Metastatic (Advanced) Prostate Cancer Resistant to Castration: The Time before Resistance Development and Therapeutic Measures Undertaken in Cote d’Ivoire

Objective: Contribute to improving care for prostate cancer patients in Cote d’Ivoire by identifying the average time before the development of the hormone-resistance and inherent therapeutic strategies. Patients and Method: It was a retro and prospective study over three years performed at the University Teaching Hospital of Treichville in Abidjan. 84 patients with metastatic prostate adenocarcinoma and resistant to hormone therapy were involved in the study. The analysis of clinical records enabled us to integrate different parameters in our study. Results: Our patients were relatively young (an average age of 61 years) and most of them belonged to the middle socio-economic class (50%). The resistance occurred within an average period of 9 months. The mixing of Docetaxel and Prednisone chemotherapy was the most used method of treatment (70% of cases). However, few patients (9.5%) received Abiraterone Acetate. Digestive and hematologic toxicities were noticed but they could be controlled by inherent treatment or disappear spontaneously. After nine months of treatment, 54.24% of patients who received specific treatment were alive, but high rates of mortality were observed as for patients who were only treated symptomatically. Conclusion: The relatively short average time before the development of hormone-resistance shows the aggressiveness of prostate adenocarcinoma from black Africans. The main therapeutic standard in our context remains Taxane-based chemotherapy with a good and fair tolerance.


Introduction
In sub-Saharan Africa in general and Cote d'Ivoire in particular, prostate cancer is most often diagnosed in metastatic stage [1] [2]. It is a hormone dependant cancer (androgen dependant) [3]. A better knowledge of prostate cancer oncogenesis has led to an efficient codification of its therapeutic strategy. Thus, hormonotherapy based on whether chemical or surgical method remains the therapeutic standard of the metastatic forms [4]. However, the development of resistance to this castration (showing a biological rise of the PSA levels after a stabilization period during treatment with LH-RH agonist or pulpectomy) is widespread and it occurs within a period from 24 to 36 months based on western series data [5] [6].
In our daily practice, a limited number of data (except observation) not only on this average time before the development of resistance but also the accessibility of our patients to the different treatments are available [7].
The general objective of this work was to contribute to improving the management of the prostate cancers in general and particularly the resistance to the castration in the Ivorian environment. Thus, the specific objective is to identify the average time before the development of hormone-resistance and determine the resulting therapeutic strategies.

Patients and Method
This is both retro and prospective study over three years (January 01, 2014-December 31, 2016). This study was carried out in the Department of Oncology of the University Teaching Hospital of Treichville in Abidjan and it involved 84 metastatic prostate adenocarcinoma patients with positive histological report.
These patients were under confirmed androgen blocking treatment. Castration resistance in patient under hormone therapy was defined as the one with testosterone < 0.50 ng/ml with increasing PSA level with or without symptoms. The sample population was both in-patients and out-patient from the Oncology Department of Treichville University Teaching Hospital.
As for the retrospective study, data collection was based on the analysis of clinical records and the results of prostate biopsies histopathologic examinations reports. Concerning prospective study, interviews and physical examination have helped to highlight the characteristics of the initial hormonal treatment (Type, date of starting treatment) and the presence or not of functional signs. At the paraclinical level, a pre-therapeutic examination including the disease activity index (thoracic-abdominal-pelvic CT scan, abdominal-pelvic MRI) and the patient check-up (complete blood count, Creatinine, Transaminases, blood sugar level) were systematically realized.  (Table 1) Our study was more retrospective than prospective and the majority of patients was followed up in a long term. However, results help us improve the care of patients with prostate cancer in Ivorian context.

Discussion
Hormone therapy by total or partial androgen blockage remains the standard therapy for metastatic prostate cancers [9]. The inevitability of resistance development as described in other studies is confirmed. Indeed, resistance is developed after an average period of 9 months since the setting of the initial hormonal treatment. This average period, which is quite short as compared to western series, could be explained by the aggressiveness of prostate cancer from black African subject (patients are young, higher Gleason rate, permanent lymph node extension, frequent metastasis) [8]. Poor adherence and poor compliance to the initial hormonal therapy, the existence of several metastatic sites could also explain the early development of resistance to the treatment. Most of our hormone-resistant patients were treated by combining Docetaxel and prednisone chemotherapy, resulting in clinical and biological satisfaction. Indeed, this is the used protocol which has proved to be effective in improving the overall survival rate in two randomized studies (SSOG 9916 and TAX 327 studies [9] [10]). While very few patients in our series were treated by Abiraterone acetate due to failure to get access to this molecule; in Western series patient under the same molecule get biological responses by about 50%.
The main toxicities were similar to other series, they were moderate and decreased spontaneously or sometimes under symptomatic treatment [11]. No deaths linked to the toxicities of the treatment and no interruption of the treatment were observed.
The rise of PSA rate observed after 9 months shows the development of a resistance to the chemotherapy which led to other therapies including cabazitaxel, Enzalutamide, and Spilucel T [11].

Conclusion
In a cohort of 84 patients relatively young with metastatic prostate adenocarcinoma initially treated by hormone therapy (chemical or surgical), resistance occurred within a relatively short time reflecting the aggressiveness of the black African patient suffering from prostate cancer. Combining Docetaxel and prednisone chemotherapy was the common used therapeutic modality in our series and this led to a clinically and biologically significant gain with an acceptable safety profile. However, a chemo-resistance could quickly appear, opening door Journal of Cancer Therapy to other therapies including anti-androgen of second generation or second-line chemotherapy. These effective drugs are still largely inaccessible to our patients not only because of their extremely high costs but also of their non-availability in our context. This work sounds like a plea towards all stakeholders involved in the management of prostate cancer, namely political authorities, health professionals and the population.