Impact of Hormonal Treatment in Patients with Metastatic Prostatic Carcinoma (Retrospective Study)

INTRODUCTION

Worldwide, prostate cancer is the second most common cancer and the fifth leading cause of death from cancer in men, with an estimated 164.690 new case diagnosed in 2018 at united states, mortality rate from prostate cancer  is also estimated to be about 9% of male cancer death in 2018. ¹

 About 4% of prostate cancer patients presented with metastatic disease on initial diagnosis, and about one-third of localized prostate cancer patients experience disease progression during the course of treatment. ²

Most of prostate cancers that diagnosed with localized disease are considered less aggressive malignancy because of their indolent course; nonetheless, metastatic prostate cancer is still lethal. The 5-year survival rate approaches 100% for low risk patients with localized disease, but once the metastases occurs the disease become practically incurable and 5 years survival declined to 28%. ³ 

Since the usage of prostate-specific antigen (PSA) tests increased as screening purpose, early detection of prostate cancer has increased, and death from prostate cancer has been gradually reduced over time. However, the concerns about the over diagnosis and over treatment have increased. As a result, in 2008 and 2012 United States Prevention Services Task Force (USPSTF) recommended against routine PSA screening. After this, a decline in the incidence of localized prostate cancer has been reported, and these have been a raising concern for worsening of prostate cancer-specific survival. Based on some recent studies, intermediate- or high-risk prostate cancer reported to increase by 6% from 2011 to 2013, which support this concern. In addition, metastatic prostate cancer has been increased from 2004 to 2013.^4,5

Androgen suppression using bilateral orchiectomy or luteinizing hormone releasing hormone (LHRH) agonist/antagonist should be first-line treatment along with short-course anti-androgen to prevent disease flare at starting treatment with LHRH.⁶ 

Androgen Deprivation Therapy (ADT) is associated with a wide range of side effects that can significantly impair quality of life, Important and/or frequent side effects include loss of lean body mass, increased body fat, decreased muscle strength, decrease bone mineral density and sexual dysfunction.⁷ The treatment of metastatic cancer prostate  has significantly changed over the past 5 years. Since 2015, two clinical trials, CHAARTED and STAMPEDE arm C, demonstrated that up-front docetaxel plus ADT improves overall survival (OS).^8,9  

Then, in 2017, two clinical trials, LATITUDE and STAMPEDE arm G, showed that up-front abiraterone plus prednisone plus ADT improves OS to a similar degree as docetaxel plus ADT did.^10,11

MATERIAL AND METHODS

 This retrospective study included all patients diagnosed with metastatic prostate cancer, registered and treated at our clinical Oncology Department, Al-Hussein University hospital in the period between January 2007 and December 2016. Charts of included patients had been reviewed and relevant data were collected and statistically analyzed.

The study Included male patient regardless of age who have had pathologically proven prostate cancer, radiological documented distant metastasis and performance status ranging from 0-III WHO; on the other hand patients who have secondary malignancy, performance status IV or received any kind of treatment outside our facility were excluded from the study.

The relevant data collected in the study included; patient related data (age, sex, family history and comorbidity); disease related data (baseline and follow-up PSA, Gleason score, tumor grade, number of biopsied cores, number of positive cores, percentage of positive disease in each core and finally, local and systemic extent of the disease); and treatment related data including type, toxicity, response and progression free survival related to each line of therapy.

Patients were classified based on metastasis load into two categories; high volume disease and low volume disease according to presence or absence of visceral metastasis and, sit and number of bone lesions, as following; high volume disease defined as the presence of visceral metastases or at least four bone lesions with one or more beyond the vertebral bodies and pelvis and low volume disease include those who had no visceral metastasis and less than three sites of bone metastasis.

 Data were coded and entered using the statistical package SPSS version 23. Data was summarized using mean, standard deviation, median, minimum and maximum for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Survival interval conspired as time between the date of histological diagnosis and the date of the last follow-up (for censored observations) or the date of death (for uncensored observations), while progression free interval was considered as time between date of the first treatment and the date of the last follow-up (for censored observations) or; date of death or disease progression whichever happen first (for uncensored observations). One-sided log-rank of Kaplan—Meier survival estimates was used for statistical analysis of overall survival and progression free survival, while the unpaired T test and one-way ANOVA test were used in the univariate analysis of the variables. Results of P-value less than 0.05 were considered statistically significant.

ETHICAL APPROVAL:

The current investigation had been approved by the ethical committee, Faculty of Medicine, Al-Azhar University, Cairo, Egypt, before the start of this study.

RESULTS

 After reviewing the charts of 100 patients who reported to have prostate cancer in our archive, 39 patients was found to have metastatic prostate cancer (illegible for the study), among these illegible patients;  mean age was 66.1 years (range 51:78 ); 19 patients (47.4%) were cigarette smoker and 20 patients (52.6%) were non-smokers; family history of malignancy was reported by  14 patients (34.2%);  most of the patients was presented with WHO performance status (PS) II, 18 patients (47.4 %), while 11 patients (26.4%), and 10  patients (26.3%) were having PS 0-I  and PS III-IV respectively;  the most common presenting symptoms were urination-related symptoms   in 24 patients (61.6%) followed by boney aches in 15 patients (38.4.8%). (Table 1)

All patients were having prostate adenocarcinoma on TRUS core needle biopsy, the median number of biopsied cores was 6 (range 6 : 12), while the median number of positive cores was 4 (range 3- 8), median percentage of malignancy in each cores was 70% (range 25 :100 ); Gleason score (GS) ≤ 6 was reported in four patients (7.9%), while GS 7 and GS 8-10 were reported in  15 patients (39.5%) and 20 patients (52.6%) respectively; all patients were having bone metastasis, of them 30 patients (76.3%) had high volume disease and 9 patients (23.7 %) had low volume disease, while 15 patients (38.3 %) was having visceral metastasis, median baseline PSA level was 70 ng/ml (range 10:1850). (Table 1)

Bilateral orchiectomy was first line treatment in 21 patients (52.6 % ), while 18 patients (47.4%) received ADT as primary treatment, in 14 patients (33.8%) ADT was LHRH agonist + bicultamide and LHRH agonist + flutamide acetate in four patient (22.2%); biochemical response to primary hormonal treatment was reported in 70% of patients; the most noticed treatment related toxicity were  mild anemia in 7 patients and osteoporosis in 4 patients while grade 3-4 toxicity was not reported. (Table 2,3)

palliative radiotherapy was used at presentation in 8 patients who presented to us with cord compression , with subjective improvement in lower limb weakness and motor power, while used during later time in 30 patients who developed bone pain as palliative treatment of pain and tenderness and in  one patient with brain metastasis, Second line hormonal treatment  in 21 patients (52.6%) as following, 9 patients (22.5%) received LHRH agonist gasroline acetate + bicultamide,10 patients (25% ) received flutamide, one patient (2.5%) received surgical casterization + biclutamide and 1patient (2.5%) received biclutamide with doubled dosage , With biochemical response in (57%) of patients  while chemotherapy was used as in 6 patients (15%) in form of Docetaxel from six to ten cycles with reported toxicity  neutropenia in halve of cases and fatigue, biochemical response was noticed in (50%) of patients. (Table 4)

Table 1: Patient characteristics

Table 2 :First line management

Table 3 : Type of Hormonal treatment in 1st line

Table 4 : Palliative radiotherapy

     After a median follow up period four years, median PFS was (18.4) months and one year PFS was reported in about (70%) of patients  after 1^st line hormonal treatment. (Figure 1)

Fig. 1: Represent the progression free survival in all eligible cases

Median OS was  (25.5) range months  and 1year OS was reported in( 83 %) Of studied cases. (Figure 2)

Fig. 2: Represent the overall survival  in all eligible cases

several factors that could affect metastatic patients who received hormonal treatment had been studied in relation to both PFS and OS . only two factors had significant impact on overall survival; performance status and PSA value at presentation. (Figure 3) (Table 5,6)

Fig. 3: Represent effect of PSA  on overall  survival  in all eligible cases

Table 5: Correlation between overall survival with different factors

Table 6: Correlation between PFS and different patient characteristics