Abstract

Background: Fosfestrol is a low-cost estrogen analog that is useful in the management of metastatic prostate cancer in resource-challenged settings. It acts by altering the pituitary axis, adrenal secretion, and 5-alpha reductase activity. Patients and Methods: The outcomes of metastatic castration-resistant prostate cancer patients treated with fosfestrol in our center between June 2012 and December 2015 were analyzed retrospectively. Fosfestrol was given orally at a dose of 120 mg thrice daily. Event was defined as the discontinuation of fosfestrol due to tumor progression or drug toxicity or death due to any cause. The event-free survival (EFS) and overall survival (OS) were calculated by the Kaplan–Meier method. Results: The analysis included 47 patients with a median age of 65 years. Initial Gleason score was available for 41 of 47 patients, of which 17% (7), 39% (16), and 44% (18) were low risk, intermediate risk, and high risk, respectively. The most common site of metastasis was bone (98%). Of 47 patients, 32 (68%) received fosfestrol as the second line of treatment after progression on complete androgen blockade, 14/47 (30%) received it as the third line, and 1/47 received it as the fourth line of treatment. The median prostate-specific antigen (PSA) value at the start of fosfestrol and the nadir PSA value were 43.7 ng/ml and 13.1 ng/ml, respectively. Ninety-one percent (n = 43) of patients had not been previously treated with chemotherapy (docetaxel). Response of PSA of >50% was observed in 55% (n = 26) of patients. The median EFS and median OS after the start of fosfestrol were 6.8 and 14.7 months, respectively, with a median follow-up of 10.9 months. Only two patients developed Grade 3 toxicity, both of whom had diarrhea. Conclusions: In resource-challenged settings, oral fosfestrol is an effective, cheap, and safe option for the management of metastatic prostate cancer progressing after first-line complete androgen blockade.

Introduction

Prostate cancer is the most common cancer in males.[1] Prostate cancer is androgen dependent, and therefore, suppression of androgens either by surgical castration or by GnRH agonists is the first line of therapy for metastatic prostate cancer. Recent evidence has shown that addition of chemotherapy upfront to androgen deprivation in high-risk patients with metastatic disease improves survival.[2] Invariably, most patients with metastatic prostatic cancer will progress while on androgen suppression and develop metastatic castration-resistant prostate cancer (mCRPC).[3] Survival of mCRPC has improved over the last decade with the advent of newer agents such as docetaxel, abiraterone, enzalutamide, and cabazitaxel.[4],[5],[6],[7],[8] However, majority of the newer antiandrogens and cabazitaxel are expensive and beyond the reach of the common people in resource-challenged settings. Estrogen therapy was an important component in the management of prostate cancer in the past; however, with the advent of newer drugs, its use has declined. Estrogen acts by inhibiting the production of adrenal androgens, increasing the testosterone-binding protein, thereby reducing the testosterone levels, and directly acting on Leydig cell steroidogenesis.[9] Estrogen receptors are also present in the stroma of prostate cancer which may negatively influence the growth of prostate cancer.[10] Fosfestrol also known as diethylstilbestrol diphosphate is an estrogen analog used in the management of metastatic prostate cancer. Fosfestrol can be administered as a high-dose intravenous infusion or a low-dose oral maintenance therapy. The high-dose infusion in comparison to oral low-dose fosfestrol has a rapid response rate, but results in serious toxicities such as deep venous thrombosis and ischemic heart disease.[11] There is a paucity of data on low-dose maintenance fosfestrol in metastatic prostate cancer. The present study was conducted to analyze the efficacy and safety of fosfestrol in metastatic prostate cancer patients undergoing treatment at our hospital.

Patients and Methods

We conducted a retrospective review of case records. All consecutive patients with metastatic prostate cancer treated with fosfestrol at our hospital between June 2012 and December 2015 were analyzed. Ethical clearance was not required as the study involved only retrospective analysis of case records. Our hospital is a charitable institution, and majority of our patients have financial constraints for treatment. The clinical features, laboratory data, treatment details, and outcomes were obtained from the patient records. Diagnosis of prostate cancer was confirmed by transrectal ultrasound-guided prostate biopsy and elevated serum prostate-specific antigen (PSA). All patients underwent bone scan; chest X-ray; ultrasound of abdomen and pelvis; and computed tomography scan of chest, abdomen, and pelvis for disease staging. Patients received fosfestrol after clinical, radiological, or PSA progression after first-line complete androgen blockade (orchiectomy or leuprolide with androgen receptor blocker bicalutamide) or beyond and with castrate levels of serum testosterone (50 ng/dL).

Fosfestrol (Honvan, Zydus Cadila, India) was prescribed at a standard dose of 120 mg three times a day continuously. The decision to start fosfestrol was based on physician and patient preference. Patients were followed up monthly with clinical assessment and PSA testing. Bone scan and other imaging were performed on follow-up, if clinically indicated. Fosfestrol was discontinued if patient had disease progression (clinical, radiological, or serial rise in PSA for 3 monthly visits) or Grade 3 or 4 toxicity. Biochemical relapse was defined as serial rise in PSA in 3 consecutive tests done a month apart in an asymptomatic patient. No absolute cutoff of PSA was taken to define biochemical relapse. Event in the study was defined as appearance of new lesions on imaging or biochemical relapse or Grade 3/4 toxicity or death. PSA normalization while on fosfestrol was defined as decline of PSA <4>50% of the value at the start of fosfestrol.

The demographic data of patients were reported as descriptive statistics. Survival was calculated by the Kaplan–Meier analysis using the statistical software SPSS version 21 (SPSS Inc., IBM, Chicago, USA), and the factors were compared using log-rank test.

Results

The study included 47 patients with metastatic prostate cancer with a median age at diagnosis of 65 years (range: 42–82 years). Baseline characteristics are described in [Table 1]. The median age at the start of fosfestrol was 67 years (range: 46–85 years). The median PSA at the start of therapy of fosfestrol was 43.7 ng/ml (5 ng/ml–1860 ng/ml). Gleason score of more than 6 at diagnosis was present in 34/47 (80%) patients. The skeletal system was the only site of metastasis in 41/47 (87%) patients, 3/47 had lymph node and bone metastases, 2/47 had lung and bone metastases, and 1/47 had only nodal metastases before initiation of fosfestrol. The common comorbidities in the patients included diabetes mellitus and hypertension in 7, 3 had diabetes mellitus alone, 8 had hypertension only, 1 had hypertension and ischemic heart disease, and 2 had ischemic heart disease.{Table 1}

| Figure 1 Event-free survival of all the patients

| Figure 2 Event-free survival based on prostate-specific antigen response

| Figure 3 Overall survival after the start of fosfestrol of all the patients

| Figure 4  Overall survival after the start of fosfestrol based on prostate-specific antigen response

1. Stangelberger A, Waldert M, Djavan B. Prostate cancer in elderly men. Rev Urol 2008; 10: 111-9
2. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163-77
3. Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol 2010; 17 Suppl 2: S72-9
4. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PE, Sternberg CN. et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152-60
5. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983-92
6. Scher HT, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-97
7. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424-33
8. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010; 376: 1147-54
9. Klijn JG. Scientific background of hormonal treatment of prostate cancer. Prog Clin Biol Res 1990; 357: 7-22
10. Thompson TC. Growth factors and oncogenes in prostate cancer. Cancer Cells 1990; 2: 345-54
11. Droz JP, Kattan J, Bonnay M, Chraibi Y, Bekradda M, Culine S. et al. High-dose continuous-infusion fosfestrol in hormone-resistant prostate cancer. Cancer 1993; 71: 1123-30
12. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12
13. Williams AR, Whelan P. Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer. Prostate Cancer Prostatic Dis 1998; 1: 204-7
14. Grise P, Mnif A, Navarra S, Foulatier O, Barret E, Sibert L. et al. ST52 treatment of cancer of the prostate during the hormonal resistance phase. Ann Urol (Paris) 1998; 32: 39-44
15. Orlando M, Chacón M, Salum G, Chacón DR. Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer. Ann Oncol 2000; 11: 177-81
16. Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9: 1877-82
17. Kujovich JL. Factor V Leiden thrombophilia. Genet Med 2011; 13: 1-6

| Figure 1 Event-free survival of all the patients

| Figure 2 Event-free survival based on prostate-specific antigen response

| Figure 3 Overall survival after the start of fosfestrol of all the patients

| Figure 4  Overall survival after the start of fosfestrol based on prostate-specific antigen response

1. Stangelberger A, Waldert M, Djavan B. Prostate cancer in elderly men. Rev Urol 2008; 10: 111-9
2. James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163-77
3. Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol 2010; 17 Suppl 2: S72-9
4. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PE, Sternberg CN. et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015; 16: 152-60
5. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983-92
6. Scher HT, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187-97
7. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424-33
8. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 2010; 376: 1147-54
9. Klijn JG. Scientific background of hormonal treatment of prostate cancer. Prog Clin Biol Res 1990; 357: 7-22
10. Thompson TC. Growth factors and oncogenes in prostate cancer. Cancer Cells 1990; 2: 345-54
11. Droz JP, Kattan J, Bonnay M, Chraibi Y, Bekradda M, Culine S. et al. High-dose continuous-infusion fosfestrol in hormone-resistant prostate cancer. Cancer 1993; 71: 1123-30
12. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12
13. Williams AR, Whelan P. Use of intravenous fosfestrol tetrasodium (Honvan) infusion in treatment of symptomatic advanced prostate cancer. Prostate Cancer Prostatic Dis 1998; 1: 204-7
14. Grise P, Mnif A, Navarra S, Foulatier O, Barret E, Sibert L. et al. ST52 treatment of cancer of the prostate during the hormonal resistance phase. Ann Urol (Paris) 1998; 32: 39-44
15. Orlando M, Chacón M, Salum G, Chacón DR. Low-dose continuous oral fosfestrol is highly active in 'hormone-refractory' prostate cancer. Ann Oncol 2000; 11: 177-81
16. Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9: 1877-82
17. Kujovich JL. Factor V Leiden thrombophilia. Genet Med 2011; 13: 1-6