Results of antiandrogen and biphosphonate therapy in treatment of bone metastatic prostate ca – La Van Truong

Journal of military pharmaco-medicine n o 1-2019 150 RESULTS OF ANTIANDROGEN AND BIPHOSPHONATE THERAPY IN TREATMENT OF BONE METASTATIC PROSTATE CANCER IN 108 MILITARY CENTRAL HOSPITAL La Van Truong1; Tran Van Ton2 SUMMARY Objectives: To evaluate the results of antiandrogen and bisphosphonate therapy in treatment of bone metastatic prostate cancer. Subjects and methods: A prospective clinical interventive study on 44 newly diagnosed bone metastatic prostate cancer patients at the 108 Military Central Hospital from July 2010 to July 2018. Results: 31.1% of the study patients was 65 years old, 27.7% had combined disease, 45.5% had severe urinary disorders, 50% had bone pain and 38.6% had systemic condition at 1 - 2 points. At the time of diagnosis: 86.4% had PSA ≥ 20 ng/mL, 52.3% had Gleason ≥ 8 points, 43.2% cT4, 77.3% had only bone metastases, 22.7% had bone metastases and nodal metastases or organ metastases. Spinal and pelvic bones were the two most frequent metastases (88.6% and 77.3%); 95.4% of patients had testicular cut, 95.4% had PSA response, 67.6% had PSA nadir ≤ 4 ng/mL; median non-progressive survival and median overall survival were 20.54 months and 38.6 months. Conclusions: Most patients with bone metastatic prostate cancer had testicular cut and PSA response in antiandrogen and pamisol therapy, however, the median non-progressive survival was short. * Keywords: Prostate cancer; Bone metastases; Antiandrogen; Bisphosphonate. INTRODUCTION Prostate cancer is one of the common cancers. According to Globocan 2012, the rate of prostate cancer is the second highest in the world and the 10th in Vietnam. As with most cancers, the treatment strategy for prostate cancer is multidisciplinary treatment, combining several therapies: surgery, radiation, antiandrogen, chemotherapy, and treatment. The specific treatment options are based on the stage of the disease, the risk level, the prognostic factors, the expectation of survival, the condition of the patient. Antiandrogen therapy is the standard treatment for prostate cancer [11]. Although at the time of diagnosis, only about 5% of prostate cancer has metastatic distances, approximately 90% of distant metastatic patients have bone metastases. Bone metastasis is a bad prognosis factor. Some studies have shown that bisphosphonate and antiandrogen therapy prolongs development time in patients with bone metastatic prostate cancer. In Vietnam, there are very few published data on this patient group. 1. 108 Military Central Hospital 2. 103 Military Hospital Correspoding author: La Van Truong (lvtruonga6108@gmail.com) Date received: 20/10/2018 Date accepted: 04/12/2018 Journal of military pharmaco-medicine n o 1-2019 151 We conducted the study with the aim of: Evaluation of the results of antiandrogen and bisphosphonate therapy in treatment of bone metastatic prostate cancer. SUBJECTS AND METHODS 1. Subjects. 44 patients newly diagnosed bone metastatic prostate cancer at the 108 Military Central Hospital from July 2010 to July 2018. * Criteria for selecting patients: - Diagnosis of prostate cancer based on tissue biopsy. - Diagnosis of bone metastases based on clinical and bone scans and/or MRI: bone metastases are diagnosed based on clinical symptoms and bone scans. If patient has painful, but bone scan is unclear will be given MRI scan for diagnosis. - New diagnosis, no treatment. - Systemic condition 0 - 2 points. - There are no contraindications to zoladex, diphereline, casodex and pamisol. * Exclusion criteria: - Patients with prostate cancer without bone metastases. - Patients with bone metastatic prostate cancer treated before. - Systemic condition > 2 points. - Failure to fully implement the research plan. - Do not agree to participate in research. 2. Methods. A prospective clinical interventive study. * Study process: - Pre-assessment of patients: Clinical examination, complete routine tests, PSA tests, computerized tomography or MRI of the abdomen, bone scans, MRI scans clinical case and bone skeletal suspicion. - Treatment: Antiandrogen + pamisol therapy. As follows: + Casodex 50 mg/day + pamisol 90 mg/month or LHRH agonist (zoladex; diphereline)/28 days + casodex 50 mg/day + pamisol 90 mg/month. Follow-up during treatment: Clinical examination every 4 weeks; PSA testing every 4 weeks or on suspected development; bone scintigraphy every 12 weeks or on suspected development; CT/MRI every 12 weeks or on suspected development. * Some criterias for evaluating treatment results: - Criterias for scrotal ablation: Blood testosterone < 20 ng/dL (1.7 nmol/L). - PSA response: + Partial response: Decrease ≥ 50% compared to pre-treatment (after 12 weeks). + No response: Not meet standard (after 12 weeks). PSA nadir (lowest): The lowest PSA level achieved during treatment. Non-progressive survival: From the onset of treatment, treatment progresses until the disease progresses. Identify progressive disease when PSA progresses after treatment response ≥ 4 ng/mL and continuous increase > 25% for 3 consecutive intervals of 1 week apart. - Overall survival: From test to death. Data were processed by SPSS software. 20.0. Estimated survival time by Kaplan-Mayer method. Journal of military pharmaco-medicine n o 1-2019 152 RESULTS AND DISCUSSION Table 1: Clinical characteristics of patients. Characteristics Number Rate (%) < 65 14 31.1 65 - 75 20 44.1 Age > 75 10 22.1 0 - 7 points 12 27.3 8 - 19 points 12 27.3 IPSS* 20 - 35 points 20 45.5 0 points 22 50.0 1 - 4 points 8 18.2 5 - 7 points 12 27.3 Bone pain 8 - 10 points 2 4.5 0 points 27 61.4 1 points 15 34.1 Systemic condition 2 points 2 4.5 No 34 72.3 Yes 10 27.7 Cardiovascular 8 18.2 Diabetes 6 13.6 Respiratory 3 6.8 Combined disease Other 1 2.3 (* IPSS: International Prostate Symptom Score) Of the 44 patients studied, only 31.1% were < 65 years old. Nearly 30% of patients had combined disease, of which 18.2% had cardiovascular disease, and 13.6% had diabetes. There were 17 patients (38.6%) with systemic condition 1 - 2 points. Eberhard Varenhorst et al studied 915 patients with bone metastatic prostate cancer with 47.4% of patients 65 - 74 years olds, 38% of patients age 75 or older, 10.4% with cardiovascular disease and 45.5% of patients had systemic condition 1 - 3 points. Thus, about two thirds of patients with metastatic bone cancer are of old age, while about one-third had combined disease and nearly half have poor systemic condition. Patients with old age, combined disease, poor systemic condition will have difficulty in having antiandrogen therapy. Journal of military pharmaco-medicine n o 1-2019 153 Lower urinary tract symptoms (difficulty urinating, frequent urination, etc) and bone pain are common symptoms in prostate cancer patients. In our study, 50% of patients had bone pain, of which 27.3% had moderate pain and 4.5% had severe pain. There were 27.3% showing mild degree of urinary disorders, 27.3% moderate and 45.5% severe. Also in the study by Eberhard Varenhorst et al, 58.6% of the 915 patients had bone pain. Natsuo Tomita et al (2015) studied 216 patients with stage prostate cancer, 124 patients (57.4%), mild (70.4%), morderate 70 patients (32.4%); 22 patients (10.2%) had severe disorders [9]. The severity of patients with severe dyslipidemia in our study was higher than Natsuo Tomita's study, probably because the patients in our study were stage IV, with distant metastasis. Bone pain and dysmenorrhoea affect the quality of life of the patient. Table 2: Clinical characteristics of patients. Characteristics Number Rate (%) < 10 1 2.3 10 - < 20 5 11.4 PSA pre-treatment ≥ 20 38 86.4 ≤ 6 9 20.5 3 + 4 6 13.6 4 + 3 6 13.6 8 13 29.6 Gleason 9 + 10 10 22.7 T1 2 4.5 T2 6 13.6 T3 17 38.7 cT T4 19 43.2 N0 34 77.3 N N1 10 22.7 M1b 34 77.3 M M1c 10 22.7 Spine 39 88.6 Pelvis 34 77.3 Other bone 32 72.7 Low volume disease 13 29.5 Bone injury High volume disease 31 70.5 Nodal 3 6.8 Lung 4 9.0 Liver 2 4.5 Distant metastasis Other position 2 4.5 Journal of military pharmaco-medicine n o 1-2019 154 PSA is a biomarker of cancer value screening, risk level, evaluation of treatment response and development tracking. In our study, 86.4% of patients had PSA ≥ 20 ng/mL at the time of diagnosis. Giorgio Gandagliaa et al analyzed SEER data from 1991 - 2009, in 3,093 patients with bone metastatic prostate cancer, at the time of diagnosis 79.8% of patients had PSA ≥ 20 ng/mL, 442 patients had both metastatic metastases with 84.4% PSA ≥ 20 ng/mL [6]. Bone metastatic prostate cancer usually has PSA ≥ 20 ng/mL. Kazuhiro Nagao et al (2016) studied 100 patients with bone metastatic prostate cancer, 6 patients (6%) had Gleason ≤ 6 points, 28 patients (28%) Gleason = 7 points, 66 patients (66%) Gleason ≥ 8 [7]. About half of patients with bone metastatic prostate cancer have Gleason score ≥ 8. In our study, the majority of patients with cT3 and cT4 (81.9%), however, 4.5% had cTl and 13.6% had cT2. This finding suggests that even in early prostate cancer, bone metastasis is possible. Kyo Chul Koo et al (2015) retrospectively analyzed 248 patients with bone metastatic prostate cancer with 27 patients (11%) in T2, 130 patients (52.4%) in T3 and 91 patients (36.6%) with T4 stage [8]. In a study of 2,607 patients with stage IV prostate cancer, Giorgio Gandagliaa et al found that 91.1% had bone metastases, 8.7% had nodal metastases, 5.7% had lung metastases, 7% had liver metastases, 1.8% had brain metastases, 1.3% had gastrointestinal tract metastases, 1.3% had abdominal and peritoneal metastases, 0.6% had kidney and adrenal metastases. On the other hand, of the 3,093 patients with bone metastases, 422 patients (13.6%) had organ metastases [6]. In 44 patients with bone metastases, we found that 3 patients (6.8%) had both nodal metastases and 8 patients (18.1%) with organ metastases. The survival is gradually deteriorated in the following order: distant nodal metastasis, bone metastasis, and organ metastasis. Folasire et al (2015) studied 82 bone metastases in 67 patients with prostate cancer, 33% had metastatic bone. The most common bone metastases were: spinal 94%, of which 92.2% had metastatic lumbar spine; pelvis (67%); rib (40%). Bone with rare metastases is ulna (1%) and tibial bone (1%). The two most common metastases in our study were spinal bones (88.6%) and pelvic bone (77.3%), 70.5% of patients in our study had a high metastatic mass. Christopher J. Sweeney et al (2015) studied 790 bone metastatic prostate cancer patients, 147 patients (18.6%) had low metastasis volume and 643 patients (81.4%) had high metastasis volume [3]. A number of clinical trials showed that docetacel supplementation in antiandrogen prolonged non-progressive and life-saving regimens in patients with a high metastatic volume. Table 3: Distribution of patients according to treatment regimen. Scheme Number Rate (%) Opreation + casodex + pamisol 22 50 Agonist LHRH + casodex + pamisol 22 50 Journal of military pharmaco-medicine n o 1-2019 155 Antiandrogen therapy is the standard treatment for bone metastatic prostate cancer. Scrotal ablation (LHRH agonist or LHRH antagonist) and surgical removal of two testicles are equally effective [1]; many studies have also shown that maximum antiandrogen (combination of scrotal ablation or surgery with nonsteroidal antiandrogen) improved the duration of onset and survival, decreases the risk of death. In patients with bone metastatic prostate cancer, the combination of antiandrogen and anti-bone mineral (zoledronic) prolongs the time to scrotal ablation [7]. In our study, 50% of patients opted for scrotal ablation and 50% opted for scrotal ablation by medicine. Patients were treated with maximum antiandrogen (casodex) and anti-spasmic pamisol. Table 4: Response to treatment. Item Number Rate (%) < 1.7 42 95.4 Testosterone (nmol/L) ≥ 1.7 02 4.6 Response 42 95.4 PSA response No response 2 4.6 Minimum 0.00 Maximum > 154 ≤ 4 25 67.6 PSA nadir (ng/mL); n = 37 > 4 12 32.4 Levels of testosterone < 1.7 nmol/L are considered as scrotal ablation. However, due to advances in test technique, some studies showed that the average testosterone in the blood after scrotal ablation surgery was 0.003 nmol/L. Some authors proposed a new testosterone level of 0.7 nmol/L. The authors also showed that survival without scrotal ablation was longer in patients with lower testosterone levels than in the other three groups < 0.7 nmol/L; < 1.7 nmol/L and ≥ 1.7 nmol/L [2]. We used testicular testosterone levels of < 1.7 nmol/L according to NCCN guidelines. Among 44 patients studied, 2 patients (4.6%) had testosterone ≥ 1.7 nmol/L after one month of treatment. Notably, 1 patient treated with scrotal ablation by medicine (zoladex + casodex) and then scrotal ablation surgery had a testosterone level < 1.7 nmol/L. Some studies showed that from 2 to 12.5% of patients with scrotal ablation by LHRH antagonist had a testosterone level of ≥ 1.7 nmol/L [2]. In our study, there were 2 cases in which testosterone did not reach the scrotal ablation level. In one case of treatment of scrotal ablation by medicine after scrotal ablation surgery, testosterone level reached the scrotal ablation level, but in both cases, the PSA did not reach the biological response. Both patients had early death (less than 12 months). In the 44 patients we studied, one had non-decreasing PSA; the PSA level at the time of diagnosis was the lowest (> 154 ng/mL). 04 patients had unstable test results, we could not identify PSA nadir. 20 patients at the end of the study, the PSA was continuing to decline. Of the 37 patients whose PSA nadir was identified, 25 patients (67.6%) had PSA nadir ≤ 4 ng/mL, 12 patients (32.4%) had PSA nadir > 4 ng/mL. In 917 patients with bone Journal of military pharmaco-medicine n o 1-2019 156 metastatic prostate cancer treated with antiandrogen in the control group of STAMPEDE test, only 457 patients had their PSA nadir identified. There were 78% of paients had PSA nadir < 4 ng/mL, 22% had PSA nadir ≥ 4 ng/mL [10]. Chaiyut Kongseang et al reviewed 248 patients with bone metastatic prostate cancer treated with androgens, high ALP levels, systemic condition ≥ 1 patients, and high PSA nadir levels were bad predictors of survival [8]. Chart 1: Non-progressive survival. Chart 2: OS. There were 42 patients responding to treatment. At the end of the study, 30 patients progressed. The shortest follow-up was 8 months, the longest was 71 months, and the mean follow-up was 24.5 months. The overall survival of 44 patients was shown in figure 2. The median overall survival was 38.6 months. In the control group of STAMPETE test, with an average follow-up of 20 months, non-progressive survival and median overall survival observed in the 917 were 11 months and 42 months, respectively [10]. Kazuhiro Nagao et al used antiandrogen and zoledronic for bone metastatic prostate cancer, median progression time was 25.2 months. CONCLUSION Most patients with bone metastatic prostate cancer achieved scrotal ablation level and achieved a PSA response when treated with maximum antiandrogen therapy and pamisol, however, the median non- progressive survival was short. This results posed the need to add chemicals, endocrine or immunotherapy to prolong the response time. REFERENCES 1. Vietnam Urological and Nephrological Association. Guidelines for the diagnosis and treatment of prostate cancer. Medical Publishing House. Hanoi. 2014. 2. Bobby Shayegan, Frédéric Pouliot, Alan So et al. Testosterone monitoring for men with Journal of military pharmaco-medicine n o 1-2019 157 advanced prostate cancer: CUAJ. 2017, Vol. 11, No. 6, June. indd 204. 3. Christopher J. Sweeney, Yu-Hui Chen, Michael Carducci et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. Engl J Med. 2015, 373, pp.737-746. 4. Chaiyut Kongseang, Worapat Attawettayanon, Watid Kanchanawanichkul, Choosak Pripatnanont. 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