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SERUM CHROMOGRANINE A AND CHEMOTHERAPY IN HORMONE RESISTANT PROSTATE CANCER
285
286
INCREASE OF CIRCULATING CHROMOGRANIN A IN PATIENTS WITH HORMONE-REFRACTORY PROSTATE CANCER
SERUM CHROMOGRANINE A AND CHEMOTHERAPY IN HORMONERESISTANT PROSTATE CANCER
Hirano D., Minei S., Sugimoto S., Yamaguchi K., Yoshikawa T., Yoshida T.
Guy L.1, Cabrespine A.2, Bay J.O.B.2, Chollet P.2, Boiteux J.P.1
Nihon University School of Medicine, Urology, Tokyo, Japan INTRODUCTION & OBJECTIVES: Recently, several studies involving the evidence of our previous immunohistochemical studies demonstrated that chromogranin A (CgA) stained carcinoma cells were significantly increased in hormone refractory prostate cancer (HRPC) and that HRPC following long-term androgen deprivation therapy was an independent predictor of neuroendocrine differentiation. However, the implications of circulating CgA levels in prostate cancer patients remain unclear. We studied to determine whether measurement of circulating CgA levels in patients with prostate cancer who had various clinical stages including hormone refractoriness status provides clinicopathological and prognostic information in prostate cancer.
1
G. Montpied Hospital, Department of Urology, Clermont-Ferrand, France,
2
Anticancer Centre, Clermont-Ferrand, France
INTRODUCTION & OBJECTIVES: The aim of this study was to evaluate the clinical relevance of serum Chromogranine A (CgA) for hormone-resistant prostate cancers treated by chemotherapy.
MATERIAL & METHODS: Between 1999 and 2003, plasma CgA levels were measured using a commercial enzyme-linked immunoadsorbent assay kit (DAKO CgA ELISA Kit, DK2600 Glostrup, Denmark) in 57 patients with histologically confirmed prostate cancer (22 stage B or less, 10 stage C, 2 stage D1 and 23 stage D2), and in 22 patients with undetected prostate cancer who underwent needle biopsy for suspected prostate cancer as a gray zone of serum PSA levels. of the patients with stage D2 11 had HRPC after androgen deprivation therapy at the time of blood sampling. Normal values of plasma CgA were defined as less than 20 U/L according to the modified commercially available data. Associations between groups and various parameters were evaluated using the Mann-Whitney U test and the Kruskal-Wallis rank test. The predictor variables were used in a logistic regression model for multivariate analysis. Cancer-specific survival curves tested using the Kaplan-Meier method and compared with the log-rank test.
MATERIAL & METHODS: Serum concentration of CgA was measured by
RESULTS: The median plasma CgA value in prostate cancer and undetected cancer was18.0 U/L (range: 5.6 - 116.0 U/L) and 12.8 U/L (range: 7.1 - 21.5 U/L), respectively (p=0.0271). The higher stage (p<0.001) and higher grade (p=0.0412) were significantly associated with higher plasma CgA levels. By multivariate a logistic regression model of plasma CgA, serum PSA and tumour grade, plasma CgA was the only independent predictor (relative risk: 1.158, 95%CI: 1.059-1.267, p=0.0013) for advanced stages with hormone refractoriness status. Of the 23 patients with stage D2, 18 (78%) had above normal CgA levels. With a median followup time of 23 months the cancer-specific survival rate at 3 years was 80% in those with normal CgA levels and 34% in those with above normal CgA levels. The patients with above normal CgA levels were associated with a poor prognosis in the subgroup (p=0.0416).
found between CgA level and initial PSA level. A decrease in PSA of more than
CONCLUSIONS: The present study showed that plasma CgA level in prostate cancers increases with severity of the disease, especially progressive HRPC after hormone therapy. Although comprised of a small number of patients and a cross sectional study, this marker may effectively predict a HRPC status and worse prognosis in metastases cases.
CONCLUSIONS: Serum CgA dosage could facilitate selection of patients with
radio-immunology in 39 patients randomly treated either by mithoxantrone or by an association of paclitaxel and carboplatine. The baseline level of CgA and its variations during chemotherapy were studied. RESULTS: CgA levels were superior to normal values in 45% of the patients. Initial serum CgA values were increased with duration of hormonal treatment (p = 0.000083) or by previous treatment by radiotherapy (p = 0.004) . No correlation was
50% was significantly associated with a higher serum CgA level before treatment. Likewise, an objective response of measurable lesions was significantly greater in patients with higher baseline CgA levels. Moreover, response to chemotherapy appreciated either by decrease of PSA or by measurable lesions was correlated to a decrease of more than 25% in CgA (p = 0.022 and 0.039, respectively).
a good chance of response to chemotherapy and provide additional elements to evaluate this response.
287
288
RANDOMISED STUDY OF DOCETAXEL (D) AND DEXAMETHASONE (DX) WITH LOW OR HIGH DOSE ESTRAMUSTINE (E) FOR PATIENTS WITH ADVANCED HORMONE-REFRACTORY PROSTATE CANCER (HRPC)
A PHASE II CLINICAL STUDY OF HIGH-DOSE CALCITRIOL PLUS DOCETAXEL AND ZOLEDRONIC ACID IN HORMONE-REFRACTORY PROSTATE CANCER (HRPC)
1
1
1
2
1
Nelius T. , Klatte T. , Reiher F. , Yap R. , Allhoff E.P.
Otto-von-Guericke-University Magdeburg, Urology, Magdeburg, Germany, 2Northwestern University Chicago, Urology, Chicago, United States
1
INTRODUCTION & OBJECTIVES: D-based chemotherapy is a burgeoning option for men with advanced HRPC. Alone or in combination with E, D has been shown to improve median survival. In this study we tested the combination of D with two different doses of E in patients (pts) with HRPC to improve response rates and to lower side effects. MATERIAL & METHODS: 72 metastatic HRPC pts were randomly assigned to receive D(70mg/m2 IV, d2, q3w) and E (3 x 280 mg/d PO starting 1 day prior to D, for 5 consecutive days) for arm A or E (3 x 140 mg/d PO starting 1 day prior to D, for 3 consecutive days) for arm B. Premedication with oral DX at a total daily dose of 16 mg, in divided doses two times a day was administered in arm A on day 1 to 5 and in arm B on day 1 to 3. Initially, 6 cycles were administered. Chemotherapy was restarted after significant PSA rise. Pts were monitored for measurable PSA response, time to progression (TTP), survival and toxicity. RESULTS: PSA declines of ≥75%, ≥50% and ≤50% were 36.8%, 55.3% and 44.7% in arm A and 38.2%, 67.6% and 32.4% in arm B, respectively (P=.442). TTP in Arm A and Arm B were 11 months (95% CI, 7-14) versus 14 months (95% CI, 8-19), P=.6911) and overall survival 21 months (95% CI, 6-35) versus 22 months (95% CI, 18-27) , respectively, (P=.4149). The primary treatment-related side effects observed in arm A and arm B were granulocytopenia (34% and 29%, P=.663) and thrombotic complications caused by E (four pts (11%) and one pt (3%), respectively, P=.206). Associated baseline factors with overall survival in univariate analysis were ECOG performance status (P<.001), haemoglobin level (P<.001), bone pain (P<.001), and PSA (P<.097) and in multivariate analysis ECOG performance status (95% CI, 2.9-13.9) and bone pain (95% CI, 3.2-20.1), (P<.001). CONCLUSIONS: In this randomised phase II study the combination of D and E had substantial activity in HRPC. We did not find a statistically significant difference of higher dose of E in combination with D compared to a lower dose of E and D regarding PSA response, TTP and survival. However, there was a tendency of higher toxicity in the high dose E group. These treatment-related toxicities were mainly hematologic and manageable. Our data support the use of D/E low dose scheme as first line therapy for HRPC. There was a clear improvement in survival compared to historical treatment groups employing mitoxantrone.
Eur Urol Suppl 2006;5(2):94
Bulbul M.1, Shamseddine A.2, Makarem J.2, Abdel Khalik Z.2, Taher A.2, El-Saghir N.2, Khawli R.2, Hemadeh K.2 1 American University of Beirut Medical Center, Surgery, Beirut, Lebanon, 2American University of Beirut Medical Center, Internal Medicine, Beirut, Lebanon
INTRODUCTION & OBJECTIVES: The purpose of this study is to assess the efficacy and safety of the use of Calcitriol, Docetaxel and Zoledronic acid in patients with metastatic HRPC. The primary end points of the study are the prostate-specific antigen PSA response, response in measurable disease and time to disease progression. Secondary end points will include toxicity profile. MATERIAL & METHODS: 16 patients with HRPC were enrolled. All recruited patients had historically confirmed diagnosis of prostate cancer and no previous cytotoxic therapy (chemonaive) and they all signed an informed consent. Patients received Calcitriol 0.5μg/kg on day 1 on weekly basis six out of eight weeks, Docetaxel 36mg/m2 on day 2 on weekly basis six out of eight weeks, and Zoledronic acid 4mg on week 1 and 5. Response was defined as more than 50% drop in PSA or decrease in measurable disease. Treatment was continued as long as there was response and no severe toxicity occurred. RESULTS: The median age was 77 ± 5.2 years (range 67-85). The involved sites of metastasis were bone (68.8%), lymph nodes (43.8%) and visceral 25%. Only 6.3% of the recruited patients had both visceral and lymph nodes involvement. Two patients (12.5%) were excluded from the analysis because they experienced serious side-effects during the first cycle of treatment and treatment was discontinued. The overall PSA response rate of our population was 57.2%. Out of the 14 patients analysed 8 (57.2%) patients had a PSA decline of more than 50%, 7 (50%) patients had a PSA decline of more than 75%. The median time to disease progression was 6.5 months (range 2-15). The 1-year survival was 57.1% (8 out of 14 patients). of the 11 patients with measurable disease, partial response by RECIST criteria was observed in 4 (36.3%), stable disease in 6 (54.5%), and progression in 1 (9%) patient. Toxicity was acceptable and no treatment–related mortality was encountered. Out of the remaining 14 patients, 7 (50%) patients showed grade III-IV nail toxicity secondary to Docetaxel, and 10 (71.4%) showed grade II to III sensory neuropathy. One patient (7.1%) reported grade IV anemia and required blood transfusion. No grade IV neutropenia or thrombocytopenia was reported. CONCLUSIONS: The overall response of 57.2% suggests that the combination of high dose Calcitriol, Docetaxel and Zoledronic acid can achieve a favourable PSA response with acceptable toxicity. The addition of Calcitriol to Docetaxel yielded a PSA response of 57.2% as compared to a 38-46% in studies using Docetaxel alone. These preliminary findings support the synergistic anti-tumour activity of Calcitriol in combination with Docetaxel. The study is still open for patient recruitment.
286
INCREASE OF CIRCULATING CHROMOGRANIN A IN PATIENTS WITH HORMONE-REFRACTORY PROSTATE CANCER
SERUM CHROMOGRANINE A AND CHEMOTHERAPY IN HORMONERESISTANT PROSTATE CANCER
Hirano D., Minei S., Sugimoto S., Yamaguchi K., Yoshikawa T., Yoshida T.
Guy L.1, Cabrespine A.2, Bay J.O.B.2, Chollet P.2, Boiteux J.P.1
Nihon University School of Medicine, Urology, Tokyo, Japan INTRODUCTION & OBJECTIVES: Recently, several studies involving the evidence of our previous immunohistochemical studies demonstrated that chromogranin A (CgA) stained carcinoma cells were significantly increased in hormone refractory prostate cancer (HRPC) and that HRPC following long-term androgen deprivation therapy was an independent predictor of neuroendocrine differentiation. However, the implications of circulating CgA levels in prostate cancer patients remain unclear. We studied to determine whether measurement of circulating CgA levels in patients with prostate cancer who had various clinical stages including hormone refractoriness status provides clinicopathological and prognostic information in prostate cancer.
1
G. Montpied Hospital, Department of Urology, Clermont-Ferrand, France,
2
Anticancer Centre, Clermont-Ferrand, France
INTRODUCTION & OBJECTIVES: The aim of this study was to evaluate the clinical relevance of serum Chromogranine A (CgA) for hormone-resistant prostate cancers treated by chemotherapy.
MATERIAL & METHODS: Between 1999 and 2003, plasma CgA levels were measured using a commercial enzyme-linked immunoadsorbent assay kit (DAKO CgA ELISA Kit, DK2600 Glostrup, Denmark) in 57 patients with histologically confirmed prostate cancer (22 stage B or less, 10 stage C, 2 stage D1 and 23 stage D2), and in 22 patients with undetected prostate cancer who underwent needle biopsy for suspected prostate cancer as a gray zone of serum PSA levels. of the patients with stage D2 11 had HRPC after androgen deprivation therapy at the time of blood sampling. Normal values of plasma CgA were defined as less than 20 U/L according to the modified commercially available data. Associations between groups and various parameters were evaluated using the Mann-Whitney U test and the Kruskal-Wallis rank test. The predictor variables were used in a logistic regression model for multivariate analysis. Cancer-specific survival curves tested using the Kaplan-Meier method and compared with the log-rank test.
MATERIAL & METHODS: Serum concentration of CgA was measured by
RESULTS: The median plasma CgA value in prostate cancer and undetected cancer was18.0 U/L (range: 5.6 - 116.0 U/L) and 12.8 U/L (range: 7.1 - 21.5 U/L), respectively (p=0.0271). The higher stage (p<0.001) and higher grade (p=0.0412) were significantly associated with higher plasma CgA levels. By multivariate a logistic regression model of plasma CgA, serum PSA and tumour grade, plasma CgA was the only independent predictor (relative risk: 1.158, 95%CI: 1.059-1.267, p=0.0013) for advanced stages with hormone refractoriness status. Of the 23 patients with stage D2, 18 (78%) had above normal CgA levels. With a median followup time of 23 months the cancer-specific survival rate at 3 years was 80% in those with normal CgA levels and 34% in those with above normal CgA levels. The patients with above normal CgA levels were associated with a poor prognosis in the subgroup (p=0.0416).
found between CgA level and initial PSA level. A decrease in PSA of more than
CONCLUSIONS: The present study showed that plasma CgA level in prostate cancers increases with severity of the disease, especially progressive HRPC after hormone therapy. Although comprised of a small number of patients and a cross sectional study, this marker may effectively predict a HRPC status and worse prognosis in metastases cases.
CONCLUSIONS: Serum CgA dosage could facilitate selection of patients with
radio-immunology in 39 patients randomly treated either by mithoxantrone or by an association of paclitaxel and carboplatine. The baseline level of CgA and its variations during chemotherapy were studied. RESULTS: CgA levels were superior to normal values in 45% of the patients. Initial serum CgA values were increased with duration of hormonal treatment (p = 0.000083) or by previous treatment by radiotherapy (p = 0.004) . No correlation was
50% was significantly associated with a higher serum CgA level before treatment. Likewise, an objective response of measurable lesions was significantly greater in patients with higher baseline CgA levels. Moreover, response to chemotherapy appreciated either by decrease of PSA or by measurable lesions was correlated to a decrease of more than 25% in CgA (p = 0.022 and 0.039, respectively).
a good chance of response to chemotherapy and provide additional elements to evaluate this response.
287
288
RANDOMISED STUDY OF DOCETAXEL (D) AND DEXAMETHASONE (DX) WITH LOW OR HIGH DOSE ESTRAMUSTINE (E) FOR PATIENTS WITH ADVANCED HORMONE-REFRACTORY PROSTATE CANCER (HRPC)
A PHASE II CLINICAL STUDY OF HIGH-DOSE CALCITRIOL PLUS DOCETAXEL AND ZOLEDRONIC ACID IN HORMONE-REFRACTORY PROSTATE CANCER (HRPC)
1
1
1
2
1
Nelius T. , Klatte T. , Reiher F. , Yap R. , Allhoff E.P.
Otto-von-Guericke-University Magdeburg, Urology, Magdeburg, Germany, 2Northwestern University Chicago, Urology, Chicago, United States
1
INTRODUCTION & OBJECTIVES: D-based chemotherapy is a burgeoning option for men with advanced HRPC. Alone or in combination with E, D has been shown to improve median survival. In this study we tested the combination of D with two different doses of E in patients (pts) with HRPC to improve response rates and to lower side effects. MATERIAL & METHODS: 72 metastatic HRPC pts were randomly assigned to receive D(70mg/m2 IV, d2, q3w) and E (3 x 280 mg/d PO starting 1 day prior to D, for 5 consecutive days) for arm A or E (3 x 140 mg/d PO starting 1 day prior to D, for 3 consecutive days) for arm B. Premedication with oral DX at a total daily dose of 16 mg, in divided doses two times a day was administered in arm A on day 1 to 5 and in arm B on day 1 to 3. Initially, 6 cycles were administered. Chemotherapy was restarted after significant PSA rise. Pts were monitored for measurable PSA response, time to progression (TTP), survival and toxicity. RESULTS: PSA declines of ≥75%, ≥50% and ≤50% were 36.8%, 55.3% and 44.7% in arm A and 38.2%, 67.6% and 32.4% in arm B, respectively (P=.442). TTP in Arm A and Arm B were 11 months (95% CI, 7-14) versus 14 months (95% CI, 8-19), P=.6911) and overall survival 21 months (95% CI, 6-35) versus 22 months (95% CI, 18-27) , respectively, (P=.4149). The primary treatment-related side effects observed in arm A and arm B were granulocytopenia (34% and 29%, P=.663) and thrombotic complications caused by E (four pts (11%) and one pt (3%), respectively, P=.206). Associated baseline factors with overall survival in univariate analysis were ECOG performance status (P<.001), haemoglobin level (P<.001), bone pain (P<.001), and PSA (P<.097) and in multivariate analysis ECOG performance status (95% CI, 2.9-13.9) and bone pain (95% CI, 3.2-20.1), (P<.001). CONCLUSIONS: In this randomised phase II study the combination of D and E had substantial activity in HRPC. We did not find a statistically significant difference of higher dose of E in combination with D compared to a lower dose of E and D regarding PSA response, TTP and survival. However, there was a tendency of higher toxicity in the high dose E group. These treatment-related toxicities were mainly hematologic and manageable. Our data support the use of D/E low dose scheme as first line therapy for HRPC. There was a clear improvement in survival compared to historical treatment groups employing mitoxantrone.
Eur Urol Suppl 2006;5(2):94
Bulbul M.1, Shamseddine A.2, Makarem J.2, Abdel Khalik Z.2, Taher A.2, El-Saghir N.2, Khawli R.2, Hemadeh K.2 1 American University of Beirut Medical Center, Surgery, Beirut, Lebanon, 2American University of Beirut Medical Center, Internal Medicine, Beirut, Lebanon
INTRODUCTION & OBJECTIVES: The purpose of this study is to assess the efficacy and safety of the use of Calcitriol, Docetaxel and Zoledronic acid in patients with metastatic HRPC. The primary end points of the study are the prostate-specific antigen PSA response, response in measurable disease and time to disease progression. Secondary end points will include toxicity profile. MATERIAL & METHODS: 16 patients with HRPC were enrolled. All recruited patients had historically confirmed diagnosis of prostate cancer and no previous cytotoxic therapy (chemonaive) and they all signed an informed consent. Patients received Calcitriol 0.5μg/kg on day 1 on weekly basis six out of eight weeks, Docetaxel 36mg/m2 on day 2 on weekly basis six out of eight weeks, and Zoledronic acid 4mg on week 1 and 5. Response was defined as more than 50% drop in PSA or decrease in measurable disease. Treatment was continued as long as there was response and no severe toxicity occurred. RESULTS: The median age was 77 ± 5.2 years (range 67-85). The involved sites of metastasis were bone (68.8%), lymph nodes (43.8%) and visceral 25%. Only 6.3% of the recruited patients had both visceral and lymph nodes involvement. Two patients (12.5%) were excluded from the analysis because they experienced serious side-effects during the first cycle of treatment and treatment was discontinued. The overall PSA response rate of our population was 57.2%. Out of the 14 patients analysed 8 (57.2%) patients had a PSA decline of more than 50%, 7 (50%) patients had a PSA decline of more than 75%. The median time to disease progression was 6.5 months (range 2-15). The 1-year survival was 57.1% (8 out of 14 patients). of the 11 patients with measurable disease, partial response by RECIST criteria was observed in 4 (36.3%), stable disease in 6 (54.5%), and progression in 1 (9%) patient. Toxicity was acceptable and no treatment–related mortality was encountered. Out of the remaining 14 patients, 7 (50%) patients showed grade III-IV nail toxicity secondary to Docetaxel, and 10 (71.4%) showed grade II to III sensory neuropathy. One patient (7.1%) reported grade IV anemia and required blood transfusion. No grade IV neutropenia or thrombocytopenia was reported. CONCLUSIONS: The overall response of 57.2% suggests that the combination of high dose Calcitriol, Docetaxel and Zoledronic acid can achieve a favourable PSA response with acceptable toxicity. The addition of Calcitriol to Docetaxel yielded a PSA response of 57.2% as compared to a 38-46% in studies using Docetaxel alone. These preliminary findings support the synergistic anti-tumour activity of Calcitriol in combination with Docetaxel. The study is still open for patient recruitment.