Acta Oncologica
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Transient Reduction in Serum Cortisol Levels After Dexamethasone Antiemetic Therapy in Cancer Patients Undergoing Chemotherapy U. Aasebø & L. Slørdal To cite this article: U. Aasebø & L. Slørdal (1990) Transient Reduction in Serum Cortisol Levels After Dexamethasone Antiemetic Therapy in Cancer Patients Undergoing Chemotherapy, Acta Oncologica, 29:3, 314-316, DOI: 10.3109/02841869009090005 To link to this article: https://doi.org/10.3109/02841869009090005
Published online: 08 Jul 2009.
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Article views: 67
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Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20
314
CORRESPONDENCE
Table 3 Serum alkaline phosphatase (Ull) and degree of response to hormonal treatment in patients with o s s e w metastasis
Best degree of response At the time of
CR/PR
NC
PD
-diagnosis -metastatic disease -3 months’ clinical control
180 k 105 297 k 110 198 f 58
176 f 55 271 f 105 264 f 113
227 f 134 433 f 247 551 rt 320
n=7
n=28
n = 30
CR = complete response PR = partial response NC = no change PD = progressive disease
Alkaline phosphatase increased from the time of initial measurement to the time of detectable osseous metastases (Table 3) and it further increased in the patients not responding to the hormonal treatment, but decreased in the patients showing a response and was about constant in the patients whose disease was clinically stable (Table 3). Alkaline phosphatase was not markedly increased in the other types of metastases and nor did it change during the treatment procedures (data not shown in the tables). Disscussion. Symptoms and careful clinical examination give often more valuable information than do chemical tests for the detection of recurrence of breast cancer (3). However, laboratory tests are often performed during the follow-up and in the evaluation of treatment response in cancer patients. The most frequently used laboratory tests include haemoglobin, erythrocyte sedimentation rate, leukocyte count and serum alkaline phosphatase. Our aim was to evaluate these tests in a controlled series of breast cancer patients undergoing hormonal treatment for their metastases. The patients with osseous metastases were the most homogenous group of patients and accordingly the trends in the laboratory values were most uniform in this group. Alkaline phosphatase is traditionally used in the follow-up and one might anticipate that serum alkaline phosphatase would have some value for the detection of bone metastases. However, the alkaline phosphatase value was pathological (over 270 U/1) in only 58% of patients with osseous metastases. Somewhat surprisingly, alkaline phosphatase continued to increase in patients treated with tamoxifen or nandrolone decanoate. This could have been due to toxic effects of the treatment on the liver, but as this phenomenon was not seen in the patients with non-osseous metastases, another explanation had to be found. As the serum alkaline phosphatase values were correlated to the degree of clinical response to the hormonal manipulation, it seems likely that the continuous increase was due to progressive disease in the patients not responding to the treatment. The alkaline phosphatase values definitely decreased in most patients with a positive response and remained approximately constant in patients with clinically stable disease. These results suggest that serum alkaline phosphatase is not a reliable method for detecting bone metastases from breast cancer. However, if serum alkaline phosphatase is pathologically increased in patients with bone metastases, its monitoring may be useful for evaluation of the response to treatment.
Key words: Breast cancer, hormonal therapy, laboratory values, alkaline phosphatase.
P. KELLOKUMPU-LEHTINEN R. HUOVINEN R. JOHANSSON
Department of Radiotherapy University of Turku Turku Department of Radiotherapy and Oncology University of Kuopio Kuopio Finland
August 1989 Request for reprints: Dr Pirkko Kellokumpu-Lehtinen, Department of Radiotherapy, University of Turku, Kiinamyllynkatu 4-6, SF-20520 Turku, Finland.
REFERENCES 1. Cantwell B, Feneley J, Jones M. Evaluation of follow-up methods to detect relapse after mastectomy in breast cancer patients. Int J Med Sci 1982; 151: 1-5. 2. Horton J. Follow-up of breast cancer patients. Cancer 1984; 53: 790-9. 3. Scanlon EF, Oviedo MA, Cunningham MP, et al. Preoperative and follow-up procedures of patients with breast cancer. Cancer 1980; 46: 977-9. 4. Kellokumpu-Lehtinen P, Huovinen R, Johansson R. Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen versus nandrorone decanoate. Cancer 1987; 60: 2376-81. 5. Miller AB, Hoogstraten B, Staquet MO, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-14.
TRANSIENT REDUCTION IN SERUM CORTISOL LEVELS AFTER DEXAMETHASONE ANTIEMETIC THERAPY IN CANCER PATIENTS UNDERGOING CHEMOTHERAPY Dexamethasone may act as a powerful adreno-cortical suppressor when given in high dosage in antiemetic therapy. In order to investigate a possible detrimental effect on delayed onset nausea and vomiting after dexamethasone administration, 21 patients with limited stage non-small cell lung cancer were entered into a randomised study; 9 patients received high-dose metoclopramide and dexamethasone as antiemetic therapy and 12 patients were given high-dose metoclopramide only. All were treated with cisplatin and etoposide as cyclic anticancer therapy. The dexamethasone group experienced a significant fall in serum cortisol on the day after chemotherapy ( p < 0.001), but cortisol levels returned to normal pretreatment values the following day. In the controls no fall in serum cortisol was evident. There were no differences between the groups with respect to incidence of nausea and vomiting. A frequently encountered and well documented side effect of anticancer chemotherapy with cisplatin is nausea and vomiting, responsive to treatment with high-dose metoclopramide and dexamethasone (1,2). Dexamethasone acts as a powerful adrenal suppressor and is indeed used in suppression tests to evaluate the adrenal cortical function (3). Since cyclic chemotherapy involving cisplatin causes endocrine gonadal dysfunction, but no other detectable hormonal abnormalities (4), we have investigated the short-term effect of dexamethasone therapy on endogenous
315
CORRESPONDENCE
cortisol levels, particularly since it has been claimed that dexamethasone used in antiemetic therapy may be responsible for nausea with delayed onset due to adrenal suppression ( 5 ) . The efficacy of a standard antiemetic regimen with or without dexamethasone was evaluated with respect to the Occurrence of delayed onset nausea and vomiting in two groups of patients over a period of one week. Material and Methods. Informed consent was obtained from 21 male patients (mean age 63 years, range 52-70). All had locally advanced non-small cell lung cancer with no signs of metastases as judged by routine clinical, biochemical and x-ray examination. A dexamethasone suppression test was performed to exclude adrenal cortical dysfunction. The patients were within the limits of WHO index 0-2, and interviews and clinical examination gave no symptoms or signs of endocrine dysfunction. Treatment consisted of cisplatin (100 mg/m2 i.v.) and etoposide (100 mg/m2 i.v. on day 1, and 200 mg/m2 p.0. on days 2 and 3) on a cyclic, 3-weekly basis. The patients were randomised into two groups. Both groups received high-dose metoclopramide antiemetic therapy (2 mg/kg as a continuous infusion during the first hour, 1 mg/kg/h as an infusion for the following 6 hours). One group (n = 9, mean age 64 years, range 52-70) received 10 mg dexamethasone as a shorttime infusion 15 min before chemotherapy. The control group (n = 12, mean age 62 years, range 52-70) were administered metoclopramide only. Antiemetics were given on day 1 only, and no further therapy was given after the initial 7 hours. Blood samples were obtained at 8 o'clock in the morning of the day chemotherapy was started (day 0), and repeated on days 1, 2, 3 and 7. Serum was separated by centrifugation at 2 000 x g for 10 min, and samples frozen at -20°C until analysis. Cortisol was analysed using kits from Farmos Diagnostica (Turku, Finland). The patients were monitored closely for duration of nausea and number of vomiting episodes. Student's t-test was used to compare the two groups. Results. Serum levels of cortisol are given in the Figure. As evident from this figure, there was a pronounced and significant (p < 0.001) decline in serum cortisol in the dexamethasone-treated patients on the day following chemotherapy. The fall was temporary and the values were normalised on the following day. There were no significant differences as compared to zero values for the
other days. In the patients who received metoclopramide only as antiemetic therapy, variations in cortisol levels were insignificant and within normal range at all time points examined. Control of emesis, arbitrarily defined as < 2 emetic episodes (6), was achieved in both groups on days 1 and 2. In addition, there was no difference between the groups with respect to the duration of nausea. The side effects on the day of chemotherapy is beyond the scope of this paper, but there were no differences between the two groups. Discussion. In patients with locally advanced non-small cell lung cancer, a single dose of 10 mg dexamethasone administered in conjunction with cisplatin/etoposide chemotherapy caused a profound but transient reduction in endogenous cortisol levels. Serum cortisol concentrations were normalised within 48 h after chemotherapy (Figure). In this respect, the effect of dexamethasone is indiscernible from what is normally observed after a synacten or dexamethasone suppression test (3). The concomitant administration of metoclopramide and cisplatin/etoposide, did not appear to delay the time-dependent reconstruction of endogenous cortisol production. Thus, the adreno-suppressive effects of dexamethasone do not seem to be of any significant clinical importance. This is further substantiated by the lack of adverse influence on the efficacy of the antiemetic therapy. Other investigators have reported that dexamethasone in a dose of 20 mg daily for 5 consecutive days after cisplatin therapy was associated with prolonged adrenal dysfunction and delayed emesis ( 5 ) . The present study demonstrates that a single dose of 10mg dexamethasone may safely be employed in an effort to reduce post-chemotherapy emesis and that its adreno-suppressive effects are transient and clinically unimportant. This does not rule out the possibility that dexamethasone-induced adrenal dysfunction can be of significance in advanced stages of the disease (WHO 3-4), or in hepatic or adrenal mestastasis, where the ability to restore endogenous steroid secretion may be severely impaired. Key words: Dexamethasone, cortisol suppression, antiemetic therapy, cancer chemotherapy.
u. h S E B 0 L. S L 0 R D A L
""1 T
Department of Chest Medicine University Hospital of Tromse and Department of Pharmacology Institute of Medical Biology University of Tromsa Tromse Norway
September 1989
.. 0
1
I
1
2
I 3 Days
1
ACKNOWLEDGEMENT Dr Lars Slrardal is a Fellow of the Norwegian Cancer Society.
I
7
Figure. Serum cortisol levels in two groups of patients, administered metoclopramide (8 mg/kg) and dexamethasone ( 10 mg) (n = 9, -0-0-) or metoclopramide only (n = 12, -0-0-) in conjunction with cisplatin/etoposide chemotherapy, given on day 0, for non-small cell lung cancer. Data are given as meankSD, and the dotted lines denote the normal range of serum cortisol.
Request for reprints: Dr Ulf Aasebe, Department of Chest Medicine, University Hospital of Tromse, N-9000 Tromse, Norway.
REFERENCES 1. Kris MG, Gralla RJ, Tyson LB, et al. Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide dexamethasone and diphenhydramine. Cancer 1985; 55: 527-34.
316
CORRESPONDENCE
2. Aaseba U, Sbrdal L, Prytz PS, Aarbakke J. High-dose metoclopramide and chlorpromazine in the treatment of cisplatin-induced emesis. Pharmacol Toxicol 1987; 60: 337-9. 3. Nelson JC, Tindall DJ. A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH. Am J Med Sci 1978; 215: 165-6. 4. Aaseba U, Slardal L, Aanderud S, Aakvaag A. Chemotherapy
and endocrine function in lung cancer. Acta Oncol 1989; 28: 667-9. 5. Alberola V, Garcia J, Lluch A, et al. Relationship between adrenal failure and delayed emesis in patients receiving dexamethasone to prevent gastrointestinal toxicity of high-dose cisplatin. Cancer Chemother Pharmacol 1986; 18 (Suppl 1): A2. 6. Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs 1983; 25 (Suppl 1): 63-73.
ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20
Transient Reduction in Serum Cortisol Levels After Dexamethasone Antiemetic Therapy in Cancer Patients Undergoing Chemotherapy U. Aasebø & L. Slørdal To cite this article: U. Aasebø & L. Slørdal (1990) Transient Reduction in Serum Cortisol Levels After Dexamethasone Antiemetic Therapy in Cancer Patients Undergoing Chemotherapy, Acta Oncologica, 29:3, 314-316, DOI: 10.3109/02841869009090005 To link to this article: https://doi.org/10.3109/02841869009090005
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 67
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ionc20
314
CORRESPONDENCE
Table 3 Serum alkaline phosphatase (Ull) and degree of response to hormonal treatment in patients with o s s e w metastasis
Best degree of response At the time of
CR/PR
NC
PD
-diagnosis -metastatic disease -3 months’ clinical control
180 k 105 297 k 110 198 f 58
176 f 55 271 f 105 264 f 113
227 f 134 433 f 247 551 rt 320
n=7
n=28
n = 30
CR = complete response PR = partial response NC = no change PD = progressive disease
Alkaline phosphatase increased from the time of initial measurement to the time of detectable osseous metastases (Table 3) and it further increased in the patients not responding to the hormonal treatment, but decreased in the patients showing a response and was about constant in the patients whose disease was clinically stable (Table 3). Alkaline phosphatase was not markedly increased in the other types of metastases and nor did it change during the treatment procedures (data not shown in the tables). Disscussion. Symptoms and careful clinical examination give often more valuable information than do chemical tests for the detection of recurrence of breast cancer (3). However, laboratory tests are often performed during the follow-up and in the evaluation of treatment response in cancer patients. The most frequently used laboratory tests include haemoglobin, erythrocyte sedimentation rate, leukocyte count and serum alkaline phosphatase. Our aim was to evaluate these tests in a controlled series of breast cancer patients undergoing hormonal treatment for their metastases. The patients with osseous metastases were the most homogenous group of patients and accordingly the trends in the laboratory values were most uniform in this group. Alkaline phosphatase is traditionally used in the follow-up and one might anticipate that serum alkaline phosphatase would have some value for the detection of bone metastases. However, the alkaline phosphatase value was pathological (over 270 U/1) in only 58% of patients with osseous metastases. Somewhat surprisingly, alkaline phosphatase continued to increase in patients treated with tamoxifen or nandrolone decanoate. This could have been due to toxic effects of the treatment on the liver, but as this phenomenon was not seen in the patients with non-osseous metastases, another explanation had to be found. As the serum alkaline phosphatase values were correlated to the degree of clinical response to the hormonal manipulation, it seems likely that the continuous increase was due to progressive disease in the patients not responding to the treatment. The alkaline phosphatase values definitely decreased in most patients with a positive response and remained approximately constant in patients with clinically stable disease. These results suggest that serum alkaline phosphatase is not a reliable method for detecting bone metastases from breast cancer. However, if serum alkaline phosphatase is pathologically increased in patients with bone metastases, its monitoring may be useful for evaluation of the response to treatment.
Key words: Breast cancer, hormonal therapy, laboratory values, alkaline phosphatase.
P. KELLOKUMPU-LEHTINEN R. HUOVINEN R. JOHANSSON
Department of Radiotherapy University of Turku Turku Department of Radiotherapy and Oncology University of Kuopio Kuopio Finland
August 1989 Request for reprints: Dr Pirkko Kellokumpu-Lehtinen, Department of Radiotherapy, University of Turku, Kiinamyllynkatu 4-6, SF-20520 Turku, Finland.
REFERENCES 1. Cantwell B, Feneley J, Jones M. Evaluation of follow-up methods to detect relapse after mastectomy in breast cancer patients. Int J Med Sci 1982; 151: 1-5. 2. Horton J. Follow-up of breast cancer patients. Cancer 1984; 53: 790-9. 3. Scanlon EF, Oviedo MA, Cunningham MP, et al. Preoperative and follow-up procedures of patients with breast cancer. Cancer 1980; 46: 977-9. 4. Kellokumpu-Lehtinen P, Huovinen R, Johansson R. Hormonal treatment of advanced breast cancer. A randomized trial of tamoxifen versus nandrorone decanoate. Cancer 1987; 60: 2376-81. 5. Miller AB, Hoogstraten B, Staquet MO, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207-14.
TRANSIENT REDUCTION IN SERUM CORTISOL LEVELS AFTER DEXAMETHASONE ANTIEMETIC THERAPY IN CANCER PATIENTS UNDERGOING CHEMOTHERAPY Dexamethasone may act as a powerful adreno-cortical suppressor when given in high dosage in antiemetic therapy. In order to investigate a possible detrimental effect on delayed onset nausea and vomiting after dexamethasone administration, 21 patients with limited stage non-small cell lung cancer were entered into a randomised study; 9 patients received high-dose metoclopramide and dexamethasone as antiemetic therapy and 12 patients were given high-dose metoclopramide only. All were treated with cisplatin and etoposide as cyclic anticancer therapy. The dexamethasone group experienced a significant fall in serum cortisol on the day after chemotherapy ( p < 0.001), but cortisol levels returned to normal pretreatment values the following day. In the controls no fall in serum cortisol was evident. There were no differences between the groups with respect to incidence of nausea and vomiting. A frequently encountered and well documented side effect of anticancer chemotherapy with cisplatin is nausea and vomiting, responsive to treatment with high-dose metoclopramide and dexamethasone (1,2). Dexamethasone acts as a powerful adrenal suppressor and is indeed used in suppression tests to evaluate the adrenal cortical function (3). Since cyclic chemotherapy involving cisplatin causes endocrine gonadal dysfunction, but no other detectable hormonal abnormalities (4), we have investigated the short-term effect of dexamethasone therapy on endogenous
315
CORRESPONDENCE
cortisol levels, particularly since it has been claimed that dexamethasone used in antiemetic therapy may be responsible for nausea with delayed onset due to adrenal suppression ( 5 ) . The efficacy of a standard antiemetic regimen with or without dexamethasone was evaluated with respect to the Occurrence of delayed onset nausea and vomiting in two groups of patients over a period of one week. Material and Methods. Informed consent was obtained from 21 male patients (mean age 63 years, range 52-70). All had locally advanced non-small cell lung cancer with no signs of metastases as judged by routine clinical, biochemical and x-ray examination. A dexamethasone suppression test was performed to exclude adrenal cortical dysfunction. The patients were within the limits of WHO index 0-2, and interviews and clinical examination gave no symptoms or signs of endocrine dysfunction. Treatment consisted of cisplatin (100 mg/m2 i.v.) and etoposide (100 mg/m2 i.v. on day 1, and 200 mg/m2 p.0. on days 2 and 3) on a cyclic, 3-weekly basis. The patients were randomised into two groups. Both groups received high-dose metoclopramide antiemetic therapy (2 mg/kg as a continuous infusion during the first hour, 1 mg/kg/h as an infusion for the following 6 hours). One group (n = 9, mean age 64 years, range 52-70) received 10 mg dexamethasone as a shorttime infusion 15 min before chemotherapy. The control group (n = 12, mean age 62 years, range 52-70) were administered metoclopramide only. Antiemetics were given on day 1 only, and no further therapy was given after the initial 7 hours. Blood samples were obtained at 8 o'clock in the morning of the day chemotherapy was started (day 0), and repeated on days 1, 2, 3 and 7. Serum was separated by centrifugation at 2 000 x g for 10 min, and samples frozen at -20°C until analysis. Cortisol was analysed using kits from Farmos Diagnostica (Turku, Finland). The patients were monitored closely for duration of nausea and number of vomiting episodes. Student's t-test was used to compare the two groups. Results. Serum levels of cortisol are given in the Figure. As evident from this figure, there was a pronounced and significant (p < 0.001) decline in serum cortisol in the dexamethasone-treated patients on the day following chemotherapy. The fall was temporary and the values were normalised on the following day. There were no significant differences as compared to zero values for the
other days. In the patients who received metoclopramide only as antiemetic therapy, variations in cortisol levels were insignificant and within normal range at all time points examined. Control of emesis, arbitrarily defined as < 2 emetic episodes (6), was achieved in both groups on days 1 and 2. In addition, there was no difference between the groups with respect to the duration of nausea. The side effects on the day of chemotherapy is beyond the scope of this paper, but there were no differences between the two groups. Discussion. In patients with locally advanced non-small cell lung cancer, a single dose of 10 mg dexamethasone administered in conjunction with cisplatin/etoposide chemotherapy caused a profound but transient reduction in endogenous cortisol levels. Serum cortisol concentrations were normalised within 48 h after chemotherapy (Figure). In this respect, the effect of dexamethasone is indiscernible from what is normally observed after a synacten or dexamethasone suppression test (3). The concomitant administration of metoclopramide and cisplatin/etoposide, did not appear to delay the time-dependent reconstruction of endogenous cortisol production. Thus, the adreno-suppressive effects of dexamethasone do not seem to be of any significant clinical importance. This is further substantiated by the lack of adverse influence on the efficacy of the antiemetic therapy. Other investigators have reported that dexamethasone in a dose of 20 mg daily for 5 consecutive days after cisplatin therapy was associated with prolonged adrenal dysfunction and delayed emesis ( 5 ) . The present study demonstrates that a single dose of 10mg dexamethasone may safely be employed in an effort to reduce post-chemotherapy emesis and that its adreno-suppressive effects are transient and clinically unimportant. This does not rule out the possibility that dexamethasone-induced adrenal dysfunction can be of significance in advanced stages of the disease (WHO 3-4), or in hepatic or adrenal mestastasis, where the ability to restore endogenous steroid secretion may be severely impaired. Key words: Dexamethasone, cortisol suppression, antiemetic therapy, cancer chemotherapy.
u. h S E B 0 L. S L 0 R D A L
""1 T
Department of Chest Medicine University Hospital of Tromse and Department of Pharmacology Institute of Medical Biology University of Tromsa Tromse Norway
September 1989
.. 0
1
I
1
2
I 3 Days
1
ACKNOWLEDGEMENT Dr Lars Slrardal is a Fellow of the Norwegian Cancer Society.
I
7
Figure. Serum cortisol levels in two groups of patients, administered metoclopramide (8 mg/kg) and dexamethasone ( 10 mg) (n = 9, -0-0-) or metoclopramide only (n = 12, -0-0-) in conjunction with cisplatin/etoposide chemotherapy, given on day 0, for non-small cell lung cancer. Data are given as meankSD, and the dotted lines denote the normal range of serum cortisol.
Request for reprints: Dr Ulf Aasebe, Department of Chest Medicine, University Hospital of Tromse, N-9000 Tromse, Norway.
REFERENCES 1. Kris MG, Gralla RJ, Tyson LB, et al. Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide dexamethasone and diphenhydramine. Cancer 1985; 55: 527-34.
316
CORRESPONDENCE
2. Aaseba U, Sbrdal L, Prytz PS, Aarbakke J. High-dose metoclopramide and chlorpromazine in the treatment of cisplatin-induced emesis. Pharmacol Toxicol 1987; 60: 337-9. 3. Nelson JC, Tindall DJ. A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH. Am J Med Sci 1978; 215: 165-6. 4. Aaseba U, Slardal L, Aanderud S, Aakvaag A. Chemotherapy
and endocrine function in lung cancer. Acta Oncol 1989; 28: 667-9. 5. Alberola V, Garcia J, Lluch A, et al. Relationship between adrenal failure and delayed emesis in patients receiving dexamethasone to prevent gastrointestinal toxicity of high-dose cisplatin. Cancer Chemother Pharmacol 1986; 18 (Suppl 1): A2. 6. Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs 1983; 25 (Suppl 1): 63-73.
