1224
regimen recommended by Albertis
is the
simplest
to
operate. We thank all the medical, nursing, and biochemical staffwho helped with this work. This study was made possible by a grant from the Bntish Diabetic Association.
Requests for reprints should be addressed to N. G. S. REFERENCES
Alberti, K. G. M. M. in Advanced Medicine Symposium 1974; p. 68. London, 1974. 2. Assal, J. Ph., Aoki, T. T., Manzano, F. M., Kozak, G. P. Diabetes, 1974. 23, 405. 3. Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Postgrad 1.
med. J.
1974, 50, 465.
Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Lancet, 1973. i, 951. 5. Alberti, K. G. M. M., Hockaday, T. D. R., Turner, R. C. ibid. 1973, ii, 515 6. Sönksen, P. H., Srivastava, M. C., Tompkins, C. V., Nabarro, J. D N. ibid. 1972, ii, 155. 7. Soler, N. G., Bennett, M. A., Dixon, K., FitzGerald, M. G., Malins, J. M ibid. 1972, ii, 665. 8. Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Diabetes,
4.
1974, 23, 610. 9. 10. 11.
Root, H. F. J. Am. med. Ass. 1945, 127, 557. Black, A. B., Malins, J. M. Lancet, 1949, i, 56. Walker, B. G., Phear, D. N., Martin, F. I. R., Baird, C. W. ibid. 1963,
remission exceeds 3 years. A similar drug regimen in which the vincristine is replaced by vinblastine (M.V.p.p.)4 gives results equivalent to those obtained with M.o.p.p., and the only combination so far tried that may prove superior is M.o.p.p. with the addition of bleomycin.s Though some patients treated initially with M.O.P.p. remain in C.R. for many years the majority sooner or later show evidence of recurrent disease. A proportion of these patients respond again to the same combination but most eventually become resistant to M.O.p.P., and an alternative chemotherapeutic regimen is then required. We report the preliminary results of treating thirtynine patients with advanced Hodgkin’s disease with the combination c.c.N.u. (1-[2-chloroethyl]-3-cyclohexyl1-nitrosourea), vinblastine, and bleomycin (c.v.B.). All the patients were partially or totally resistant to M.o.p.p. or M.v.p.p. We believe the results in this series justify the more widespread use of C.V.B. in the treatment of patients with advanced resistant H.D.
Patients and Methods
ii,
964. 12. Beigelman, P. M. Diabetes, 1971, 20, 490. 13. Porte, D. Archs intern. Med. 1969, 123, 252. 14. Beigelman, P. M. Am. J. Med. 1973, 54, 419. 15. Page, M. McB., Alberti, K. G. M. M., Greenwood, R., Gumaa, K. A., Hockaday, T. D. R., Lowy, C., Nabarro, J. D. N., Pyke, D. A., Sönksen, P. H., Watkins, P. J., West, T. E. T. Br. med. J. 1974, ii, 687. 16. Posner, J. B., Plum, F. New Engl. J. Med. 1967, 277, 605. 17. DeFronzo, R. A., Cooke, C. R., Andres, R., Faloona, G. R., Davis, P. J. J clin. Invest. 1975, 55, 845.
COMBINATION THERAPY FOR ADVANCED RESISTANT HODGKIN’S DISEASE
J. M. GOLDMAN M. R. C. Leukæmia
Unit, Hammersmith Hospital, London W12
AUDREY A. DAWSON University Department of Pathology, Foresterhill, Aberdeen
Thirty-nine patients with advanced Hodgkin’s disease (H.D.) resistant to standard combinations of cytotoxic drugs were treated with C.C.N.U., vinblastine and bleomycin (C.V.B.). Ten patients (25%) achieved complete remission (C.R.) and
Summary
of these are still in C.R. at the time of this report. A further 23 patients (59%) achieved partial remissions. The overall response-rate was thus 85%. C.C.N.U. caused less nausea and vomiting than that usually associated with nitrogen mustard. C.C.N.U. and vinblastine caused myelosuppression, but C.V.B. could be administered every 4 weeks to 21 (54%) of the 39 patients. A combination of cytotoxic drugs such as C.V.B. may be preferable to single agents in the treatment of patients with advanced resistant H.D. seven
Patients From
June, 1973, until June, 1975, patients
at
partkupat-
ing hospitals England and Scotland were entered in the c.v.B. pilot study if their disease was considered resistant to a previous cytotoxic drug combination. Of forty-four patients entered in the study five were excluded because they received potentially effective cytotoxic drugs in addition to c.v.B. Details of the thirty-nine patients whose responses could be evaluated are given in table i. The diagnosis of H.D. was estab. lished by biopsy at the time of presentation in each patient, and histological classification was based on the criteria of Lukes and Butler.6 The clinical staging of patients followed the principles originally established at Rye,’ and the Ann Arbor modifications8 were adopted in 1972. Twenty-four of the thirty-nine evaluable patients had originally been entered in a study of the British National Lymphoma Investigation and had been randomised for treatment according to clinical stage and histological type (table n). The extent of further staging procedures in those patients who relapsed after radiotherapy as primary treatment differed somewhat among different clinicians, but all patients in this study were eventually deemed to have progressed to stage ma or tv disease and were therefore eligible for M.o.p.p. or M.v.p.p. Details of the initial chemotherapy and the clinical responses are given in table m. Patients became eligible for C.V.B. if (1) they failed to respond to M.O.p.P. or M.V.p.P., (2) their disease responded but then progressed despite continuing treatment, or (3) their disease responded but recurred shortly after an adequate course of M.o.p.p. or M.v.p.p. Complete remission of disease was defined as absence of all symptoms and physical signs attributable to H.D. with a peripheral blood count which was normal or showed only the effects of cytotoxic drugs. Persisting abnormal radiographic findings excluded a patient from the category c.R. The criteria of partial remission (P.R.) were a clear-cut improvement in "B" symptoms’or measurable reduction in tumour size (or both) that lasted for at least a month. Patients who achieved c.R. or P.R. were judged to have responded to chemotherapy. in
C.V.B.
Introduction THE introduction of combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone (M.o.p.p.) was a major breakthrough in the treatment of advanced Hodgkin’s disease (H,D,),l3 70-80% of patients with previously untreated H.D. enter complete remission (C.R.) during treatment with this com-
bination and the median duration of unmaintained
Regimen is a highly lipid-soluble nitrosourea compound with broad anti-tumour activity. It is known to inhibit the replication of D.N.A. and may act in part by alkylation.9 It was given by mouth in a dose of 100 mg/m2. Nausea and vomiting may C.C.N.U.
within a few hours of administration and may be folby anorexia lasting 2-3 days. The most important sideis myelosuppression, which is characteristically delayed-the nadirs of the platelet and leucocyte counts occur after about 30 and 42 days respectively.
occur
lowed effect
1225 TABLE
1-DETA1LS OF PATIENTS AND RESPONSE TO TREATMENT WITH C.V.B.
vinblastine also. When sufficient experience had accumulated recommendations for dose reductions were related to specific leucocyte and platelet counts (table v). Bleomycin was never reduced or omitted for hmmatological reasons. A total bleomycin dose of 180 mg (equivalent to treatment for 6 months) was not, however, exceeded. Maintenance No specific recommendations were made for the treatment of those patients who achieved complete remission with c.v.B. Most clinicians chose to continue C.V.B. at monthly intervals to a total of six cycles and to continue c.v. (without bleomycin) thereafter.
Results N.R.
no
Response to C. V.B.
response.
TABLE II--ORIGINAL HISTOLOGY AND STAGE RELATED TO
SUBSEQUENT
RESPONSE TO C.V.B.
)..)’.
= lymphocytic predominance.
N.
=
nodular sclerosis.
M.c.
=
I.. D. =
mixed
cellularity.
lymphocytic depletion.
is the generic name for a group of polypeptides isolated from a strain of Streptomyces verticillus obtained originally from a sample of soil collected in a Japanese coalmine.lO It appears to act by splitting single-stranded D.N.A. and so preventing R.N.A. and protein synthesis. The principal sideeffects are fever and chills starting within 6 hours of administration of the drug and a variety of rashes which can proceed to ulceration of the skin and mucosae. The most serious toxic effect is progressive pulmonary fibrosis which may prove fatal. This complication is seen particularly in elderly patients but is dose-related and rarely occurs when the total dose is less than 300 mg. Bleomycin produces little or no myelosuppression. Vinblastine has been used to treat H.D. since 1961 and is one of the most effective single agents for the disease." It was included in the C.V.B. combination because patients resistant to vincristine may still respond to vinblastine. In patients whose primary chemotherapy was M.v.p.p. rather than M.O.P.P. the vinblastine in C.V.B. was occasionally replaced by vincristine (14 mg/m2) (see table VI). The c.v.B. regimen is shown schematically in table IV. Courses of C.V.B were repeated with a new course beginning every 28 days. The aim was to give a total of not less than six consecutive courses but clinicians were free to stop c.v.B. if the disease was progressing despite treatment or if a patient
Bleomycin
appeared unlikely to achieve c.R. Dose Modifications In the early part of the study definite haematological limits were not specified. In the presence of persisting leucopenia or thrombocytopenia clinicians had the option of either (1) delay ing the administration of the next course for 1 or 2 weeks, or (2) giving the course on schedule with a reduced dose of c.c.N.u. In some patients C.C.N.U. was given in full dosage for and omitted from the next and from each alternate thereafter. Severe marrow depression attributable to chemotherapy was an indication for reducing or omitting the one course
course
When one compares those patients who achieved c.R. with C.V.B. with those who achieved only P.R. or who did not respond, there are no important differences with respect to age, histological type, or stage at diagnosis (tablesand n). Similarly the duration of disease before treatment with C.V.B. was not related to the likelihood of achieving c.R. All but one of the patients treated with c.v.B. had responded to a previous cytotoxic drug combination (table III) and 22 (56%) had achieved c.R. The majority of patients who achieved c.R. with c.v.B. had also achieved C.R. with a previous drug combination. It was, however, notable that two of the ten patients who achieved C.R. with C.V.B. had only responded partially to an earlier combination (cases 3 and 5, table V!). Patients who achieved complete remission with c.v.B did so rapidly (table vi). The mean number of courses necessary to achieve c.R. was two, and no patient who had not achieved c.R. after four courses did so subseTABLE !i1-DETAILS OF PREVIOUS TREATMENT RELATED TO SUBSEQUENT RESPONSE TO C.V.B.
fit
C.C.T.
R.T.
=
=
I
combination chemotherapy (M.O.P.P. or M.v.p.p.).
radiotherapy. TABLE IV—C.V.B. REGIMEN
Bleomycin dosage was not related to body-surface area.
ft.v.
=
intravenous.
).M.
=
intramascular.
TABLE V-MODIFICATIONS OF THE C.V.B. REGIMEN
1226 TABLE VI-DETAILS Of PATIENTS WHO ACHIEVED COMPLETE REMISSION DURING TREATMENT WITH C.V.B.
*N.S. = nodular sclerosis. M.C. mixed cellularity. L.D. lymphocytic depletion. tB’.1, 13. vmblastine. P.C.Z.procarbazine. M.O. -= mustine, vincristine, prednisone, procarbazine. M. V.P.P.= mustine, $One patient previously treated with M.v.r.p. received vmcristine instead of V.L.B. in c.v.B. §Patients still in C.R. at time of analysis (Oct. 1, 1975). =
=
=
quently. In three patients complete remission lasted 5, 8, and 32 weeks but c.R. continues in 7 patients. The median duration of c.R. has
not
yet been reached.
Toxicity Administration of C.C.N.U. was frequently followed by and vomiting. Twenty-six (67%) of the thirtynine patients vomited within 24 hours but vomiting was generally less severe than that experienced after nitrogen mustard. No patient refused to continue treatment on account of vomiting. Myelosuppression attributable to C.C.N.u. and vinblastine was variable, and in some patients no depression of leucocyte or platelet numbers was seen throughout treatment. Seventeen (44%) of the thirty-nine evaluable patients tolerated c.c.N.u. in full dosage every 4 weeks. C.C.N.U. was given every 4 weeks to four (10%) other patients but the dose was reduced because of leucopenia or thrombocytopenia on one or more occasions. In nine (23%) patients courses ofc.v.B. had regularly to be delayed so that they eventually received c.v.B. at 5 or 6 week intervals. In the remaining nine (23%) patients c.c.N.u. was given every 8 weeks or, in some cases, rather erratically. No patients in this last group achieved c.R. No evidence of pulmonary toxicity due to bleomycin was observed. Of the six patients who showed no response to c.v.B. three died within 12 weeks of starting therapy. In two death was clearly due to progressive H.D., while the third patient died of a massive haematemesis within 3 weeks of his first course of drugs. The hsematemesis was associated with severe thrombocytopenia to which the use of cytotoxic drugs may have contributed. nausea
TABLE VII—TREATMENT OF
RESISTANT HODGKIN’S
DISEASE WITH SINGLE
AGENTS
vmblastine, prednisone, procarbazine.
Discussion
variety of drugs is available for the treatment of patients with H.D. who have become refractory to M.O.P.P. or equivalent combinations. Of the so-called second-line drugs, only C.C.N.U. gives a high incidence of response when used as a single agent, and with all the drugs complete remissions are rare (table vn). It is logical therefore to use a combination of drugs to which the patient’s disease is not likely to have become resistant. The M.A.B.O.P., 18 A.B.V.D.,22 and c.v.B. regimens have been designed to meet this need (table vm). In this series thirty-three (85%) of thirty-nine patients responded to c.v.B. and ten (26%) achieved c.R. Seven of these ten patients are still in c.R., so the median duration of c.R. has not yet been reached. The majority of patients treated with c.v.B. experienced nausea and vomiting after the administration of C.C.N.U. but these wide-effects were acceptable. Though C.C.N.U. can cause significant depression of bone-marrow most patients tolA
TABLE VIII-TREATMENT OF RESISTANT
HODGKIN’S
DISFASE WITH
MULTIPLE AGENTS
’M.A.B.O.P.-mustme, adriamycm, bleomycin, vincristine, predmsone.
*A.B.V.D.=adriamycin, bleomycin, vinblastine, imidazole carboxamide (D.T.I.C.).
erated c.c.N.u. administered every month during remission induction and during maintenance of c.R. Febrile reactions due to bleomycin occurred but never led to withdrawal of the drug. No pulmonary toxicity due to
bleomycin was seen. The c.v.B combination appears to be safe and may be considered as a possible alternative to A.B.V.D. or M.A.B.O.P. in the treatment of advanced resistant H.D. It could also be suitable for use as "consolidation" for those who have achieved c.R. after treatment with six or more courses ofM.o.p.p.
Patients included in response categories that were not accurately defined in the reports t An additional 16 patients in this senes were classified as "poor partial remission". t An additional 6 patients in this series were classified as "partial failures".
*
original
Patients included in this pilot study were treated at the following hospitals: Aberdeen Royal Infirmary, Dr A. A. Dawson; Addenbrooke’s Hospital, Cambridge, Dr J. K. Rees; Cookridge Hospital, Leeds, Dr L. A. Firth, Sr J. Stone, Dr T. S. Worthy; District Hospital, Margate, Dr H. Sterndale; Hammersmith Hospital, London, Dr J. M. Goldman, Dr L. Szur; Liverpool Royal Infirmary, Dr J. Bradley; Middlesex Hospital, London, Dr A. M. Jelliffe; Mount Vernon Hospi-
tal, Northwood, Dr A.
M.
Jelliffe, Dr P. Strickland; Norfolk and Nor-
1227 wich Hospital, Dr A. J. Black; Plymouth General Hospital, Dr M. L. Fenner; Royal Devon and Exeter Hospital, Dr C. R. H. Penn; Royal Sussex County Hospital, Brighton, Dr G. P. Deutsch; Wessex Radiotherapy Centre, Dr T. T. Rutkowska. We are grateful to Dr Stephen K. Carter and his associates at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A., who supplied the C.C.N.U. used in this study; and to the many clinicians who supplied details of the patients treated under their care.
In programme-treated patients, standard medication
was
used; diuretics effectively lowered blood-pressure in a third of patients, and diuretics plus reserpine were effective for another 20%. Special features of the programme included assisance to physicians by health counsellor therapists. Methods for achieving a high adherence-rate and satisfactory blood-pressure control probably have wider applicability.
REFERENCES
Introduction
1. DeVita, V. T., Serpick, A. A., Carbone, P. P. Ann. intern. Med 1970, 73, 881. 2. Frei, E., Luce, J. K., Gamble, J. F., Coltman, C. A., Constanzi, J. J., Talley, R. W., Monto, R. W., Wilson, H. E., Hewlett, J. S., Delaney, F. C., Gehan, E. A. ibid. 1973, 79, 376. 3. British National Lymphoma Investigation. Br. med. J. 1975, iii, 413. 4. Nicholson, W. M., Beard, M. E. J., Crowther, D., Stansfeld, A. G., Vartan, C. P., Malpas, J. S., Hamilton Fairley, G., Scott, R. B. ibid. 1970, iii, 7. 5. Coltman, C. A., Delaney, F. C. Abstract for A.F.C.R., 1975. 6. Lukes, R. J., Craver, L. F., Hall, T. C., Rappaport, H., Ruben, P. Cancer Res. 1966, 26, 1311. 7. Rosenberg, S. A. ibid. 1310. 8. Carbone, P. P., Kaplan, H. S., Musshoff, K., Smithers, D. W., Tubiana, M. ibid. 1971, 31, 1860. 9. Wheeler, G. P., Chumley, S. J. med. Chem. 1967, 10, 259. 10. Yagoda, A., Mukherji, B., Young, C., Etcubanas, E., Lamonte, C., Smith, J. R., Tan, C. T. C., Krakoff, I. H. Ann. intern. Med. 1972, 77, 861. 11. Goldsmith, M. A., Carter, S. K. Cancer, 1974, 33, 1. 12. Lessner, H. E. ibid. 1968, 22, 451. 13. Young, R. C., DeVita, V. T., Serpick, A. A., Canellos, G P. New Engl. J. Med. 1971, 285, 475. 14. Selawry, O. S., Hansen, H. H. Proc. Am. Ass. Cancer Res. 1972, 13, 46. 15. E.O.R.T.C. Br. med. J. 1972, i, 285. 16. Halnan, K. E., Bleehen, N. M., Brewin, T. B., Deeley, T. J., Harrison, D. F. N., Howland, C., Kunkler, P. B., Ritchie, G. L., Wiltshaw, E., Todd, I. D. H. ibid. 1972, iv, 635. 17. Rudders, R. Blood, 1972, 40, 317. 18. Bonadonna, G., De Lena, M., Monfardini, S., Beretta, G., Valagussa, P. in E.O.R.T.C. International Symposium: Adriamycin Review; p. 200. Ghent, Belgium, 1975. 19. E.O.R.T.C. Br. med. J. 1972, ii, 744. 20. E.O.R.T.C. ibid. 1972, iii, 199. 21. Mathé, G., Schwarzenberg, L., Pouillart, P., Oldham, R., Weiner, R., Jas-
min, C., Rosenfeld, C., Hayat, M., Misset, J. L., Musset, M., Schneider, M., Amiel, J. L., DeVassal, F. Cancer, 1974, 34, 985. 22. Bonadonna, G., Uslenghi, C., Zucali, R. Eur. J. Cancer, 1975, 11, 251.
WILL symptom-free but hypertensive people persist with treatment long term, despite problems such as possible side-effects, time, and cost? And will the blood-pressure of most of those treated with standard drugs return to normal and stay that way? These questions gain in importance as more previously unknown hypertensives are detected and as doctors and the public increasingly realise the value of treatment to lower the blood-pressure of those with marked or even moderate hypertension (average diastolic 105mm Hg or greater).’-3 Patient response-both in adherence and in physiological response to medication-is now under investigation in the largest U.S. study to date of hypertension in the community. One of the fourteen centres for this study (the Hypertension Detection and Follow-up Program, H.D.F.P.) is in Chicago, with patients drawn from employed populations of men and women aged 30-69. In the first, preliminary, year of work a pilot phase was launched to get experience in treatment procedures and the use of paramedical personnel. Patients recruited in Chicago in this pilot phase are expected to continue for at least 5 years, and have already completed 2-3 years. We describe here our experience of patient adherence and blood-pressure control in the first 2 years of the pilot phase in Chicago.
Population and Methods ADHERENCE AND BLOOD-PRESSURE RESPONSE TO HYPERTENSION TREATMENT ROSE STAMLER JEREMIAH STAMLER JEAN CIVINELLI DIANA PRITCHARD Northwestern
FLORA C. GOSCH SARAH TICHO BEVERLY RESTIVO DORIS FINE
University Medical School, Chicago, Illinois 60611, U.S.A.
Characteristics
of Participants The participants had been identified as hypertensive (i.e., diastolic 90 mm Hg) by the Chicago Heart Association Detection Project in Industry.4 181 were enrolled in the pilot phase, after verification of blood-pressure elevation at a second screen. A random third of these (65 people) were referredfor treatment to their own doctors, to be seen annually by H.D.F.P. for comparison with those treated directly by H.D.F.P. The long-term special treatment programme thus began with 116 hypertensives as the group whose adherence and blood-pressure response would be assessed. Their average age
2 years of experience in the first phase of a large cooperative national hypertension programme yielded data indicating that a good level of patient adherence can be achieved and that satisfactory blood-pressure control can be maintained long term. For 116 participants, all employed persons, dropout in the first year was 20% but only 3% dropped out in the second year. At the second annual examination, 82% of those still in the programme had diastolic pressures under 90 mm Hg, with an average reduction of 18 mm Hg. Thus, nearly two-thirds (64%) of all patients originally enrolled were both active and with normal levels of blood-pressure after two years. Only 18% of active programme-treated patients had diastolic pressure 90 mm Hg or higher at the second anniversary in contrast with 33% of patients referred to their own doctors.
Summary
at
entry
was
48-3 years. Two-thirds
are
male, and most of them (87 1%) are White (table 1). As expected of an employed, middle-aged, predominantly White group, the
severity of hypertension
at
entry
was not
great.
TABLE I-ENTRY CHARACTERISTICS OF ALL 116 PROGRAMME-TREATED PARTICIPANTS
regimen recommended by Albertis
is the
simplest
to
operate. We thank all the medical, nursing, and biochemical staffwho helped with this work. This study was made possible by a grant from the Bntish Diabetic Association.
Requests for reprints should be addressed to N. G. S. REFERENCES
Alberti, K. G. M. M. in Advanced Medicine Symposium 1974; p. 68. London, 1974. 2. Assal, J. Ph., Aoki, T. T., Manzano, F. M., Kozak, G. P. Diabetes, 1974. 23, 405. 3. Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Postgrad 1.
med. J.
1974, 50, 465.
Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Lancet, 1973. i, 951. 5. Alberti, K. G. M. M., Hockaday, T. D. R., Turner, R. C. ibid. 1973, ii, 515 6. Sönksen, P. H., Srivastava, M. C., Tompkins, C. V., Nabarro, J. D N. ibid. 1972, ii, 155. 7. Soler, N. G., Bennett, M. A., Dixon, K., FitzGerald, M. G., Malins, J. M ibid. 1972, ii, 665. 8. Soler, N. G., Bennett, M. A., FitzGerald, M. G., Malins, J. M. Diabetes,
4.
1974, 23, 610. 9. 10. 11.
Root, H. F. J. Am. med. Ass. 1945, 127, 557. Black, A. B., Malins, J. M. Lancet, 1949, i, 56. Walker, B. G., Phear, D. N., Martin, F. I. R., Baird, C. W. ibid. 1963,
remission exceeds 3 years. A similar drug regimen in which the vincristine is replaced by vinblastine (M.V.p.p.)4 gives results equivalent to those obtained with M.o.p.p., and the only combination so far tried that may prove superior is M.o.p.p. with the addition of bleomycin.s Though some patients treated initially with M.O.P.p. remain in C.R. for many years the majority sooner or later show evidence of recurrent disease. A proportion of these patients respond again to the same combination but most eventually become resistant to M.O.p.P., and an alternative chemotherapeutic regimen is then required. We report the preliminary results of treating thirtynine patients with advanced Hodgkin’s disease with the combination c.c.N.u. (1-[2-chloroethyl]-3-cyclohexyl1-nitrosourea), vinblastine, and bleomycin (c.v.B.). All the patients were partially or totally resistant to M.o.p.p. or M.v.p.p. We believe the results in this series justify the more widespread use of C.V.B. in the treatment of patients with advanced resistant H.D.
Patients and Methods
ii,
964. 12. Beigelman, P. M. Diabetes, 1971, 20, 490. 13. Porte, D. Archs intern. Med. 1969, 123, 252. 14. Beigelman, P. M. Am. J. Med. 1973, 54, 419. 15. Page, M. McB., Alberti, K. G. M. M., Greenwood, R., Gumaa, K. A., Hockaday, T. D. R., Lowy, C., Nabarro, J. D. N., Pyke, D. A., Sönksen, P. H., Watkins, P. J., West, T. E. T. Br. med. J. 1974, ii, 687. 16. Posner, J. B., Plum, F. New Engl. J. Med. 1967, 277, 605. 17. DeFronzo, R. A., Cooke, C. R., Andres, R., Faloona, G. R., Davis, P. J. J clin. Invest. 1975, 55, 845.
COMBINATION THERAPY FOR ADVANCED RESISTANT HODGKIN’S DISEASE
J. M. GOLDMAN M. R. C. Leukæmia
Unit, Hammersmith Hospital, London W12
AUDREY A. DAWSON University Department of Pathology, Foresterhill, Aberdeen
Thirty-nine patients with advanced Hodgkin’s disease (H.D.) resistant to standard combinations of cytotoxic drugs were treated with C.C.N.U., vinblastine and bleomycin (C.V.B.). Ten patients (25%) achieved complete remission (C.R.) and
Summary
of these are still in C.R. at the time of this report. A further 23 patients (59%) achieved partial remissions. The overall response-rate was thus 85%. C.C.N.U. caused less nausea and vomiting than that usually associated with nitrogen mustard. C.C.N.U. and vinblastine caused myelosuppression, but C.V.B. could be administered every 4 weeks to 21 (54%) of the 39 patients. A combination of cytotoxic drugs such as C.V.B. may be preferable to single agents in the treatment of patients with advanced resistant H.D. seven
Patients From
June, 1973, until June, 1975, patients
at
partkupat-
ing hospitals England and Scotland were entered in the c.v.B. pilot study if their disease was considered resistant to a previous cytotoxic drug combination. Of forty-four patients entered in the study five were excluded because they received potentially effective cytotoxic drugs in addition to c.v.B. Details of the thirty-nine patients whose responses could be evaluated are given in table i. The diagnosis of H.D. was estab. lished by biopsy at the time of presentation in each patient, and histological classification was based on the criteria of Lukes and Butler.6 The clinical staging of patients followed the principles originally established at Rye,’ and the Ann Arbor modifications8 were adopted in 1972. Twenty-four of the thirty-nine evaluable patients had originally been entered in a study of the British National Lymphoma Investigation and had been randomised for treatment according to clinical stage and histological type (table n). The extent of further staging procedures in those patients who relapsed after radiotherapy as primary treatment differed somewhat among different clinicians, but all patients in this study were eventually deemed to have progressed to stage ma or tv disease and were therefore eligible for M.o.p.p. or M.v.p.p. Details of the initial chemotherapy and the clinical responses are given in table m. Patients became eligible for C.V.B. if (1) they failed to respond to M.O.p.P. or M.V.p.P., (2) their disease responded but then progressed despite continuing treatment, or (3) their disease responded but recurred shortly after an adequate course of M.o.p.p. or M.v.p.p. Complete remission of disease was defined as absence of all symptoms and physical signs attributable to H.D. with a peripheral blood count which was normal or showed only the effects of cytotoxic drugs. Persisting abnormal radiographic findings excluded a patient from the category c.R. The criteria of partial remission (P.R.) were a clear-cut improvement in "B" symptoms’or measurable reduction in tumour size (or both) that lasted for at least a month. Patients who achieved c.R. or P.R. were judged to have responded to chemotherapy. in
C.V.B.
Introduction THE introduction of combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone (M.o.p.p.) was a major breakthrough in the treatment of advanced Hodgkin’s disease (H,D,),l3 70-80% of patients with previously untreated H.D. enter complete remission (C.R.) during treatment with this com-
bination and the median duration of unmaintained
Regimen is a highly lipid-soluble nitrosourea compound with broad anti-tumour activity. It is known to inhibit the replication of D.N.A. and may act in part by alkylation.9 It was given by mouth in a dose of 100 mg/m2. Nausea and vomiting may C.C.N.U.
within a few hours of administration and may be folby anorexia lasting 2-3 days. The most important sideis myelosuppression, which is characteristically delayed-the nadirs of the platelet and leucocyte counts occur after about 30 and 42 days respectively.
occur
lowed effect
1225 TABLE
1-DETA1LS OF PATIENTS AND RESPONSE TO TREATMENT WITH C.V.B.
vinblastine also. When sufficient experience had accumulated recommendations for dose reductions were related to specific leucocyte and platelet counts (table v). Bleomycin was never reduced or omitted for hmmatological reasons. A total bleomycin dose of 180 mg (equivalent to treatment for 6 months) was not, however, exceeded. Maintenance No specific recommendations were made for the treatment of those patients who achieved complete remission with c.v.B. Most clinicians chose to continue C.V.B. at monthly intervals to a total of six cycles and to continue c.v. (without bleomycin) thereafter.
Results N.R.
no
Response to C. V.B.
response.
TABLE II--ORIGINAL HISTOLOGY AND STAGE RELATED TO
SUBSEQUENT
RESPONSE TO C.V.B.
)..)’.
= lymphocytic predominance.
N.
=
nodular sclerosis.
M.c.
=
I.. D. =
mixed
cellularity.
lymphocytic depletion.
is the generic name for a group of polypeptides isolated from a strain of Streptomyces verticillus obtained originally from a sample of soil collected in a Japanese coalmine.lO It appears to act by splitting single-stranded D.N.A. and so preventing R.N.A. and protein synthesis. The principal sideeffects are fever and chills starting within 6 hours of administration of the drug and a variety of rashes which can proceed to ulceration of the skin and mucosae. The most serious toxic effect is progressive pulmonary fibrosis which may prove fatal. This complication is seen particularly in elderly patients but is dose-related and rarely occurs when the total dose is less than 300 mg. Bleomycin produces little or no myelosuppression. Vinblastine has been used to treat H.D. since 1961 and is one of the most effective single agents for the disease." It was included in the C.V.B. combination because patients resistant to vincristine may still respond to vinblastine. In patients whose primary chemotherapy was M.v.p.p. rather than M.O.P.P. the vinblastine in C.V.B. was occasionally replaced by vincristine (14 mg/m2) (see table VI). The c.v.B. regimen is shown schematically in table IV. Courses of C.V.B were repeated with a new course beginning every 28 days. The aim was to give a total of not less than six consecutive courses but clinicians were free to stop c.v.B. if the disease was progressing despite treatment or if a patient
Bleomycin
appeared unlikely to achieve c.R. Dose Modifications In the early part of the study definite haematological limits were not specified. In the presence of persisting leucopenia or thrombocytopenia clinicians had the option of either (1) delay ing the administration of the next course for 1 or 2 weeks, or (2) giving the course on schedule with a reduced dose of c.c.N.u. In some patients C.C.N.U. was given in full dosage for and omitted from the next and from each alternate thereafter. Severe marrow depression attributable to chemotherapy was an indication for reducing or omitting the one course
course
When one compares those patients who achieved c.R. with C.V.B. with those who achieved only P.R. or who did not respond, there are no important differences with respect to age, histological type, or stage at diagnosis (tablesand n). Similarly the duration of disease before treatment with C.V.B. was not related to the likelihood of achieving c.R. All but one of the patients treated with c.v.B. had responded to a previous cytotoxic drug combination (table III) and 22 (56%) had achieved c.R. The majority of patients who achieved c.R. with c.v.B. had also achieved C.R. with a previous drug combination. It was, however, notable that two of the ten patients who achieved C.R. with C.V.B. had only responded partially to an earlier combination (cases 3 and 5, table V!). Patients who achieved complete remission with c.v.B did so rapidly (table vi). The mean number of courses necessary to achieve c.R. was two, and no patient who had not achieved c.R. after four courses did so subseTABLE !i1-DETAILS OF PREVIOUS TREATMENT RELATED TO SUBSEQUENT RESPONSE TO C.V.B.
fit
C.C.T.
R.T.
=
=
I
combination chemotherapy (M.O.P.P. or M.v.p.p.).
radiotherapy. TABLE IV—C.V.B. REGIMEN
Bleomycin dosage was not related to body-surface area.
ft.v.
=
intravenous.
).M.
=
intramascular.
TABLE V-MODIFICATIONS OF THE C.V.B. REGIMEN
1226 TABLE VI-DETAILS Of PATIENTS WHO ACHIEVED COMPLETE REMISSION DURING TREATMENT WITH C.V.B.
*N.S. = nodular sclerosis. M.C. mixed cellularity. L.D. lymphocytic depletion. tB’.1, 13. vmblastine. P.C.Z.procarbazine. M.O. -= mustine, vincristine, prednisone, procarbazine. M. V.P.P.= mustine, $One patient previously treated with M.v.r.p. received vmcristine instead of V.L.B. in c.v.B. §Patients still in C.R. at time of analysis (Oct. 1, 1975). =
=
=
quently. In three patients complete remission lasted 5, 8, and 32 weeks but c.R. continues in 7 patients. The median duration of c.R. has
not
yet been reached.
Toxicity Administration of C.C.N.U. was frequently followed by and vomiting. Twenty-six (67%) of the thirtynine patients vomited within 24 hours but vomiting was generally less severe than that experienced after nitrogen mustard. No patient refused to continue treatment on account of vomiting. Myelosuppression attributable to C.C.N.u. and vinblastine was variable, and in some patients no depression of leucocyte or platelet numbers was seen throughout treatment. Seventeen (44%) of the thirty-nine evaluable patients tolerated c.c.N.u. in full dosage every 4 weeks. C.C.N.U. was given every 4 weeks to four (10%) other patients but the dose was reduced because of leucopenia or thrombocytopenia on one or more occasions. In nine (23%) patients courses ofc.v.B. had regularly to be delayed so that they eventually received c.v.B. at 5 or 6 week intervals. In the remaining nine (23%) patients c.c.N.u. was given every 8 weeks or, in some cases, rather erratically. No patients in this last group achieved c.R. No evidence of pulmonary toxicity due to bleomycin was observed. Of the six patients who showed no response to c.v.B. three died within 12 weeks of starting therapy. In two death was clearly due to progressive H.D., while the third patient died of a massive haematemesis within 3 weeks of his first course of drugs. The hsematemesis was associated with severe thrombocytopenia to which the use of cytotoxic drugs may have contributed. nausea
TABLE VII—TREATMENT OF
RESISTANT HODGKIN’S
DISEASE WITH SINGLE
AGENTS
vmblastine, prednisone, procarbazine.
Discussion
variety of drugs is available for the treatment of patients with H.D. who have become refractory to M.O.P.P. or equivalent combinations. Of the so-called second-line drugs, only C.C.N.U. gives a high incidence of response when used as a single agent, and with all the drugs complete remissions are rare (table vn). It is logical therefore to use a combination of drugs to which the patient’s disease is not likely to have become resistant. The M.A.B.O.P., 18 A.B.V.D.,22 and c.v.B. regimens have been designed to meet this need (table vm). In this series thirty-three (85%) of thirty-nine patients responded to c.v.B. and ten (26%) achieved c.R. Seven of these ten patients are still in c.R., so the median duration of c.R. has not yet been reached. The majority of patients treated with c.v.B. experienced nausea and vomiting after the administration of C.C.N.U. but these wide-effects were acceptable. Though C.C.N.U. can cause significant depression of bone-marrow most patients tolA
TABLE VIII-TREATMENT OF RESISTANT
HODGKIN’S
DISFASE WITH
MULTIPLE AGENTS
’M.A.B.O.P.-mustme, adriamycm, bleomycin, vincristine, predmsone.
*A.B.V.D.=adriamycin, bleomycin, vinblastine, imidazole carboxamide (D.T.I.C.).
erated c.c.N.u. administered every month during remission induction and during maintenance of c.R. Febrile reactions due to bleomycin occurred but never led to withdrawal of the drug. No pulmonary toxicity due to
bleomycin was seen. The c.v.B combination appears to be safe and may be considered as a possible alternative to A.B.V.D. or M.A.B.O.P. in the treatment of advanced resistant H.D. It could also be suitable for use as "consolidation" for those who have achieved c.R. after treatment with six or more courses ofM.o.p.p.
Patients included in response categories that were not accurately defined in the reports t An additional 16 patients in this senes were classified as "poor partial remission". t An additional 6 patients in this series were classified as "partial failures".
*
original
Patients included in this pilot study were treated at the following hospitals: Aberdeen Royal Infirmary, Dr A. A. Dawson; Addenbrooke’s Hospital, Cambridge, Dr J. K. Rees; Cookridge Hospital, Leeds, Dr L. A. Firth, Sr J. Stone, Dr T. S. Worthy; District Hospital, Margate, Dr H. Sterndale; Hammersmith Hospital, London, Dr J. M. Goldman, Dr L. Szur; Liverpool Royal Infirmary, Dr J. Bradley; Middlesex Hospital, London, Dr A. M. Jelliffe; Mount Vernon Hospi-
tal, Northwood, Dr A.
M.
Jelliffe, Dr P. Strickland; Norfolk and Nor-
1227 wich Hospital, Dr A. J. Black; Plymouth General Hospital, Dr M. L. Fenner; Royal Devon and Exeter Hospital, Dr C. R. H. Penn; Royal Sussex County Hospital, Brighton, Dr G. P. Deutsch; Wessex Radiotherapy Centre, Dr T. T. Rutkowska. We are grateful to Dr Stephen K. Carter and his associates at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A., who supplied the C.C.N.U. used in this study; and to the many clinicians who supplied details of the patients treated under their care.
In programme-treated patients, standard medication
was
used; diuretics effectively lowered blood-pressure in a third of patients, and diuretics plus reserpine were effective for another 20%. Special features of the programme included assisance to physicians by health counsellor therapists. Methods for achieving a high adherence-rate and satisfactory blood-pressure control probably have wider applicability.
REFERENCES
Introduction
1. DeVita, V. T., Serpick, A. A., Carbone, P. P. Ann. intern. Med 1970, 73, 881. 2. Frei, E., Luce, J. K., Gamble, J. F., Coltman, C. A., Constanzi, J. J., Talley, R. W., Monto, R. W., Wilson, H. E., Hewlett, J. S., Delaney, F. C., Gehan, E. A. ibid. 1973, 79, 376. 3. British National Lymphoma Investigation. Br. med. J. 1975, iii, 413. 4. Nicholson, W. M., Beard, M. E. J., Crowther, D., Stansfeld, A. G., Vartan, C. P., Malpas, J. S., Hamilton Fairley, G., Scott, R. B. ibid. 1970, iii, 7. 5. Coltman, C. A., Delaney, F. C. Abstract for A.F.C.R., 1975. 6. Lukes, R. J., Craver, L. F., Hall, T. C., Rappaport, H., Ruben, P. Cancer Res. 1966, 26, 1311. 7. Rosenberg, S. A. ibid. 1310. 8. Carbone, P. P., Kaplan, H. S., Musshoff, K., Smithers, D. W., Tubiana, M. ibid. 1971, 31, 1860. 9. Wheeler, G. P., Chumley, S. J. med. Chem. 1967, 10, 259. 10. Yagoda, A., Mukherji, B., Young, C., Etcubanas, E., Lamonte, C., Smith, J. R., Tan, C. T. C., Krakoff, I. H. Ann. intern. Med. 1972, 77, 861. 11. Goldsmith, M. A., Carter, S. K. Cancer, 1974, 33, 1. 12. Lessner, H. E. ibid. 1968, 22, 451. 13. Young, R. C., DeVita, V. T., Serpick, A. A., Canellos, G P. New Engl. J. Med. 1971, 285, 475. 14. Selawry, O. S., Hansen, H. H. Proc. Am. Ass. Cancer Res. 1972, 13, 46. 15. E.O.R.T.C. Br. med. J. 1972, i, 285. 16. Halnan, K. E., Bleehen, N. M., Brewin, T. B., Deeley, T. J., Harrison, D. F. N., Howland, C., Kunkler, P. B., Ritchie, G. L., Wiltshaw, E., Todd, I. D. H. ibid. 1972, iv, 635. 17. Rudders, R. Blood, 1972, 40, 317. 18. Bonadonna, G., De Lena, M., Monfardini, S., Beretta, G., Valagussa, P. in E.O.R.T.C. International Symposium: Adriamycin Review; p. 200. Ghent, Belgium, 1975. 19. E.O.R.T.C. Br. med. J. 1972, ii, 744. 20. E.O.R.T.C. ibid. 1972, iii, 199. 21. Mathé, G., Schwarzenberg, L., Pouillart, P., Oldham, R., Weiner, R., Jas-
min, C., Rosenfeld, C., Hayat, M., Misset, J. L., Musset, M., Schneider, M., Amiel, J. L., DeVassal, F. Cancer, 1974, 34, 985. 22. Bonadonna, G., Uslenghi, C., Zucali, R. Eur. J. Cancer, 1975, 11, 251.
WILL symptom-free but hypertensive people persist with treatment long term, despite problems such as possible side-effects, time, and cost? And will the blood-pressure of most of those treated with standard drugs return to normal and stay that way? These questions gain in importance as more previously unknown hypertensives are detected and as doctors and the public increasingly realise the value of treatment to lower the blood-pressure of those with marked or even moderate hypertension (average diastolic 105mm Hg or greater).’-3 Patient response-both in adherence and in physiological response to medication-is now under investigation in the largest U.S. study to date of hypertension in the community. One of the fourteen centres for this study (the Hypertension Detection and Follow-up Program, H.D.F.P.) is in Chicago, with patients drawn from employed populations of men and women aged 30-69. In the first, preliminary, year of work a pilot phase was launched to get experience in treatment procedures and the use of paramedical personnel. Patients recruited in Chicago in this pilot phase are expected to continue for at least 5 years, and have already completed 2-3 years. We describe here our experience of patient adherence and blood-pressure control in the first 2 years of the pilot phase in Chicago.
Population and Methods ADHERENCE AND BLOOD-PRESSURE RESPONSE TO HYPERTENSION TREATMENT ROSE STAMLER JEREMIAH STAMLER JEAN CIVINELLI DIANA PRITCHARD Northwestern
FLORA C. GOSCH SARAH TICHO BEVERLY RESTIVO DORIS FINE
University Medical School, Chicago, Illinois 60611, U.S.A.
Characteristics
of Participants The participants had been identified as hypertensive (i.e., diastolic 90 mm Hg) by the Chicago Heart Association Detection Project in Industry.4 181 were enrolled in the pilot phase, after verification of blood-pressure elevation at a second screen. A random third of these (65 people) were referredfor treatment to their own doctors, to be seen annually by H.D.F.P. for comparison with those treated directly by H.D.F.P. The long-term special treatment programme thus began with 116 hypertensives as the group whose adherence and blood-pressure response would be assessed. Their average age
2 years of experience in the first phase of a large cooperative national hypertension programme yielded data indicating that a good level of patient adherence can be achieved and that satisfactory blood-pressure control can be maintained long term. For 116 participants, all employed persons, dropout in the first year was 20% but only 3% dropped out in the second year. At the second annual examination, 82% of those still in the programme had diastolic pressures under 90 mm Hg, with an average reduction of 18 mm Hg. Thus, nearly two-thirds (64%) of all patients originally enrolled were both active and with normal levels of blood-pressure after two years. Only 18% of active programme-treated patients had diastolic pressure 90 mm Hg or higher at the second anniversary in contrast with 33% of patients referred to their own doctors.
Summary
at
entry
was
48-3 years. Two-thirds
are
male, and most of them (87 1%) are White (table 1). As expected of an employed, middle-aged, predominantly White group, the
severity of hypertension
at
entry
was not
great.
TABLE I-ENTRY CHARACTERISTICS OF ALL 116 PROGRAMME-TREATED PARTICIPANTS
