| Objective: To investigate the risk factors and prognosis analysis of patients with prostate cancer after endocrine therapy.also detected the relationship between the expression level changes of Neurotensin before and after endocrine therapy and clinical pathological features and survival time of patients with CRPCMethods: 371 patients with prostate cancer from January 2010 to August 2015 are admitted,among which 152 cases are included in this study.There are 30 cases who had been excluded from the study because of loss to follow up,therefore the research has followed up 122 patients through telephone to learn patient's survival situation till January 29,2016.The follow-up range was 5 months to 72 months and the median follow-up time was 28 months.Results:1.Clinical characteristic and Survial situation122 patients with prostate cancer were 51~88 years old,with an average age of 70.1years.All of the patients' body mass index(BMI)is17.2~34.2Kg/?(mean value is 24.0Kg/?).There are 7(7/122)patients whose BMI are lower than18.5Kg/ ?,which accounts for 5.7%.There are 49(49/122)patients whose BMI range from 18.5Kg/?to 24 Kg/?,which accounts for 40.2%.There are 36(36/122)patients whose BMI range from 24Kg/? to 27 Kg/?,which accounts for 29.5%.There are 24(24/122)patients whose BMI range from 27Kg/? to 30 Kg/?,which accounts for 19.7%.There are 6(6/122)patients whose BMI are higher than 30 Kg/?,which accounts for 4.9%.61.5%(75/122)of patients with prostate cancer who have been treated by hormone therapy progressed to have castration resistant prostate cancer(CRPC).Among these patients,34.7%(26/75)of patients have progressed to have CRPC in less than 18 months,while 48%(36/75)of patients have progressed to have CRPC in 18 months to36 months,and 17.3%(13/75)patients have progressed to have CRPC in more than36 months.The median time is 22 months.According to the 2002 AJCC(American Joint Committee on Cancer)staging system,40.2%(49/122)cases in stage T1~T2,of which 36.7%(18/49)progressed to have CRPC;59.8%(73/122)cases are in stage T3~T4,of which 78.1%(57/73)progressed to have CRPC.The two groups were statistically significant(P<0.05).The time that the patients has progressed CRPC clinically: 34.7%(26/75)of cases in less than 18 months,including 3.8% of cases in stage T1~T2(1/26)and 96.2% of cases in stage T3~T4;48%(36/75)of cases range from 18 months to 36 months,including 30.6%(11/36)of cases in stage T1~T2 and 69.4%(25/36)of cases in stage T3~T4;17.3%(13/75)of cases in more than 36 months,including 46.2% of cases in stage T1~T2(6/13)and 53.8% of cases in stage T3~T4(7/13).Pathological grading by Gleason scoring system: 12.3%(15/122)of cases have 6scores,of which 40%(6/15)patients with CRPC;31.1%(38/122)of cases have 7scores,of which 42.1%(16/38)cases with CRPC;56.6%(69/122)of cases have more than 8 scores,of which 76.8%(53/69)of cases with CRPC.The three groups were statistically significant(P<0.05).According to the progress time of CRPC,we divided it into three groups,the first group consists of patients with CRPC in less than 18 months(26/75,34.7%),of which 15.4%(4/26)of cases have 6 to 7 scores and 84.6%(22/26)of cases have 8 to10 scores.The second group consists of patients with CRPC in >18?36 months(36/75,48%),of which 36.1%(13/36)of cases have 6 to 7 scores and 63.9%(23/69)of cases have 8 to 10 scores.The third group consists of patients with CRPC in more than 36 months(17.3%,13/75),of which 38.5%(5/13)of cases have 6 to 7 scores and61.5%(8/13)of cases have 8 to 10 scores.6.6%(8/122)of cases have progressed to PSA lower than10 ng/ml,of which 50%(4/8)of cases have CRPC.22.1%(27/122)of cases have PSA between 10 to 20 ng/ml,of which 51.9%(14/27)of cases have progressed to CRPC.71.3%(87/122)of cases have PSA higher than 20 ng/ml,of which 65.5%(57/87)of cases have progressed to CRPC.The three groups have no statistical significance(P>0.05).According to the progress time of CRPC,we divided it into three groups.The first group consists of patients with CRPC in less than 18 months(26/75,34.7%),of which 3.8%(1/26)of cases have PSA lower than 10 ng/ml,7.7%(2/26)of cases have PSA between 10 to 20 ng/ml and 88.5%(23/26)of cases have PSA level higher than20 ng/ml.The second group consists of patients with CRPC in >18?36 months(36/75,48%),of which 5.6%(2/36)of cases have PSA lower than 10 ng/ml,19.4%(7/36)of cases have PSA between 10 to 20 ng/ml and 75%(27/36)of case have PSA higher than 20 ng/ml.The third group consists of patients with CRPC in more than 36months(13/75,17.3%),of which 7.7%(1/13)of cases have PSA lower than 10 ng/ml,38.5%(5/13)of cases have PSA between 10 to 20 ng/ml and 53.8%(7/13)of cases have PSA higher than 20 ng/ml.The lowest value of serum PSA was 0~450(ng/ml)during endocrine therapy,and the median value was 0.4ng/ml.According to the minimum level of PSA,we divided it into two groups.There are 51(51/122)patients in the first group whose PSA were lower than or equal to 0.4ng/ml,which accounts for 41.8%.And there are 71(71/122)patients in the second group whose PSA level were higher than 0.4ng/ml,which accounts for 58.2%.The two groups were statistically significant(P<0.05).According to the progress time of CRPC,we divided it into three groups.The first group consists of patients with CRPC in less than 18 months(26/75,34.7%),of which 11.5%(3/26)of cases have PSA level lower than or equal to 0.4 ng/ml and88.5%(23/26)of cases have PSA level higher than 0.4 ng/ml.The second group consists of patients with CRPC in >18?36 months(36/75,48%),of which 22.2%(8/36)of cases have PSA level lower than or equal to 0.4 ng/ml and 77.8%(28/36)of cases have PSA level higher than 0.4 ng/ml.The third group consists of patients with CRPC in more than 36 months(13/75,17.3%),of which 30.8%(4/13)of cases have PSA level lower than or equal to 0.4 ng/ml and 69.2%(9/13)of cases have have PSA level higher than 0.4 ng/ml.(70/122)patients who have no metastasis(M0),which accounts for 57.4%,of which38.6%(29/70)of patients have progressed to CRPC,and the median progression time was 27 months.(41/122)patients who have bone metastasis(M1b),which accounts for 33.6%,of which 90.2%(37/41)of patients have progressed to CRPC,and the median progression time was 21 months.(11/122)patientswho have organ metastasis with or without bone metastasis(M1c),which accounts for 9%,of which all patients have progressed to CRPC,and themedian progression time was 18 months.The three groups were statistically significant.(P<0.05)(69/122,56.6%)patients who have endocrine therapy alone.10.1%(7/69)of patients who have surgical castration combined with anti androgen therapy have progressed to CRPC,the median progression time was 28 months;and 89.1%(62/69)of patients have drug therapy combined with anti androgen therapy,of which 77.4%(48/62)of patients have progressed to CRPC and 22.6%(14/62)of patients haven't progressed to CRPC,the median progression time was 18.4 months.There were 33(33/122,27%)patients who have radical resection combined with endocrine therapy,of which21.2 %(7/33)of patients have progressed to CRPC and median progression time was54 months.There were 20(20/122,16.4%)patients who have brachytherapy combined with endocrine therapy,of which 65%(13/20)of cases have progressed to CRPC and the median progression time was 39 months.The three groups were statistically significant.(P<0.05)Till the last follow-up period of January 29,2016,77(77/122,63.1%)patients survived and 45(45/122,36.9%)died.40(40/45,88.9%)patients died of advanced prostate disease and 5 patients(5/45,11.1%)died of other diseases.The survival rate of 1,2,3,4 and 5 years were 97.5%,91.8%,83.6%,75.4% and 68% respectively.The survival rate of patients with CRPC of 1,2,3,4 and 5 years were 98.7%,92%,81.3%,65.3% and 54.7% respectively.2.Experimental results2.1 immunohistochemistry;75 patients with CRPC are admitted to the urology department of the Second Hospital of Tianjin Medical University from January 2010 to Aug 2015.Pathological data indicates all the cases were diagnosed as prostate cancer.The NTs expression level in specimen and significance in 56 cases before androgen deprivation therapy and 36 cases after androgen deprivation therapy are tested.The results of this study showed that the positive rate of NTs expression was19.6%(11/56)in 56 cases before ADT.After ADT,the positive rate of NTs expression was 38.9%(14/36)in 36 cases.The results abovementioned showed that the positive rate of NTs expression after ADT was higher than that before ADT.two groups werestatistically significant(P<0.05).The positive rate of neuroendocrine differentiation marker(Cg A)expression was35.7%(20/56)in 56 cases before androgen deprivation therapy.After androgen deprivation therapy,the positive rate of Cg A expression was 61.1%(22/36)cases in36 cases.The results showed that the positive rate of Cg A expression after ADT was higher than that before ADT.two groups were statistically significant(P<0.05).(1)Gleason score The positive rate of Gleason score(6~7 scores)was13.3%(2/15)before androgen deprivation therapy and the positive rate of Gleason score(8~10 scores)was 22%(9/41)before androgen deprivation therapy in 56 cases.Afterandrogen deprivation therapy,the positive rate of Gleason score(6~7 scores)was 30%(3/10)and the positive rate of Gleason score(8~10 scores)was 42.3%(11/26)in 36 cases.The results showed that the positive rate of NTs expression increases as Gleason score increases and the positive rate of NTs expression after ADT is higher than that before ADT.The results also showed that the positive rate of Cg A expression increases as the increase of Gleason score and the positive rate of Cg A expression ADT was higher than that before ADT.(2)PSA level before treatment In 56 cases of prostate cancer specimens,when PSA ?20 ng/ml before treatment,the positive rate of NTs expression was 18.8%(3/16),otherwise when PSA> 20 ng/ml,the positive rate of NTs expression was 20%(8/40).In 36 cases of prostate cancer specimens,when PSA ?20 ng/ml after treatment,the positive rate of NTs expression was 25%(2/8),otherwise when PSA level> 20 ng/ml,the positive rate of NTs expression was 42.9%(12/28)The results showed that the NTs expression increases as PSA level increases before treatment and the NTs expression decreases as PSA level increases after endocrine treatment.The positive rate of NTs expression after endocrine therapy was higher than that before treatment.The results also showed that the expression of Cg A expression increases as PSA level increases before endocrine therapy and the expression of Cg A decreases as PSA level increases after endocrine therapy.The positive rate of Cg A expression after endocrinetherapy was higher than that before treatment.(3)Clinical stage Before endocrine treatment,the positive expression of NTs expression in patients with stage T2 was 13.3%(2/15),and the positive rate of NTs expression in patients with stage T3 ~ T4 was 22%(9/41)in 56 cases.After endocrine treatment,the positive expression of NTs expression in patients with stage T2 was 37.5%(3/8)and the positive rate of NTs expression in patients with stage T3 ~ T4 was 39.3%(11/28)in 36 cases.The results showed that the positive rate of NTs expression gradually increases as clinical stage increases.The positive rate of NTs expression after treatment was higher than that before treatment.The results of this study also showed that the positive rate of Cg A expression gradually increases as clinical stage increases.The positive rate of Cg A expression after treatment was higher than that before treatment.(4)distant metastasis The positive rate of NTs expression in patients without distant metastasis(M0)before endocrine treatment was 13%(3/23),and that in patients with bone metastasis alone(M1b)was 23.3%(7/30),and that in patients with organ metastasis(M1C)was 33.3%(1/3)in 56 cases.After endocrine treatment in 36 patients,the positive rate of NTs expression in patients without distant metastasis(M0)was 27.3%(3/11),that in patients with bone metastasis alone(M1b)was 40%(8/20),and that in patients with organ metastasis(M1C,with or without bone metastasis)was 60%(3/5).The results showed that the positive rate of NTs expression in patients without distant metastasis is lower than that in patients with bone metastasis alone and organ metastasis.The positive rate of NTs expression in patients with organ metastasis was higher than that in patients with bone metastasis alone.The positive rate of NTs expression after endocrine treatment was higher than that before treatment.The results of this study also showed that the positive rate of Cg A expression in patients without distant metastasis(M0)was lower than that in patients with bone metastasis alone(M1b)and organ metastasis(M1c),and the positive rate of Cg A expression in patients with organ metastasis(M1c)was higher than that in patients with bone metastasis alone(M1b).The positive rate of Cg A expression afterendocrine treatment was higher than that before treatment.(5)The relationship between NTs and Cg A Before endocrine therapy,the positive rate of neuroendocrine differentiation(Cg A)expression was 35.7%(20/56),including 20%(4/20)of cases have positive NTs expression.After endocrine therapy,the positive rate of neuroendocrine differentiation(Cg A)expression was 61.1%(22/36),including 40.9%(9/22)of cases have positive NTs expression.The relevance between NTs and Cg A is computed by SPSS V20 Spearman,which showed that NTs is not related to Cg A before endocrine treatment(P>0.05)and NTs is positively correlated to Cg A after endocrine treatment(P< 0.05).2.2 Enzyme linked immunosorbent assay(ELISA)results75 patients with CRPC are admitted to the urology department of the Second Hospital of Tianjin Medical University from January 2010 to Aug 2015.And the NTs expression level in plasma of 30 cases before and after androgen deprivation therapy are tested to explore the the significant relationship between NTs expression level and prognosis of patients with CRPC.The plasma in 30 patients with CRPC were tested before and after endocrine therapy in all stages(during endocrine treatment,when endocrine treatment failed and progressed to CRPC)to see NTs expression changes.The plasma in 20 healthy volunteers were tested as well to see NTs expression as control group.The results showed that the NTs expression level in the control group(0.053±0.02)was lower than that(0.29±0.49)in patients with CRPC before the endocrine treatment,and the NT expression level after treatment were 0.42±0.63 and 0.5±0.72 respectively The results showed that NTs expression level increases as endocrine treatment advances.The four groups were statistically significant(P<0.05).2.2.1 The relationship between clinicopathological features and NT expression level(ng/ml);(1)The relationship between NTs and Gleason score The results showed that when Gleason score ranges from 6~7 scores,NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.261±0.444,0.306±0.56,0.449± 0.69respectively.When,NT expression level were 0.308±0.522,0.486±0.674,0.531±0.755 respectively.The NTs expression level increases as Gleason score increases.The NTs level when Gleason score ranges from 8~10 scores is higher than that when Gleason score ranges from 6~7 scores,and there is no statistical significance between the two groups(P>0.05).(2)The relationship between NTs and clinical stage When patients were in stage T2 clinically,NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.277±0.477,0.398±0.649 and 0.415±0.624 respectively.When patients were in stage T3~T4 clinically,NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.378±0.628,0448±0.775 and 0.525±0.943 respectively.The NTs expression level increases as clinical stage increases.The NTs level when patients are in stage T3~T4 clinically is higher than that when patients are in stage T2clinically(no pathological result when patients are in stage T1).There is no statistical significance between the two groups(P>0.05)(3)The relationship between NTs and distant metastasis When patients don't have distant metastasis(M0),NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.055±0.007,0.06±0.028,0.07±0.014 respectively.When patients have bone metastasis(M1b)alone,NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.324±0.525,0.402±0.615,0.498 ±0.717 respectively.When patients have organ metastasis(M1c),NTs expression level before endocrine treatment,during endocrine treatment and when endocrine treatment failed and progressed to CRPC were 0.234±0.412,0.644±0.824,0.686±0.899 respectively.The Results showed that the NTs level when patients have bone metastasis alone before endocrine treatment was higher than that when patients have organ metastasis or patients don't have metastasis.During endocrine treatment and when endocrine treatment failed and progressed to CRPC,NTs level in patients with organ metastasiswas higher than that in patients with bone metastasis or patients without metastasis.NTs level in patients with bone metastasis was higher than that in patients without metastasis.The three groups had no statistical significance(P>0.05).(4)The relationship between NTs and PSA The results showed that NT level increased as PSA increased before endocrine treatment when endocrine treatment failed and progressed to CRPC,and NTs level decreased as PSA increased during endocrine treatment and after 3 cycles of chemotherapy of CRPC.The results showed that NTs levels decreased as PSA level elevated and NTs levels increased as PSA level decreased.(5)The relationship between NTs and FPSA Before and during endocrine treatment and after 3 cycles of chemotherapy of CRPC,NT level decreased as FPSA level elevated while NTs level increased as FPSA decreased.When endocrine treatment failed and progressed to CRPC,NTs level increased as FPSA level elevated.(6)The relationship between NTs and testosterone The results showed that NTs level increased as testosterone level increased before endocrine.During endocrine treatment and when endocrine treatment failed and progressed to CRPC and after 3 cycles of chemotherapy of CRPC,NTs level increased as testosterone level decreased while NT level decreased as testosterone level increased;2.2.2 The relationship between survival time and NTs expression level Till January 29,2016,the most recent follow-up time,43.3%(13/30)of patients survived while 56.7%(17/30)of patients died.The average survival time of 30 patients with CRPC was 14.3(5~24)months;when NT level increased,30% of patients with CRPC have the average survival time of 14(5~23)months;when NTs level was normal,70% of patients with CRPC have the average survival time of 15(5 ~24)months.The results showed that the survival time of patients with normal NTs level was higher than that in patients with elevated NTs level and NTs level could be used as a prognostic indicator of castration resistant prostate cancer(CRPC).Conclusions;1.Studies show that NTs expression level increases as CRPC advances and NTs expression level before treatment is lower than that after treatment for CRPC.NTs expression level when endocrine treatment failed and progressed to CRPC is higher than that during endocrine treatment.NTs could be expected to be one independent indicator in the treatment for CRPC.2.Patients who have low NTs expression level have higher survival rate than that patients who have high NTs expression level,therefore NTs could be used as an prognostic indicator of patients with castration resistant prostate cancer(CRPC).3.The expression level of NTs is closely related to neuroendocrine differentiation of castration resistant prostate cancer.4.Patients who have been treated by endocrine therapy alone have shorter survival period than that of those patients who have underwent radical resection combined with endocrine therapy and who have undergone brachytherapy combined with endocrine therapy.Therefore,it is one of factors affecting prognosis.5.Patients who have distant metastasis have greater risk of progression to CRPC and shorter survival period than those patients who haven't had distant metastasis.Therefore,metastasis is one of independent prognostic factors for prostate cancer patients to progress to CRPC and survival period.6.The higher the level of PSA during endocrine therapy,the greater the risk of developing CRPC,the shorter the survival time,which is an independent prognostic factor for prostate cancer patients to progress to CRPC and survival period.7.The higher the clinical stage,the greater the risk of developing CRPC,the shorter the survival time,which is an important factor for prostate cancer patients to progress to CRPC and survival period. |
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