- Email: [email protected]
VERAPAMIL, LOW-SODIUM REGIMENS, AND BLOOD PRESSURE
1164
ADJUVANT CHEMOTHERAPY COMBINED WITH TAMOXIFEN IN POSTMENOPAUSAL PATIENTS WITH STAGE II BREAST CANCER
StR,—The ideal adjuvant treatment for postmenopausal stage II breast cancer has yet to be identified. Although tamoxifen delays the recurrence of disease in these patients,l;2 the benefit of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) found in premenopausal patients could not be reproduced in the postmenopausal group.3 Studies of combined chemotherapeutic and endocrine treatment have produced conflicting data.4,s In a prospective randomised controlled trial we have investigated the value of adjuvant CMF3 administered in six courses, tamoxifen (20 mg daily given over two years), or the simultaneous treatment with both in 84 postmenopausal patients with stage II disease. All patients had a modified radical mastectomy and were randomised to CMF (25 patients), tamoxifen (34), or CMF plus tamoxifen (25), adjuvant therapy beginning 2-4 weeks after surgery. Patients over ’ 70 years of age were not included in the trial. Toxicity from both endocrine treatment and chemotherapy did not exceed the usual spectrum. The mean observation period is 48 months so far. Oestrogen receptor (ER) levels were analysed by saturation analysis.6 The statistical analysis was done by the Wilcoxon and Mantel-Cox tests and by the actuarial life-table method. 31 of the 84 patients have had recurrent breast cancer. The duration of the relapse-free interval (RFI) in the three groups of patients modalities is shown in fig 1. 53% of patients treated with
Fig 2-Actuarial recurrence curves at 48 months. >
ER <10(- - - -), 11-30g( ( 100 fmol/mg (— — —). ).
and 31 - 100 g (------ ), and
I
groups, a significantly lower percentage of metastases was found in patients with ER levels between 30 and 100 fmol/mg (10%) and above 100 fmol/mg (18 %); respectively (p < 0-01). Our data suggest that the clinically significant borderline for the dissection of the ER status between positivity and negativity in postmenopausal women could be located at 30 fmol/mg, higher than previously assumed.
Departments of Medicine II, Gynaecology I, and Surgery II, University Hospital, A-1090 Vienna, Austria
C. C. ZIELINSKI E. KUBISTA H. SALZER P. SEVELDA M. LANGER A. STAFFEN J. SPONA P. AIGINGER
development conference statements: Adjuvant chemotherapy for breast Bethesda, Maryland: National Institute of Health, 1985 2. Cummings FJ, Gray R, Davis TE, et al. Adjuvant tamoxifen treatment of elderly women with stage II breast cancer. Ann Intern Med 1985; 103: 324-29 3. Bonadonna G, Rossi A, Valagussa P. Adjuvant chemotherapy in operable breast 1. Consensus cancer.
Fig 1—Actuarial recurrence curves at 48 months. adjuvant treatment with adjuvant CMF chemotherapy; combined adjuvant therapy with CMF plus tamoxifen; -
=
-------
-
-
-
cancer. Ten years later. Lancet 1985; i: 976-77. 4. Fisher B, Redmond C, Brown A, et al. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 1981; 305: 1-6 5. Krook JE, Ingle JM, Green SJ, et al. Randomized clinical trial of cyclophosphamide, 5-FU and prednisone with or without tamoxifen in postmenopausal women with advanced breast cancer. Cancer Treat Rep 1985; 69: 355-61. 6 Zielinski CC, Kuzmits R, Kubista E, et al. The importance of hormone receptors of breast cancer cells for the duration of the relapse-free interval. Wien Klin Wochenschr 1985; 97: 493-97.
=
=
tamoxifen.
VERAPAMIL, LOW-SODIUM REGIMENS, AND BLOOD PRESSURE
CMF and 36 % of the patients on tamoxifen alone had a recurrence but the recurrence rate in the group treated with CMF plus tamoxifen was only 16% (p 0-009 vs the other treatment groups). It can be concluded, therefore, that a combination of CMF with tamoxifen may be beneficial in postmenopausal patients with breast cancer and lymph node involvement. The duration of relapse-free survival depended heavily on ER concentration (fig 2): patients with ER concentrations below 30 fmol/mg had a significantly higher frequency of metastasis (36%) and thus a more severe disease course than did patients with ER concentrations above 30 fmol/mg (13%; p =- 0 001). The frequency of disease recurrence was the same (33 %) both in patients with ER levels between 10 and 30 fmol/mg and in patients with ER concentrations below 10 fmol/mg. In comparison with these two =
SIR,-A paradoxical rise in supine and erect diastolic blood (DBP) has been reported in clinical trials combining
pressure
low-salt diets with the calcium-channel blocking agents verapamil and nifedipine.1,2 These findings would suggest that this therapeutic combination should be avoided in routine clinical practice. Most doctors, however, record blood pressure with the patient in the sitting position and reduce the dose of any antihypertensive drug as the blood pressure (BP) falls to normal. Following this routine in the Canberra Blood Pressure Trial (an uncontrolled feasibility study for a trial in primary prevention 3) and in a Low Sodium Advisory Service based on that trial, we have not met any significant paradoxical effect attributable to verapamil. Patients avoided salted foods as completely as possible for 12 weeks, and compliance was evaluated by the potassium/sodium
1165 CHANGES IN MEDICATION, SYSTOLIC AND DIASTOLIC BLOOD PRESSURE (SBP, DBP), AND MEAN ARTERIAL PRESSURE (MAP)
y-glutamyltransferase (191 at entry, 209 on completion; normal laboratory range 5--60 units). In clinical practice the BP may fall for many reasons unrelated to the treatmenr,5 and our findings do not refute those of a controlled trial but, since we are not seeing adverse effects with verapamil, patients taking calcium channel blockers will continue to be accepted at the Low Sodium Advisory Service and carefully observed. We have no information on nifedipine. Low Sodium Advisory Service, Woden Valley Hospital, Woden, ACT 2606, Australia; and Central Statistical Unit, Commonwealth Department of Health, Canberra
1.
2.
TREVOR C. BEARD HELEN M. COOKE WENDY R. GRAY PETER WILD
Morgan T, Anderson A, Wilson D, Myers J, Murphy J, Nowson C. Paradoxical effect of sodium restriction on blood pressure in people on slow-channel calcium blocking drugs. Lancet 1986; i: 793. Kingswood JC, Thompson FD. Sodium, blood pressure, and calcium antagonists.
Lancet 1986; i. 1102. TC, Cooke HM, Gray WR, Ellem DP. Spontaneous remission and its significance for trials in primary prevention of hypertension. Ann Clin Res 1984; 16 (suppl 43): 132-35. 4. Rouse IL, Beilin IJ. Nutrition, blood pressure and hypertension: a critical review of dietary intervention studies in humans. Med J Aust 1983; ii (suppl): S19-S23. 5. Parr GD, Huitson A. Identification of elderly hypertensives Lancet 1986; ii: 809-10. 3. Beard
*Dinamap records MAP directly by an oscillometric technique, but for SBP, DBP and MAP in real time.
not
simultaneously
SEROLOGICAL DIAGNOSIS OF STAPHYLOCOCCAL BACTERAEMIA
(K/Na) ratio in the first morning urine sample (R. P. Mensink, T. C. Beard, D. P. Ellem, unpublished). We saw nine people whose BP had stabilised before entry with verapamil as sole therapy for mild essential hypertension, and whose morning urinary K/Na ratio on at least two of the last three trial visits was 10 or more (corresponding roughly with a 24 h sodium excretion below 70 mmol). The whole group had a mean weight loss of 1kg but three of the patients gained weight (mean 11I kg). Routine plasma biochemical studies were normal or almost normal for all except one, who had a raised urate, and another with a raised y-glutamyltransferase, who admitted to heavy drinking. Four finished the trial in a warmer month than at entry and five in a cooler month. The daily dose of verapamil at entry was 80-320 mg and medication was withdrawn incrementally when the mean arterial pressure (MAP) recorded by ’Dinamap’ was below 105 mm Hg (conventional equivalent 135/90 mm Hg) at two consecutive visits, and the total dosage of 1760 mg at entry was reduced by 48 % to 920 mg on completion. A paired t-test showed no significant difference between diastolic BP at the start and finish. Except for the patient who remained on 320 mg verapamil daily throughout, who had a diastolic BP rise of 1 mm Hg, the only rises in DBP occurred in three patients who had stopped medication or reduced the dose (figure). The patient taking 160 mg daily throughout had falls in MAP and diastolic BP of 18 mm and 10 mm Hg, respectively. This was the patient with the high
SIR,-As discussed in your editorial,l the combined use of three detecting antibody to teichoic acid, peptidoglycan, and alpha-toxin2 has been suggested to distinguish complicated from uncomplicated Staphylococcus aureus bacteraemia. Certainly, more than one serological test is needed for the diagnosis of complicated Staph aureus bacteraemia. However, to reach acceptable predictive values for positive as well as negative results the specificity for complicated bacteraemia must be close to 100%. This was not the 2 case in the report by Verbrugh et al. assays
I have used a combination of three different enzyme-linked immunosorbent assays (ELISA) measuring antibodies to Staph aureus lipase,’ peptidoglycan (PG),’ and crude staphylococcal antigen (SA).’ The criterion for a positive result was a positive antibody level or pronounced titre rise during the second week of infection in the anti-lipase ELISA and in either the anti-PG ELISA or the anti-SA ELISA or both.s The very high specificity of the anti-lipase ELISA2 for Staph aureus thus remains in this combination. Moreover, patients with complicated Staph aureus bacteraemia or endocarditis could be entirely separated from those with uncomplicated Staph aureus bacteraemia, those patients with bacteraemia caused by other microorganisms, and from febrile but non-bacteraemic subjects (see table). This, however, is not to imply that the specificity for complicated bacteraemia was 100%. Because the upper normal cut-off level for each separate assay was based upon the 99 % confidence intervals of the antibody levels in the febrile control group, specificity was estimated to be at least 99 5% when the three tests were used in combination. The prevalence of complicated Staph aureus bacteraemia is about 10 % at our hospital and probably most others. With a sensitivity of 88% for complicated bacteraemia including endocarditis, very high predictive values are reached: a positive result of this test combination during the second week of infection NUMBER OF PATIENTS WITH POSITIVE ANTIBODY TEST TO STAPH
AUREUS LIPASE PLUS PEPTIDOGLYCAN
AND/OR CRUDE
STAPHYLOCOCCAL ANTIGEN
Sitting diastolic blood pressures at start and finish.
ADJUVANT CHEMOTHERAPY COMBINED WITH TAMOXIFEN IN POSTMENOPAUSAL PATIENTS WITH STAGE II BREAST CANCER
StR,—The ideal adjuvant treatment for postmenopausal stage II breast cancer has yet to be identified. Although tamoxifen delays the recurrence of disease in these patients,l;2 the benefit of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) found in premenopausal patients could not be reproduced in the postmenopausal group.3 Studies of combined chemotherapeutic and endocrine treatment have produced conflicting data.4,s In a prospective randomised controlled trial we have investigated the value of adjuvant CMF3 administered in six courses, tamoxifen (20 mg daily given over two years), or the simultaneous treatment with both in 84 postmenopausal patients with stage II disease. All patients had a modified radical mastectomy and were randomised to CMF (25 patients), tamoxifen (34), or CMF plus tamoxifen (25), adjuvant therapy beginning 2-4 weeks after surgery. Patients over ’ 70 years of age were not included in the trial. Toxicity from both endocrine treatment and chemotherapy did not exceed the usual spectrum. The mean observation period is 48 months so far. Oestrogen receptor (ER) levels were analysed by saturation analysis.6 The statistical analysis was done by the Wilcoxon and Mantel-Cox tests and by the actuarial life-table method. 31 of the 84 patients have had recurrent breast cancer. The duration of the relapse-free interval (RFI) in the three groups of patients modalities is shown in fig 1. 53% of patients treated with
Fig 2-Actuarial recurrence curves at 48 months. >
ER <10(- - - -), 11-30g( ( 100 fmol/mg (— — —). ).
and 31 - 100 g (------ ), and
I
groups, a significantly lower percentage of metastases was found in patients with ER levels between 30 and 100 fmol/mg (10%) and above 100 fmol/mg (18 %); respectively (p < 0-01). Our data suggest that the clinically significant borderline for the dissection of the ER status between positivity and negativity in postmenopausal women could be located at 30 fmol/mg, higher than previously assumed.
Departments of Medicine II, Gynaecology I, and Surgery II, University Hospital, A-1090 Vienna, Austria
C. C. ZIELINSKI E. KUBISTA H. SALZER P. SEVELDA M. LANGER A. STAFFEN J. SPONA P. AIGINGER
development conference statements: Adjuvant chemotherapy for breast Bethesda, Maryland: National Institute of Health, 1985 2. Cummings FJ, Gray R, Davis TE, et al. Adjuvant tamoxifen treatment of elderly women with stage II breast cancer. Ann Intern Med 1985; 103: 324-29 3. Bonadonna G, Rossi A, Valagussa P. Adjuvant chemotherapy in operable breast 1. Consensus cancer.
Fig 1—Actuarial recurrence curves at 48 months. adjuvant treatment with adjuvant CMF chemotherapy; combined adjuvant therapy with CMF plus tamoxifen; -
=
-------
-
-
-
cancer. Ten years later. Lancet 1985; i: 976-77. 4. Fisher B, Redmond C, Brown A, et al. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 1981; 305: 1-6 5. Krook JE, Ingle JM, Green SJ, et al. Randomized clinical trial of cyclophosphamide, 5-FU and prednisone with or without tamoxifen in postmenopausal women with advanced breast cancer. Cancer Treat Rep 1985; 69: 355-61. 6 Zielinski CC, Kuzmits R, Kubista E, et al. The importance of hormone receptors of breast cancer cells for the duration of the relapse-free interval. Wien Klin Wochenschr 1985; 97: 493-97.
=
=
tamoxifen.
VERAPAMIL, LOW-SODIUM REGIMENS, AND BLOOD PRESSURE
CMF and 36 % of the patients on tamoxifen alone had a recurrence but the recurrence rate in the group treated with CMF plus tamoxifen was only 16% (p 0-009 vs the other treatment groups). It can be concluded, therefore, that a combination of CMF with tamoxifen may be beneficial in postmenopausal patients with breast cancer and lymph node involvement. The duration of relapse-free survival depended heavily on ER concentration (fig 2): patients with ER concentrations below 30 fmol/mg had a significantly higher frequency of metastasis (36%) and thus a more severe disease course than did patients with ER concentrations above 30 fmol/mg (13%; p =- 0 001). The frequency of disease recurrence was the same (33 %) both in patients with ER levels between 10 and 30 fmol/mg and in patients with ER concentrations below 10 fmol/mg. In comparison with these two =
SIR,-A paradoxical rise in supine and erect diastolic blood (DBP) has been reported in clinical trials combining
pressure
low-salt diets with the calcium-channel blocking agents verapamil and nifedipine.1,2 These findings would suggest that this therapeutic combination should be avoided in routine clinical practice. Most doctors, however, record blood pressure with the patient in the sitting position and reduce the dose of any antihypertensive drug as the blood pressure (BP) falls to normal. Following this routine in the Canberra Blood Pressure Trial (an uncontrolled feasibility study for a trial in primary prevention 3) and in a Low Sodium Advisory Service based on that trial, we have not met any significant paradoxical effect attributable to verapamil. Patients avoided salted foods as completely as possible for 12 weeks, and compliance was evaluated by the potassium/sodium
1165 CHANGES IN MEDICATION, SYSTOLIC AND DIASTOLIC BLOOD PRESSURE (SBP, DBP), AND MEAN ARTERIAL PRESSURE (MAP)
y-glutamyltransferase (191 at entry, 209 on completion; normal laboratory range 5--60 units). In clinical practice the BP may fall for many reasons unrelated to the treatmenr,5 and our findings do not refute those of a controlled trial but, since we are not seeing adverse effects with verapamil, patients taking calcium channel blockers will continue to be accepted at the Low Sodium Advisory Service and carefully observed. We have no information on nifedipine. Low Sodium Advisory Service, Woden Valley Hospital, Woden, ACT 2606, Australia; and Central Statistical Unit, Commonwealth Department of Health, Canberra
1.
2.
TREVOR C. BEARD HELEN M. COOKE WENDY R. GRAY PETER WILD
Morgan T, Anderson A, Wilson D, Myers J, Murphy J, Nowson C. Paradoxical effect of sodium restriction on blood pressure in people on slow-channel calcium blocking drugs. Lancet 1986; i: 793. Kingswood JC, Thompson FD. Sodium, blood pressure, and calcium antagonists.
Lancet 1986; i. 1102. TC, Cooke HM, Gray WR, Ellem DP. Spontaneous remission and its significance for trials in primary prevention of hypertension. Ann Clin Res 1984; 16 (suppl 43): 132-35. 4. Rouse IL, Beilin IJ. Nutrition, blood pressure and hypertension: a critical review of dietary intervention studies in humans. Med J Aust 1983; ii (suppl): S19-S23. 5. Parr GD, Huitson A. Identification of elderly hypertensives Lancet 1986; ii: 809-10. 3. Beard
*Dinamap records MAP directly by an oscillometric technique, but for SBP, DBP and MAP in real time.
not
simultaneously
SEROLOGICAL DIAGNOSIS OF STAPHYLOCOCCAL BACTERAEMIA
(K/Na) ratio in the first morning urine sample (R. P. Mensink, T. C. Beard, D. P. Ellem, unpublished). We saw nine people whose BP had stabilised before entry with verapamil as sole therapy for mild essential hypertension, and whose morning urinary K/Na ratio on at least two of the last three trial visits was 10 or more (corresponding roughly with a 24 h sodium excretion below 70 mmol). The whole group had a mean weight loss of 1kg but three of the patients gained weight (mean 11I kg). Routine plasma biochemical studies were normal or almost normal for all except one, who had a raised urate, and another with a raised y-glutamyltransferase, who admitted to heavy drinking. Four finished the trial in a warmer month than at entry and five in a cooler month. The daily dose of verapamil at entry was 80-320 mg and medication was withdrawn incrementally when the mean arterial pressure (MAP) recorded by ’Dinamap’ was below 105 mm Hg (conventional equivalent 135/90 mm Hg) at two consecutive visits, and the total dosage of 1760 mg at entry was reduced by 48 % to 920 mg on completion. A paired t-test showed no significant difference between diastolic BP at the start and finish. Except for the patient who remained on 320 mg verapamil daily throughout, who had a diastolic BP rise of 1 mm Hg, the only rises in DBP occurred in three patients who had stopped medication or reduced the dose (figure). The patient taking 160 mg daily throughout had falls in MAP and diastolic BP of 18 mm and 10 mm Hg, respectively. This was the patient with the high
SIR,-As discussed in your editorial,l the combined use of three detecting antibody to teichoic acid, peptidoglycan, and alpha-toxin2 has been suggested to distinguish complicated from uncomplicated Staphylococcus aureus bacteraemia. Certainly, more than one serological test is needed for the diagnosis of complicated Staph aureus bacteraemia. However, to reach acceptable predictive values for positive as well as negative results the specificity for complicated bacteraemia must be close to 100%. This was not the 2 case in the report by Verbrugh et al. assays
I have used a combination of three different enzyme-linked immunosorbent assays (ELISA) measuring antibodies to Staph aureus lipase,’ peptidoglycan (PG),’ and crude staphylococcal antigen (SA).’ The criterion for a positive result was a positive antibody level or pronounced titre rise during the second week of infection in the anti-lipase ELISA and in either the anti-PG ELISA or the anti-SA ELISA or both.s The very high specificity of the anti-lipase ELISA2 for Staph aureus thus remains in this combination. Moreover, patients with complicated Staph aureus bacteraemia or endocarditis could be entirely separated from those with uncomplicated Staph aureus bacteraemia, those patients with bacteraemia caused by other microorganisms, and from febrile but non-bacteraemic subjects (see table). This, however, is not to imply that the specificity for complicated bacteraemia was 100%. Because the upper normal cut-off level for each separate assay was based upon the 99 % confidence intervals of the antibody levels in the febrile control group, specificity was estimated to be at least 99 5% when the three tests were used in combination. The prevalence of complicated Staph aureus bacteraemia is about 10 % at our hospital and probably most others. With a sensitivity of 88% for complicated bacteraemia including endocarditis, very high predictive values are reached: a positive result of this test combination during the second week of infection NUMBER OF PATIENTS WITH POSITIVE ANTIBODY TEST TO STAPH
AUREUS LIPASE PLUS PEPTIDOGLYCAN
AND/OR CRUDE
STAPHYLOCOCCAL ANTIGEN
Sitting diastolic blood pressures at start and finish.