- Email: [email protected]
899Study of the anaemia associated with androgen deprivation therapy in prostate cancer patients
897
898
IMPACT OF 3, 6 AND 9 MONTHS NEO-ADJUVANT H O R M O N A L TREATMENT ON TARGET VOLUME AND RECTAL TOXICITY IN PROSTATE CONFORMAL R A D I O T H E R A P Y
COMBINED A N D R O G E N BLOCKADE SIX MONTHS A YEAR IN THE M A N A G E M E N T OF ADVANCED PROSTATE CANCER: A RANDOMIZED STUDY
Langenhuijsen j.1, Hoffman A. 2, Van Lin E. 2, Witjes J?, Mulders P.~
Irani j.1, Hubert j.2, Bladou F. 3, Orget j.4, Rouxel A. 5, Ragni E.6, Association pour la Recherche en Oncologie Urolegique, Poitiers, France
JUMC St. Radboud, Urology, Nijmegen, The Netherlands, 2UMC St. Radboud, Radiation Oncology, Nijmegen, The Netherlands INTRODUCTION & O B J E C T I V E S : To monitor the reduction in target volume and irradiated rectum volume for 3D conformal radiotherapy (3D-CRT) during nine months of neoadjuvant hormonal therapy in order to establish the optimal duration of neoadjuvant treatment. MATERIAL & METHODS: 20 patients received combined androgenic blockade (CAB) for nine months prior to radiotherapy. Repeated CT scans were acquired at baseline, tbree, six, and nine months prior to radiotherapy. On each CT scan the prostate gland (P), seminal vesicles (SV), and surrounding normal tissues were delineated. For each patient the rectum was delineated over the same length. Two PTVs (planning target volume) were defined: prostate only (PTV-P) and prostate plus seminal vesicles (PTV-PSV). 3D-CRT treatment plans were constructed with a four-field box technique (prescription dose of 70 Gy in 35 fractions, 10-ram margin). The prostate volume was measured from repeated CT scans. The rectum NTCP (normal tissue complication probability, NTCP-R) and the rectal volume receiving at least 95% of the prescription dose (Vgsvo) were calculated and statistically analysed for reduction. RESULTS: In the first three months of CAB, a significant (p<0.05) reduction in the mean prostate volume of 30% (95% CI: 25%-35%) was observed. Between three and six months the reduction in mean prostate volume was 7% (95% CI: 2%12%) and 12% (95% CI: 7%-17%) for small (< 60cc) and large (> 60cc) prostates, respectively.Prostate volume reduction was not statistically significant between six and nine months. A significant decrease (r~<0~.002), in mean V950/o for rectal volume for both PTV-P (-3%) and PTV-PSV (-6%) was observed over the first six months. Although NTCP-R showed a significant reduction in the first three months (p<0.02) for PTV-P, a mean NTCP-R reduction of 1% was not considered to be clinically relevant. For PTV-PSV no significant reduction in NTCP-R was found. C O N C L U S I O N S : The optimal duration for CAB to reduce the prostate volume is between three and six months. Most of the volume reduction occurs in the first three months Although V of the rectal volume decreased during the first six months, a chmcally relevant reductmn m NTCP-R could not be demonstrated. .
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9
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1CHU la Mil6trie, Urology, Poitiers, France, 2CHU, Urology, Nancy, France, 3CHU, Urology, Marseille, France, 4CHR, Urology, Niort, France, 5CHR, Urology, Pont-l'Abb6, France, 6CHR, Urology, Marseille, France INTRODUCTION & OBJECTIVES: Criteria for stopping and restarting treatment in intermittent androgen suppression are not standardized. They are usually based on an empirical PSA cut-off that varies depending on the investigators' decision. Waiting for the verdict of PSA is a factor of anxiety for the patient. To avoid the latter problems, we decided to explore a new path using systematic interruption of LH-RH analogs six months a year. MATERIAL & METHODS: Patients included in this study were recruited by 13 urological centres. They had a documented advanced prostate cancer and a 0 or 1 ECOG performance status. They all gave informed consent. All patients had a combined androgen blockade (flutamide t.i.d and 10.8 mg goserelin acetate implant every 3 month) either continuously (CONT arm) or intermittently, for a six-month period every year i.e. 2 injections in a row a year (INT arm) according to a random assignment. Serum PSA and testosterone as well as EORTC QLQ-C30 and Prostate Cancer-Specific questionnaires to assess quality of life were included in the pre-therapeutic assessment and then at each visit. Progression was defined in patients under androgen suppression when PSA exceeded the double of the value reached at the end of the sixth month. RESULTS: Between 1997 and 2000, 123 patients (60 CONT and 63 INT) were included in the study. Mean age was 71.2 years. Median PSA was 56.4 ng/ml at the time of diagnosis and 0.6 ng/ml at 6 month. Mean follow-up was 27.4 months. Among the 60 patients of the CONT group, 30 progressed while 24 progressed among the 63 patients of the INT group (p>0.05; Logrank test). Semm testosterone returned to a normal value at least once in 19% in the INT group. Among the 18 patients of the 1NT grnnp who reported obtaining and maintaining erections before treatment onset, 9 declared having regained a satisfactory erection at least at one visit. QLQ-C30 and Prostate Cancer-Specific questionnaires analyses did not show a significant difference between the 2 arms except for question 29 "How would you rate your overall health during the past week?" in favour of the INT arm (13-0.04; Mann-Whitney). CONCLUSIONS: Systematic interruption 6 months a year of LH-RH analogs in advanced prostate cancer was not associated with a higher rate of progression compared to patients treated continuously. No patients in the latter group recovered normal testosterone value or satisfactory erections conversely to the intermittent group, although this was the case only in a minority of patients. Intermittent treatment as described in this study should lead to significant reduction of costs.
899
900
STUDY OF THE A N A E M I A A S S O C I A T E D W I T H A N D R O G E N DEPRIVATION THERAPY IN PROSTATE C A N C E R PATIENTS
IS THERE A RELATIONSHIP BETWEEN EARLY CHANGES IN SEX H O R M O N E PROFILE A N D G Y N A E C O M A S T I A I N D U C E D BY BICALUTAMIDE 150 MG?
Salvador C., Trilla E., Esquena S., Abascal J., Ceccbini L., Ravent6s C., Planas J., Catalfin R., Morote J. Hospital Vall d'Hebron, Urology, Barcelona, Spain INTRODUCTION & OBJECTIVES: Anaemia has been described as a common side effect of androgen deprivation therapy (ADT). It is believed that anaemia is more frequent and great in patients under maximal androgen blockade (MAB). However, any study comparing anaemia between castration and MAB has been reported. The objective of this study was to analyze the anaemia induced by ADT, even under castration or MAB. MATERIAL & METHODS: Complete blood cell count with differential and red blood cell indices were evaluated in 308 patients with non metastatic prostate cancer in a prospective cross-sectional study. A group of 106 patients submitted to radical prostatectomy alone and free of biochemical relapse became the control group and other 202 patients under castration with LH-RH agonist (128 of them plus bicalntamide, MAB) became the study group. The median age was 70 years (53-89) and the mean follow up of the patients under ADT was 42.5 months (6-218). In 201 patients, 46 of the control group, 101 under MAB and 54 under castration, a serum determination of ferritin, folates, B2 vitamin, transferrin, iron, transferrin saturation and haptoglobin was determined.
Comhaire F5, Van Cangh P?, Van Poppel H. 3 1UZ Gent, Endocrinology, Gent, Belgium, 2Cliniques Universitaires Saint Luc, Urology, Brussels, Belgium, 3KUL, Urology, Leuven, Belgium INTRODUCTION & OBJECTIVES: Gynaecomastia and/or breast pain are the most frequent side-effects of bicalutamide 150 mg daily, with a reported prevalence of approximately 86%. There are presently no known predictors of the development of gynaecomastia. Here, we have prospectively measure changes in several sex hormones m 130 consecutive patients receiving bicalutamide. MATERIAL & METHODS: Patients included in the study should not have received bicalutamide for longer than 14 days before inclusion. At inclusion and after 4 weeks, sex hormone levels were determined (total estradiol (E2), free estradiol (fE2), 17/3-estradiol (I713-E2), total testosterone (T), free testosterone (ff), dihydrotestosterone (DHT), steroid hormone binding globulin (SHBG), luteinizing hormone (LH), prolactin (PRO)), and triglycerides (TG). All samples were taken at about the same time in the morning, to avoid the effects of diurnal fluctuations.
RESULTS: Patients under ADT had a significant decrease in the red blood cells quantification related to those of the control group, 4.8x10E12/L (3.3-5.9) and 4.3x10E12/L (3.4-5.4) respectively, p<0.001. Serum haemoglobin was 14.7 g/dL (10.i-18.7) and 13.2 g/dL (6.5-16.8) respectively, p<0.001. Haematocrito was 43.5% (30.3-53.7) and 39.2% (22-49.1) respectively, p<0.001. The mean corpuscular volume and the mean corpuscular haemoglobin were similar in both groups, p>0.05. The comparison between the group of patients under castration and MAB demonstrated not significant differences in any of the analyzed parameters, p>0.05. The serum level of haemoglobin in patients under ADT decrease at 6 and 12 months of follow up and thereafter it was stable. The rate of patients with anaemia (Hb < 13 g/dL) was 7.3% in the control group and 43.7% in those patients under ADT. However, the concentration of serum Hb lower than 11 g/dL was 0.9 and 2.3% respectively.
RESULTS: After 6 months of treatment, 74% of the patient had developed some level of gynaecomastia, including only 19% with bothersome symptoms. In most cases, symptoms appeared 3-4 months after the start of the treatment. Significant changes (p <0.05) were measured in SHBG (from 40.3 to 44.8 nM/1), T (from 495 to ng/dl), DHT (from 62 to 83 nM/1), E2 (from 27 to 35 pg/ml), 1713-E2 (from 0.57 to 0.71 pg/ml), and PRO (from 11.4 to 13.4 ng/ml). No significant difference was found in hormone levels between patients with bothersome gynaecomastia and those without gynaecomastia, neither at baseline nor after one month of follow-up. From a logistic regression model, early changes in SHBG, DHT, E2, Free E2 and the ratio fE2/tT were retained as predictive factors (!0: 0.04). Patients with increased SHBG and fE2 are highly likely to develop bothersome gynaecomastia (O.R. 24.4 and 18.4 respectively), while a negative association was with DHT and E2 (OR 0.41 and 0.08 respectively) but with lower statistical power. However, this model is poorly predictive of the development of bothersome gynaecomastia. Among the choices of criterion values (ROC analysis) the model reached, at best, a sensitivity of 62.5% and a specificity of 49.2% with a false positive rate of 77.3%.
CONCLUSIONS: ADT associates frequently with a normocytic and normochromic anaemia. Serum haemoglogin declines mainly during the first 12 months of ADT and them stabilizes. MAB is not associated with a higher risk of anaemia compared to those patients treated with LH-RH agonist alone.
CONCLUSIONS: Several hormonal changes have been identified in patients receiving bicalutamide 150 mg. Despite a linear relation between some sex hormone factors and bothersome gynaecomastia, the corresponding model does not although reliably predict its development.
European Urology Supplements 4 (2005) No. 3, pp. 227
898
IMPACT OF 3, 6 AND 9 MONTHS NEO-ADJUVANT H O R M O N A L TREATMENT ON TARGET VOLUME AND RECTAL TOXICITY IN PROSTATE CONFORMAL R A D I O T H E R A P Y
COMBINED A N D R O G E N BLOCKADE SIX MONTHS A YEAR IN THE M A N A G E M E N T OF ADVANCED PROSTATE CANCER: A RANDOMIZED STUDY
Langenhuijsen j.1, Hoffman A. 2, Van Lin E. 2, Witjes J?, Mulders P.~
Irani j.1, Hubert j.2, Bladou F. 3, Orget j.4, Rouxel A. 5, Ragni E.6, Association pour la Recherche en Oncologie Urolegique, Poitiers, France
JUMC St. Radboud, Urology, Nijmegen, The Netherlands, 2UMC St. Radboud, Radiation Oncology, Nijmegen, The Netherlands INTRODUCTION & O B J E C T I V E S : To monitor the reduction in target volume and irradiated rectum volume for 3D conformal radiotherapy (3D-CRT) during nine months of neoadjuvant hormonal therapy in order to establish the optimal duration of neoadjuvant treatment. MATERIAL & METHODS: 20 patients received combined androgenic blockade (CAB) for nine months prior to radiotherapy. Repeated CT scans were acquired at baseline, tbree, six, and nine months prior to radiotherapy. On each CT scan the prostate gland (P), seminal vesicles (SV), and surrounding normal tissues were delineated. For each patient the rectum was delineated over the same length. Two PTVs (planning target volume) were defined: prostate only (PTV-P) and prostate plus seminal vesicles (PTV-PSV). 3D-CRT treatment plans were constructed with a four-field box technique (prescription dose of 70 Gy in 35 fractions, 10-ram margin). The prostate volume was measured from repeated CT scans. The rectum NTCP (normal tissue complication probability, NTCP-R) and the rectal volume receiving at least 95% of the prescription dose (Vgsvo) were calculated and statistically analysed for reduction. RESULTS: In the first three months of CAB, a significant (p<0.05) reduction in the mean prostate volume of 30% (95% CI: 25%-35%) was observed. Between three and six months the reduction in mean prostate volume was 7% (95% CI: 2%12%) and 12% (95% CI: 7%-17%) for small (< 60cc) and large (> 60cc) prostates, respectively.Prostate volume reduction was not statistically significant between six and nine months. A significant decrease (r~<0~.002), in mean V950/o for rectal volume for both PTV-P (-3%) and PTV-PSV (-6%) was observed over the first six months. Although NTCP-R showed a significant reduction in the first three months (p<0.02) for PTV-P, a mean NTCP-R reduction of 1% was not considered to be clinically relevant. For PTV-PSV no significant reduction in NTCP-R was found. C O N C L U S I O N S : The optimal duration for CAB to reduce the prostate volume is between three and six months. Most of the volume reduction occurs in the first three months Although V of the rectal volume decreased during the first six months, a chmcally relevant reductmn m NTCP-R could not be demonstrated. .
"
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9
5
%
.
.
1CHU la Mil6trie, Urology, Poitiers, France, 2CHU, Urology, Nancy, France, 3CHU, Urology, Marseille, France, 4CHR, Urology, Niort, France, 5CHR, Urology, Pont-l'Abb6, France, 6CHR, Urology, Marseille, France INTRODUCTION & OBJECTIVES: Criteria for stopping and restarting treatment in intermittent androgen suppression are not standardized. They are usually based on an empirical PSA cut-off that varies depending on the investigators' decision. Waiting for the verdict of PSA is a factor of anxiety for the patient. To avoid the latter problems, we decided to explore a new path using systematic interruption of LH-RH analogs six months a year. MATERIAL & METHODS: Patients included in this study were recruited by 13 urological centres. They had a documented advanced prostate cancer and a 0 or 1 ECOG performance status. They all gave informed consent. All patients had a combined androgen blockade (flutamide t.i.d and 10.8 mg goserelin acetate implant every 3 month) either continuously (CONT arm) or intermittently, for a six-month period every year i.e. 2 injections in a row a year (INT arm) according to a random assignment. Serum PSA and testosterone as well as EORTC QLQ-C30 and Prostate Cancer-Specific questionnaires to assess quality of life were included in the pre-therapeutic assessment and then at each visit. Progression was defined in patients under androgen suppression when PSA exceeded the double of the value reached at the end of the sixth month. RESULTS: Between 1997 and 2000, 123 patients (60 CONT and 63 INT) were included in the study. Mean age was 71.2 years. Median PSA was 56.4 ng/ml at the time of diagnosis and 0.6 ng/ml at 6 month. Mean follow-up was 27.4 months. Among the 60 patients of the CONT group, 30 progressed while 24 progressed among the 63 patients of the INT group (p>0.05; Logrank test). Semm testosterone returned to a normal value at least once in 19% in the INT group. Among the 18 patients of the 1NT grnnp who reported obtaining and maintaining erections before treatment onset, 9 declared having regained a satisfactory erection at least at one visit. QLQ-C30 and Prostate Cancer-Specific questionnaires analyses did not show a significant difference between the 2 arms except for question 29 "How would you rate your overall health during the past week?" in favour of the INT arm (13-0.04; Mann-Whitney). CONCLUSIONS: Systematic interruption 6 months a year of LH-RH analogs in advanced prostate cancer was not associated with a higher rate of progression compared to patients treated continuously. No patients in the latter group recovered normal testosterone value or satisfactory erections conversely to the intermittent group, although this was the case only in a minority of patients. Intermittent treatment as described in this study should lead to significant reduction of costs.
899
900
STUDY OF THE A N A E M I A A S S O C I A T E D W I T H A N D R O G E N DEPRIVATION THERAPY IN PROSTATE C A N C E R PATIENTS
IS THERE A RELATIONSHIP BETWEEN EARLY CHANGES IN SEX H O R M O N E PROFILE A N D G Y N A E C O M A S T I A I N D U C E D BY BICALUTAMIDE 150 MG?
Salvador C., Trilla E., Esquena S., Abascal J., Ceccbini L., Ravent6s C., Planas J., Catalfin R., Morote J. Hospital Vall d'Hebron, Urology, Barcelona, Spain INTRODUCTION & OBJECTIVES: Anaemia has been described as a common side effect of androgen deprivation therapy (ADT). It is believed that anaemia is more frequent and great in patients under maximal androgen blockade (MAB). However, any study comparing anaemia between castration and MAB has been reported. The objective of this study was to analyze the anaemia induced by ADT, even under castration or MAB. MATERIAL & METHODS: Complete blood cell count with differential and red blood cell indices were evaluated in 308 patients with non metastatic prostate cancer in a prospective cross-sectional study. A group of 106 patients submitted to radical prostatectomy alone and free of biochemical relapse became the control group and other 202 patients under castration with LH-RH agonist (128 of them plus bicalntamide, MAB) became the study group. The median age was 70 years (53-89) and the mean follow up of the patients under ADT was 42.5 months (6-218). In 201 patients, 46 of the control group, 101 under MAB and 54 under castration, a serum determination of ferritin, folates, B2 vitamin, transferrin, iron, transferrin saturation and haptoglobin was determined.
Comhaire F5, Van Cangh P?, Van Poppel H. 3 1UZ Gent, Endocrinology, Gent, Belgium, 2Cliniques Universitaires Saint Luc, Urology, Brussels, Belgium, 3KUL, Urology, Leuven, Belgium INTRODUCTION & OBJECTIVES: Gynaecomastia and/or breast pain are the most frequent side-effects of bicalutamide 150 mg daily, with a reported prevalence of approximately 86%. There are presently no known predictors of the development of gynaecomastia. Here, we have prospectively measure changes in several sex hormones m 130 consecutive patients receiving bicalutamide. MATERIAL & METHODS: Patients included in the study should not have received bicalutamide for longer than 14 days before inclusion. At inclusion and after 4 weeks, sex hormone levels were determined (total estradiol (E2), free estradiol (fE2), 17/3-estradiol (I713-E2), total testosterone (T), free testosterone (ff), dihydrotestosterone (DHT), steroid hormone binding globulin (SHBG), luteinizing hormone (LH), prolactin (PRO)), and triglycerides (TG). All samples were taken at about the same time in the morning, to avoid the effects of diurnal fluctuations.
RESULTS: Patients under ADT had a significant decrease in the red blood cells quantification related to those of the control group, 4.8x10E12/L (3.3-5.9) and 4.3x10E12/L (3.4-5.4) respectively, p<0.001. Serum haemoglobin was 14.7 g/dL (10.i-18.7) and 13.2 g/dL (6.5-16.8) respectively, p<0.001. Haematocrito was 43.5% (30.3-53.7) and 39.2% (22-49.1) respectively, p<0.001. The mean corpuscular volume and the mean corpuscular haemoglobin were similar in both groups, p>0.05. The comparison between the group of patients under castration and MAB demonstrated not significant differences in any of the analyzed parameters, p>0.05. The serum level of haemoglobin in patients under ADT decrease at 6 and 12 months of follow up and thereafter it was stable. The rate of patients with anaemia (Hb < 13 g/dL) was 7.3% in the control group and 43.7% in those patients under ADT. However, the concentration of serum Hb lower than 11 g/dL was 0.9 and 2.3% respectively.
RESULTS: After 6 months of treatment, 74% of the patient had developed some level of gynaecomastia, including only 19% with bothersome symptoms. In most cases, symptoms appeared 3-4 months after the start of the treatment. Significant changes (p <0.05) were measured in SHBG (from 40.3 to 44.8 nM/1), T (from 495 to ng/dl), DHT (from 62 to 83 nM/1), E2 (from 27 to 35 pg/ml), 1713-E2 (from 0.57 to 0.71 pg/ml), and PRO (from 11.4 to 13.4 ng/ml). No significant difference was found in hormone levels between patients with bothersome gynaecomastia and those without gynaecomastia, neither at baseline nor after one month of follow-up. From a logistic regression model, early changes in SHBG, DHT, E2, Free E2 and the ratio fE2/tT were retained as predictive factors (!0: 0.04). Patients with increased SHBG and fE2 are highly likely to develop bothersome gynaecomastia (O.R. 24.4 and 18.4 respectively), while a negative association was with DHT and E2 (OR 0.41 and 0.08 respectively) but with lower statistical power. However, this model is poorly predictive of the development of bothersome gynaecomastia. Among the choices of criterion values (ROC analysis) the model reached, at best, a sensitivity of 62.5% and a specificity of 49.2% with a false positive rate of 77.3%.
CONCLUSIONS: ADT associates frequently with a normocytic and normochromic anaemia. Serum haemoglogin declines mainly during the first 12 months of ADT and them stabilizes. MAB is not associated with a higher risk of anaemia compared to those patients treated with LH-RH agonist alone.
CONCLUSIONS: Several hormonal changes have been identified in patients receiving bicalutamide 150 mg. Despite a linear relation between some sex hormone factors and bothersome gynaecomastia, the corresponding model does not although reliably predict its development.
European Urology Supplements 4 (2005) No. 3, pp. 227