated myocardial degeneration in virtually all patients treated with 240 rag/mr, s I n prospective evaluations o f doxorubicin cardiotoxicity, done by serial radionuclide angiography, the left-ventricular ejection fraction was decreased significantly during rest and exercise after cumulative doses of 200-300 mg/mZ. 6 Until recently there was a general agreement that the spectre o f doxorubicin cardiotoxicity had relegated this d r u g to the adjuvant treatment of breast cancer patients at higher risk. 7 T h e full implications for symptomless cardiomyopathy m a y not be realised for many years and the I B C S G approach seems misguided. Christian Sauter Division of Oncology, Department of Medicine, University Hospital, CH-8091 Z~rich, Switzerland
1 Bonadonna G. Conceptual and practical advances in the management of breast cancer.J Clin Onco11989; 7:1380-97. 2 Carpenter JT, Velez-Garcia E, Aron BS, et al. Prospective randomized comparison of cyclophosphamide, doxorubicin (adriamycin)and fluorouracil (CAF) vs cyclophosphamide,methotrexate and fluorouracil (CMF) for breast cancer with positive axillary nodes. Southeastern Cancer Study Group study. Proc/ISCO 1991; 10: 45. 3 O'Brian R, Green S, O'Sullivan J, et al. A comparison of CMFVP for one year to short term adriamycin based chemotherapy for patients with receptor-negative node positive operable breast cancer: an intergroup-study. Proc ASCO 1992; 11: 61. 4 Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophoaphamidewith and without interval reinduction therapy compared with 6 months of cyclophosphamide,methotrexate, and fluorouracil in tamoxifen-nonresponsivetumors: results from the national surgical adjuvant breast and bowel project B-15. J Clin Oncol 1990; 8: 1483--96. 5 Henderson IC, Frei E Ill. Adriamycin cardiotoxicity. Am Heartff 1980; 99: 671-74.
Vo1342 • December 18/25, 1993
Tdal
Regimens
No
Follow.,p (m0)
P A Stephenson centre for Public Health Research, S-651 82 Karlstad, Sweden
Ministry of Health of Romania, Institute for Mother and Child, Bucharest, United Nation's Children's Fund. Preventing maternal death in Romania: an analysisof maternity care and maternal mortality with recommendationsfor a Safe Motherhood programme. Bucharest: UNICEF, 1993.
Survival(%) Diseasefree
ECSG'
CA~/CMF
82-'7--
~2
SWOG'
FACM
28;
SS
S2
NSABP4
CMFVP AC
265 734 739
44
52 64 64
CMF
Overal~ 71 88 58 75 75
C = cyclophosphamide,A = doxorubicin (anthracycline), F= 541uorouracil,M = methotrexate, V = vincristine, P= prednisone.
Table: Randomlsed trials of adjuvant chemotherapy In breast cancer with or without anthracycllnes
HIV in the developing world SIR--Gilks (Oct 23, p 1037) rightly emphasises the importance o f moving away from a narrow focus on A I D S . But I believe he is not justified in speaking of an "absence o f an appropriate response or strategy" to cope with H I V infection in developing countries. T h e W H O Global Programme on A I D S has developed guidelines for the clinical management o f H I V infection in adults and children 1,2which uses.the approach Gilks describes. T h e s e guidelines focus on treatable conditions and, in the absence o f diagnostic resources, prescribe a symptomatic approach to clinical care; they do not mention A I D S as the entry criteria, but look at the broad spectrum of symptomatic H I V infection. T h e guidelines are presented as a flow-chart, which increases their use for training and facilitates local adaptation. T h e y are addressed to health centre, district, and hospital settings. T h e W H O clinical guidelines could be a model for the development o f individual countries or institution guidelines that would consider both clinical presentation and available resources. T h e methodology o f local adaptation was successfully field-tested in Burundi, Malawi, Thailand, Barbados, and Uganda, and in 15 countries in the Caribbean. s T o help countries to go through this process and to provide basic information on the use and procurement o f drugs for H I V care, W H O has developed additional background material. 4~ F r o m spring, 1994, software versions o f the clinical guidelines, in D O S and Macintosh, will further help improve clinical care in developing countries. R Wabitsch Health Care Support, Office of Intervention Develo0ment and Support, Global Programme on AIDS, World Health Organisation, 1211 Geneva 27, Switzerland
1 WHO. Guidelines for the clinicalmanagement of HIV infection in children. Geneva: WHO, 1991: WHO/GPA/IDS/HCS/91.6. 2 WHO. Guidelines for the clinicalmanagement of HIV infection in adults. Geneva: WHO, 1993: WHO/GPA[IDS/HCS[93.3. 3 Wabitsch R, van Praag E. WHO guidelines on the clinical management of HIV infection, evaluation of the process of national adaptation (PoB 3847). Presented at 8th International Conferenceon AIDS/3rd STD World Congress, 19-24 July 1992, Amsterdam, Netherlands. 4 WHO standardizing guidelines for the clinical management of HIV infection: a facilitatorguide. Geneva: WHO (in press). 5 WHO. Drugs used in HIV and associatedinfections. (Limited distribution.) Geneva: WHO, 1991. WHO/HQ. 6 Interim procedures for the provision of commonly used drugs for HIV/AIDS harougb,national aids programme medium-term plans. (Limited distribution.) Geneva: WHO, 1991. WHO/HQ.
Doxorubicin adjuvant combinations for breast cancer S I R - - F r o m May 1, 1993, the International Breast Cancer Study G r o u p (IBCSG) with participating centres in eleven countries activated protocols 11-14 for the adjuvant treatment of node-positive breast cancer. Every patient up to the age o f 70, regardless of risk factors, will be given either doxorubicin
1550
(60 m g / m a intravenously) or epirubicin (90 m g / m 2) plus intravenous cyclophosphamide (600 m g / m 2) every 21 days for four cycles (AC). I question the decision to administer an anthracycline to all such patients. Adjuvant chemotherapy trials with cyclophosphamide, methotrexate, and 5-fluorouracil ( C M F ) produced an increase in Survival in patients with a minimal axillary l y m p h - n o d e involvement (less than four) but not of patients with more nodes affected. 1 Randomised trials comparing doxorubicincontaining combinations with C M F were started about 10 years ago (table) 2-4 but none revealed an advantage for doxorubicin with respect to disease-free and overall survival. T h e 1993 update o f the NSABP-15 trial confirms (B Fisher, personal communication), at 59 m o n t h s ' median time on study, the results published in 1990; 4 and in that trial the dose and schedule o f AC was the same as that in the new I B C S G protocols. Is 240 m g / m 2 (the total dose of doxorubicin in the new I B C S G trials) irrelevant to the myocardium? T h a t is the crucial question since the superiority o f doxorubicincontaining combinations has not been demonstrated, at least for patients with fewer t h a n four positive l y m p h nodes. Morphological and functional studies show that 200-300 m g / m 2 may harm the myocardium. Endomyocardial biopsy revealed doxorubicin-associated myocardial degeneration in virtually all patients treated with 240 rag/mr, s I n prospective evaluations o f doxorubicin cardiotoxicity, done by serial radionuclide angiography, the left-ventricular ejection fraction was decreased significantly during rest and exercise after cumulative doses of 200-300 mg/mZ. 6 Until recently there was a general agreement that the spectre o f doxorubicin cardiotoxicity had relegated this d r u g to the adjuvant treatment of breast cancer patients at higher risk. 7 T h e full implications for symptomless cardiomyopathy m a y not be realised for many years and the I B C S G approach seems misguided. Christian Sauter Division of Oncology, Department of Medicine, University Hospital, CH-8091 Z~rich, Switzerland
1 Bonadonna G. Conceptual and practical advances in the management of breast cancer.J Clin Onco11989; 7:1380-97. 2 Carpenter JT, Velez-Garcia E, Aron BS, et al. Prospective randomized comparison of cyclophosphamide, doxorubicin (adriamycin)and fluorouracil (CAF) vs cyclophosphamide,methotrexate and fluorouracil (CMF) for breast cancer with positive axillary nodes. Southeastern Cancer Study Group study. Proc/ISCO 1991; 10: 45. 3 O'Brian R, Green S, O'Sullivan J, et al. A comparison of CMFVP for one year to short term adriamycin based chemotherapy for patients with receptor-negative node positive operable breast cancer: an intergroup-study. Proc ASCO 1992; 11: 61. 4 Fisher B, Brown AM, Dimitrov NV, et al. Two months of doxorubicin-cyclophoaphamidewith and without interval reinduction therapy compared with 6 months of cyclophosphamide,methotrexate, and fluorouracil in tamoxifen-nonresponsivetumors: results from the national surgical adjuvant breast and bowel project B-15. J Clin Oncol 1990; 8: 1483--96. 5 Henderson IC, Frei E Ill. Adriamycin cardiotoxicity. Am Heartff 1980; 99: 671-74.
Vo1342 • December 18/25, 1993