Androgen Ablation Following Radiotherapy in Patients with Localized Prostatic Carcinoma

Transcription

1 Med. J. Cairo Univ., Vol. 81, No. 2, March: , Androgen Ablation Following Radiotherapy in Patients with Localized Prostatic Carcinoma EL SAYED M. EL HINDAWY, M.D.*; IBRAHIM A. AWAD, M.D.* and EL-HOUSSEINY EL ZALLOUEY, M.D.** The Departments of Clinical Oncology & Nuclear Medicine* and Surgical Nephrology**, Faculty of Medicine, Mansoura University Abstract Background: Approximately 25% of patients treated with adjuvant radiotherapy (RT) will develop a biochemical failure within 5 yr after RT when doses of Gray (GY) are used. Androgen deprivation therapy (ADT) is increasingly used for the treatment of prostate cancer (PCa), even in clinical settings in which there's no evidence-based proof of prolonged overall survival (OS). ADT, however, may be associated with numerous side effects, including an increased therapy-related cardiovascular mortality. Abstract: This study was performed on forty cases of and locally advanced prostate cancer, with mean follow-up period of 19 months, range (6-42 months). All patients were referred Clinical Oncology and Nuclear Medicine Department Outpatient Clinic, from Urology and Nephrology centre, Mansoura University Hospital, during the period from September 2001 to July And patients were blindly randomized into two groups. Group 1: Included twenty patients, who received combined external beam irradiation and androgen ablation therapy. Group II: Included twenty patients, who received external beam irradiation alone. Radiation therapy was delivered as a conventional fractionation schedule with a dose of 5000cGy over 5.5 weeks in 27 fractions to the whole pelvis followed by 2000cGy boost to the prostate over 2 weeks in 10 fractions. Concurrent and adjuvant hormonal therapy was given in the form of cyproterone acetate (androcur) which is steroidal antiandrogen in a dose of mg daily. Results: The overall response rate was 90% in group I versus 60% in group II, this difference was statistically significant (p=0.048). Complete remission occurs in 35% of group I versus 10% in group II. Partial remission occur in 55% of group I versus 50% in group II. No response occurred in 5% in both groups. The mean overall survival & progression free survival was & for group I versus & for group II. This difference was statistically significant as regard PFs (p=0.013). Correspondence to: Dr. El Sayed M. El Hindawy, The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University Two year overall survival was 84.6% for group I versus 71.4% for group II. As regard the complication there is significant increased rate of complication in group I than group II including Gil complication (proctatits & bleeding ), hormonal related complication (easy fatigue) elevated liver enzymes and decreased lipido. Conclusion: The wide spread use of serum (PSA) as a case finding tool has patently increased the proportion of asymptomatic patients who present with non-palpable, clinically localized tumors. With the diagnosis of prostate cancer being made earlier, the emphasis of treatment has shifted from palliation of symptoms to altering disease related morbidity & morality & thus improving overall survival. It is highly apparent that a substantial proportion of men with clinically localized (Intermediate & high risk) or locally advanced prostate cancer not cured by radical radiotherapy for curative intent, and we have therefore explored the benefit of hormone therapy as adjuvant to radical radiotherapy which was feasible, tolerable & resulted in increase in overall survival, which did not reach statistical significance. Nevertheless, resulted in statistically significant improvement in both overall response rate & progression-free survival. Key Words: Androgen ablation Radiotherapy Prostatic carcinoma. Introduction PROSTATE cancer is the most prevalent malignancy among US adult males, accounting for an estimated newly diagnosed cases and deaths annually ill. Prostate cancer is the commonest nondermatologic malignancy and the second leading cause of cancer death in males in western cotmtries [2,3]. There is no national incidence of prostatic carcinoma in Egypt. However, Mansoura Urology & Nephrology Center reported a relative incidence of 37 cases out of 833 urologic patients (4.4%) 101

2 102 Androgen Ablation Following Radiotherapy attending the center from February 1997 to February 1999 [3]. The beneficial role of ADT with external-beam RT (EBRT) has been reported. Several wellconducted randomized trials tmiformly demonstrated a statistically significant improvement in OS when EBRT was combined with ADT. Consequently, the combination of RT and ADT is widely accepted for patients with high-grade or locally advanced PCa, which is also stated in the guidelines of the European Association of Urology (EAU 18) and of the American Urological Association (AUA 24). The aim of this study is: - Elucidate the potential of androgen ablation following standard external beam radiation therapy in patients with localized and locally advanced prostate cancer. - Emphasizing the impact of such treatment on local control and freedom from disease progression in those patients receiving the adjuvant hormonal manipulation. Patients and Methods This study was performed on forty cases of localized and locally advanced prostate cancer. All patients were referred to Clinical Oncology and Nuclear Medicine Department Outpatient Clinic, from Urology and Nephrology centre, Mansoura University Hospitals, during the period from September 2001 to July 2005, with mean follow-up period of 19 months, range (6-42 months). Each patient underwent clinical, laboratory, radiologic & transrectal ultrasonic biopsy for proper diagnosis & staging. Selection criteria: Inclusion criteria included: Histologicallyconfirmed prostatic carcinoma, T1 to T3, No-1 according to TNM staging system as determined by transrectal ultrasonic biopsy & MRI abdomen & pelvis. Absence of distant metastasis confirmed by clinical examination, C.T. chest, abdomen, pelvis & bone scan. Treatment plan: Patients were blindly randomized into two groups. Group 1: Included twenty patients, who received combined external beam irradiation and androgen ablation therapy. Group 2: Included twenty patients, who received external beam irradiation alone. Dose: Radiation therapy was delivered as a conventional fractionation schedule with a dose of 5000cGy over 5.5 weeks in 27 fractions to the whole pelvis followed by 2000cGy boost to the prostate over 2 weeks in 10 fractions. Hormonal therapy: Concurrent and adjuvant hormonal therapy was given in the form of cyproterone acetate (androcur) which is a steroidal antiandrogen in a dose of mg daily. Assessment of treatment complications: Evaluation of radiation reactions & complications of the adopted treatment modality were also assessed using acute & chronic radiation morbidity scoring criteria of RTOG/EORTC toxicity score [4]. Statistical analysis: To test for normal distribution frequency of data was plotted against normal distribution curve. As most of the data showed obvious deviation from the normal distribution curve, non-parametric statistical methods were used. Mean, median, standard deviation and range were used to describe data. Mann-Whitney pt test was used to test for significance of between groups difference in quantitative data. Chi-square, Chi-square for trends were used to test for association between categorical and ordered data. Univariate and multivariate Cox regression and hazard ratio were used to test for effect of different risk factors on overall survival and progression free survival. Results The results of this study is illustrated in the following Tables (1-9) and Figs. (1,2). Table (1) shows the pretreatment levels of PSA. It was normal in 12.5% of patients, 4-10 ng in 50% of patients & >10ng/m1 in 37.5% of patients. Adencarcinoma accounted for 95% of these cases, while transional cell carcinoma & mucinous adenocarcinoma accounted for the remaining 5%. Low grade tumer (gleason score 2-4) represented (17.5%), while moderate grade tumor (gleason score 5-7) represented 60%. High grade tumors (gleason score 8-10) were represented in 22.5% of the studied group of patients. The response rate of the studied groups of patients was demonstrated in (Table 2). Overall response rate was 90% in group I versus 60% in group II, this difference was statistically significant (p=0.048).

3 El Sayed M. El Hindawy, et al 103 Complete remission occur in 35% of group I versus 10% in group II. Partial remission occur in 55% of group I versus 50% in group II. No reponse occurred in 5% in both groups. Table (3) shows the relationship between response rate and clinical stage in the studied groups of patients. The higher the stage, the lower the overall response rate and the difference was statistically significant in group I (p=0.04). The overall response was higher in patients with low gleason score (2-4) 100% & 66.7% in group II respectively, The difference was found statistically insignificant in both groups. The overall response rate was found to be significantly affected by lymph node involvement (p=0.021), being hogher in patients with-ve LN (70.6%) than those with L.N involvement (zero%) (Table 4). The relationship between overall survival rate and clinical stage was shown in (Table 5). The higher the stage the lower the overall survival. The results were statistically significant (p=0.040 & 0.020) for group I and group II respectively. The overall survival was higher in patients with negative L.Ns (82.4 %) than those with +ve L.N involvement (66.7%), but this result was statistically insignificant (p=0.531). In group I, the overall survival was (100%) in patients with PSA (4-10ng/m1), while in patients with PSA >10ng/ml, the overall survival decrease to (83.3%), and the difference was also statistically insignificant (p=0.300). Table (6) shows overall progression free survival rate in both treatment groups. It revealed no progression in 85% & 65% of patients in group I & group II respectively. The difference was statistically significant (p=0.01). Pattern of distant metastasis is shown in (Table 7) 5% of patients of group II developed lung & liver metastasis, 30% of patients of group II developed bone metastasis. On the other hand 5% of patients of group I developed bone metastasis without lung metastasis. This result is statistically significant as regard bone metastasis only (p=0.037). Tables (8,9) shows acute and late treatment toxicity complications). Treatment reated complications, which were in the form of easy fatigue in 40% of the patients, elevated liver enzymes in 30% of patients & decrease lipido in 60% of the patients. The mean overall survival & progression free survival was illustrated in (Table 8) and (Figs. 1,2) being & for group I versus & for group II. This difference was statistically significant as regard PFs (p=0.013). The 2 year overall survival was 84.6% for group I versus 71.4% for group II, but this was statistically not significant. The 2 year progression free survival being 90.9% for group I versus 41.7% for group II (p=0.013). Table (1): Pretreatment PSA level. PSA No. % <4 ng/ml ng/m >10ng/m Total Table (2): Response rate of the studied cases. Response Group I Group II X 2 P CR 7 (35%) 2 (10%) PR 11 (55%) 10 (50%) SD 1 (5%) 1 (5%) PD 1 (5%) 7 (35%) Total 20 (100%) 20 (100%) Over all response rate 18/20 (90%) 12/20 (60%) CR: Complete remission. PR: Partial remission. SD: Stable disease. PD: Progressive disease including metastasis. Table (3): Tumor response according to stage. Clinical stage Group I Group II T1 c 2/2 (100%) - T2 a 2/2 (100%) 5/6 (83.5%) T2 b 11/11 (100%) 4/8 (50%) T3 a 2/3 (66.7%) 1/2 (50%) T3 b 1/2 (50%) 2/4 (50%) Total 18/20 (90%) 12/20 (60%) X2 for trends p-value Table (4): Relation between response rate & lymph node involvement. L.N involvement Group I Group II X2 p-value ve L.N 18/20(90%) 12/17 (70.6%) +ve L.N 0/3 (zero%) Total 18/20 (90%) 12/20 (60%)

4 104 Androgen Ablation Following Radiotherapy Table (5): Relation between overall survival rate and clinical stage. Clinical stage TI c T2 a T2 b T3 a T3 b Group I 2/2 (100%) 2/2 (100%) 11/11 (100%) 2/3 (66.7%) 1/2 (50%) Group II 6/6 (100%) 7/8 (87.5%) 3/4 (75%) Table (9): Late treatment toxicity complications. UrMary Group I Group II Total X2 p2 G1 hematuria 1 (5%) 1 (2.5%) G2 hematuria 1 (5%) 1 (2.5%) G1 frequency 1 (5%) 1 (2.5%) G1 incontinence 3 (15%) 1 (5%) 4 (10%) Total X2 for trends p-value 18/20 (90%) Table (6): Overall progression free survival rate in both treatment groups. PFS X2 p-value Group I 19 (95%) Group II 13 (65%) Table (7): Pattern of treatment failure. Treatment Group I Group II Total No. % No. % No. % Bone (R/C) 6 metastasis Lung metastasis Liver metastasis Local progression NED: No evidence of disease. LWD: Living with disease. DWD: Dead patients with disease. Table (8): Acute treatment toxicity complications. Urinary Group I Group II Total X2 p2 G1 dysuria 9 (45%) 8 (40%) 17 (42.5%) G1 hematuria 1 (5%) 1 (2.5%) G1 frequency 1 (5%) 1 (2.5%) G1 necroturia 3 (15%) 2 (10%) 5 (12.5%) GIT: G1 Proctatitis 7 (35%) 1 (5%) 8 (20%) G1 bleeding 1 (5%) 1 (2.5%) G2 bleeding 1 (5%) 1 (2.5%) G2 diarrhea 1 (5%) 1 (2.5%) Skin: Dry 1 (5%) 1 (2.5%) desquamation Wet 1 (5%) 1 (2.5%) desquamation x2 16/20 (80%) P.R p2 relative risk Cumuiative probitity of survival G2 bleeding 1 (5%) 1 (2.5%) G3 bleeding 2 (10%) 2 (5%) G2 incontinence 2 (10%) 1 (5%) 3 (7.5%) P., ,.0 0 4' 0.4 a)... O 0.2 -o- Combined -0- Radio Duration (months) Fig. (1): Cumulative probability of overall survival in relation to treatment in all patients A 1 * v.. I _._ g t Combined -0- Radio I I I Duration (months) Fig. (2): Cumulative probability of progression free survival in relation to treatment in all patients. Discussion The rate of death from prostate cancer has recently declined in many areas of the world. Over the past 15 years prostate-specific antigen (PSA) screening has increased in Popularity, which has resulted in increase in the incidence of prostate cancer [5].

5 El Sayed M. El Hindawy, et al 105 The ultimate goal of any treatment is the eradication of disease with minimal toxicity to the patient. Multiple modalities have been developed for the treatment of prostate cancer. Selection of the appropriate regimen depends upon a range of factors including the patient's age & overall health status, grade & stage of tumor & patient's wishes [6]. The present study was performed on forty patients with localized & locally advanced prostate cancer who were referred to Clinical Oncology & Nuclear Medicine Department Outpatient Clinical, from Urology & Nephrology Centre, Mansoura University hospital from September 2001 to July The aim of this work was mainly to evaluate the effect of external beam radiation therapy with or without adjuvant hormonal therapy on local & distant metastasis, overall survival & progression free survival in localized prostate cancer patients. Treatments complications were also assessed in the two groups. As regard pretreatment PSA level, 12.5% of the patient had normal pretreatment PSA level & 87.5% had elevated pretreatment PSA level. This conforms with study whom reported that only 25% of men with prostate cancer have PSA levels less than 4ng/m1 [7]. Prostatic adenocarcinoma represented the commonest pathologic type in the present study (95%). This coincided with the data reported by Carroll [8]. As for degree of differentiation, the moderately differentiated tumors had the commonest presentation (60%), followed by poorly differentiated tumors (22.5%) & the lowest incidence was for well differentiated tumors (17.5%), Post and his colleagues studied 849 patients with prostate cancer & found that well differentiated, moderately differentiated & poorly differentiated adenocarcinoma are present in 37%,43% & 20% of the patients respectively [9]. These differences in results can be explained by variable number of studied cases in each study & the histological grade of biopsies was scored by several pathologists & thus there is likely to be inter-observer variations [in We treated 40 cases of prostate cancer (T1-T3, No-N1, MO), 20 patients received radiotherapy & adjuvant hormonal treatment antiandrogen in the form of cyproterone acetate (androcur) mg daily (group I), while 20 patients received radio- therapy alone (group II). All patients were treated by conventional radiotherapy using supervoltage linac 6-10 MV with 2-D planning system, 5000 cgy/27 ttt (whole pelvic irradiation) & 2000 cgy/10 ttt (boost prostate). The overall response rate was 90% (35% CR & 55% PR) in group I versus 60% (10% CR & 50% PR) in group II, this difference was found statistically significant (p=0.048). This result was in agreement with the result obtained by RTOG trial who showed that adjuvant hormonal arm had a beneficial effect in local control (84% vs 71%) (p<0.0001) mi. In the present study we found that the overall response rate was significantly affected by L.N metastasis, being better in node negative patients (70.6%) than patients with lymph node metastasis (zero%) (p=0.021). This conforms with [12] whom stated that the presence of L.N metastasis was associated with low probability of total eradication of tumor & high probability of treatment failure. The overall survival was better in group I (90%) than group II (80%) but this difference was not statistical significant (p=0.376). This finding coincided with Moreover we reported that overall survival was not significantly affected by pretreatment PSA level. However it was higher in patient with normal PSA & lower in patient with elevated PSA (group II). This is in agreement with [13] whom reported that elevated pretreatment PSA level & occurrence of biochemical failure after radiotherapy were statistically significant associated factors with an increased overall mortality. This difference in level of significance may be due to smallsample size 20 patients in our study versus 1571 patients in Williams study. We reported in this study during follow-up bone metastasis in (17.5%) of patients, lung & liver metastasis (2.5%) for each. These result were in agreement with the results obtained by [14] who fotmd that skeletal metastasis was the most common site of distant metastasis. Moreover, bone metastasis was fotmd significantly affected by line of treatment (30% vs 5%) in favour with combined treatment modality (p=0.037). This result were in agreement with the results obtained by [15] in the RTOG study [16]. Complications was found nearly compatible with international results of cases treated by radical radiotherapy since [17] reported an incidence of 67% of patients has mild or no urinary toxicity [18]. Who reported G1 acute G1T toxicity in 48% of cases, G3 or 4 acute G1T toxicity in 0.8% of cases.

6 106 Androgen Ablation Following Radiotherapy However, we noticed an increase in the incidence of radiation proctatits & late G1 incontinence in group I than group II & this observation was reported also by [19] who found that when adjuvant androgen ablation was used, the risk of developing late G2-4 GII toxicity was 2.2 times. We found that hormonal treatment related complications were in the form of loss of libido & impotency in 60% of cases. This was in agreement with, [201 whom found that the most patients treated with cyproterone acetate have loss of libido & impotence. The median survival for the studied cases was 36 months for group 1 & months for group II. The 2 year overall survival rates was 84.6% for group I & 71.4% for group II but this difference was statistically insignificant [21]. From EORTC trial reported that the 5-year overall survival was 62% for men assigned to radiotherapy alone & 79% for those treated by combined therapy. Moreover, [22] confirmed the same 5 year overall survival values after a median follow-up of 66 months in the updated results of EORTC From multivariate analysis in this series, the most independent prognostic factors were line of treatment (p=0.050) & clinical stage (p=0.024). This was in agreement with the results obtained by [21] who reported that clinical stage & line of treatment were the most statistically independent prognostic factors affecting progression free survival in prostate patients. References 1- GREENLEEE R.T., MURRAY T., BOLDEN S. and- WINGO P.A.: Cancer statistics. CA Cancer J. Clin., 50: 7-33, PARKIN D.M., BARY F., FERLAY J. and PISANI P.: Global cancer statistics CA Cancer J. Clin., 55: , JEMAL A., SIEGEL R., WARD E., MURRAY T., XU J. and THUN M.J.: Cancer statistics. CA Cancer J. Clin., 57: 43-66, EL- NAHAS A.R., ABOL-ENEIN H., ABDEL-KHALEK M., EL-AS SMY A., AL-KOLHANY K., EL-BAZ M.A. and IBRAHEIM E.I.: A rational for prostate cancer detection in a developing country: Comparison of screening & case finding. African journal of Urology, 9: , O. SULLIVAN J.M., GRIBBIN A., TAYLOR J., O'NEILL L., COSGROVE S. and AMSTRONG J.C.: Complications of treatment with local field external beam radiotherapy for localized prostate cancer. Clin. Oncol., , COLDMAN A.J., PHILLIPS N. and PICKLES T.A.: Trends in prostate cancer incidence and mortality: An analysis of mortality change by screening intensity. Intensity CMAJ, 168 (1): 31-35, HILL B. and KYPRIANOU N.: Sequencing hormonal ablation & radiotherapy in prostate cancer: A molecular & therapeutic perspective. Oncology, 9: , CARTER H.B. and PARTIN A.W.: Diagnosis and staging of prostater cancer. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ. Campbell's Urology, -th / ea,., Philadelphia, Saunders Company, pp , CARROLL P.R., LEE K.L., FUKES Z.Y. and KANTOFF P.W.: Cancer of the prostate. In: Devita V.T., Hellman S., Rosenberg S.A. Principles and Practice of Oncology 6th ed, Philadelphia, Lippincott Williams & Wilkins, pp , POST P.N., HANSEN B.E., KIL P.J.M., JANSSEN- HEIJNEN M.L.G. and COEBERGH J.W.W.: The independent prognostic value of comorbidity among men aged <75 years with localized cancer; a population-based study. BJU International, 87: , GOTTSCHALK A.R. and ROACH M.: The use of hormonal therapy with radiotherapy for prostate cancer: Analysis of prospective randomized trials. British Journal of Cancer, 90: , CATALONA W.J. and SMITH D.S.: 5-year tumor recurrence rates, after anatomic radical retropubic prostatectomy for prostate cancer. Urol., 143: , WILLIAMS S.G., DUCHESNE G.M., MILLAR G.L. and PRATT G.R.: Both pretreatment PSA level & post treatment biochemical failure are independent predictors of overall survival after radiotherapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys., 60: , PAULSON D.F.: The impact of current staging procedures in assessing disease extant of prostatic adenocarcinoma Urol., 199: , HANKS G.E., LU J., MACHTAY M., et al.: RTOG protocol 92-02: A phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction & radiotherapy in locally advanced carcinoma of the prostate. Proc. Am. Soc. of Clin. Oncol., 19: 1284, LAWTON C.A., WINTER K., MURRAY K., MACHTAY M., et al.: Updated results of the phase III Radiation Therapy oncology group (RTOG) trial evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int. J. Radiate. Oncol. Biol. Phys., 49: , VAN PUTTEN W.L.J., KORVAAR G.A., HEIJMEN B.J.M., et al.: Acute morbidity reduction using 3DCRT for prostate carcinoma: A randomized study. Int. J. Radiat. Oncal. Biol. Phys., , SANGUINETI G., AGOSTINELLI S., FOPPIANO F., et al.: Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma. Br. J. Cancer, 86: , SCHRODER F.H., COLLETTE L., DE. REIJKE T.M. and WHELAN P.: Prostate cancer treated by antiandrogen: Is sexual function preserved? EORTC genitourinary Group. European Organization for research & treatment of cancer Br. J. Cancer, 82: , 2000.

7 El Sayed M. El Hindawy, et al ANDERSON J.: The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU. International, 91; , BOLLA M., COLLETTE L., et al.: Long-term results with immediate androgen suppression & external irradiation in patients with locally advanced prostate cancer (an EORTC study ): A phase III randomized trail. Lancet, 360: 103-6, GROSSFELD H, VALICENTI R., LU J., et al.: Survival advantage from higher dose radiation therapy for clinically localized prostate cancer treated on the radiation therapy oncology group trial. J. Clin. Oncol., 23: , 2000.