Early results of prostate cancer radiation therapy: an analysis with emphasis on research strategies to improve treatment delivery and outcomes

With Institutional Review Board approval from KBTH and Thomas Jefferson University, patient and treatment data were collected retrospectively from the charts of all patients referred to the National Center for Radiotherapy and Nuclear Medicine at KBTH for prostate cancer treatment from January 2003 to December 2009, representing a total of 379 patients. These patients comprise the cohort for evaluation of patient- and tumor-related factors presented in the current report (overall cohort). Among these patients, a total of 251 patients (organ-confined cohort) had non-metastatic disease and were, thus, considered eligible to receive treatment with curative intent consisting of external beam radiotherapy (EBRT) (Cobalt-60 unit), brachytherapy, and/or androgen deprivation therapy (ADT). A subset of this group, the Freedom From biochemical Failure (FFbF) analysis cohort, was identified for evaluation of outcomes after EBRT, with or without ADT (52 patients). Patients who received radical prostatectomy were not included in this analysis, since follow up data were not available. Patients who received radical prostatectomy prior to EBRT or were treated with brachytherapy were excluded from the FFbF analysis cohort, as were patients with radiologic or pathologic evidence of metastatic disease prior to treatment. Inclusion criteria included a biopsy-proven diagnosis of prostate adenocarcinoma, a minimum of 2 years of follow up data, and at least 2 of the following available: clinical T stage, Gleason score, or initial PSA. All patients were initially evaluated by a thorough history, physical examination (including digital rectal examination) followed by routine laboratory studies, bone scan, and serial serum prostate-specific antigen (PSA) during and after treatment. All patients were staged according to the 1992 American Joint Committee on Cancer staging system [22]. Patients were further stratified into low, intermediate and high risk groups according to the recent NCCN guidelines [23].

All patients in the FFbF analysis cohort, but not the overall cohort, had a follow up of at least two years. Patients were seen in follow up every three months for two years, then every six months for the next three years and once a year subsequently. At each follow up visit, evaluation included DRE and serial PSA values were determined and recorded. When data were available, biochemical failure in the analysis cohort was defined according to the Phoenix definition (PSA nadir + 2 ng/mL). Time to biochemical failure was defined from the end of EBRT. Freedom From biochemical Failure (FFbF) was used as an endpoint in this analysis, since it serves as a surrogate for disease-free survival [26]. Patients with follow up data of less than 24 months after end of EBRT were excluded from FFbF analysis to reduce the influence of long-term ADT on the observed values in the high-risk patients.

Frequency counts and descriptive statistics were used to present information regarding clinical and pathological features of the cohort. Associations between initial PSA level and other factors, including Gleason score, clinical T stage and patient age, were tested using Wilcoxon-Mann–Whitney tests due to the highly skew distribution of PSA levels. For the FFbF Analysis cohort, 3- and 5-year FFbF rates were evaluated using the Kaplan-Meier method. Comparisons of FFbF were performed using the log-rank statistic. The threshold for statistical significance was defined a p-value of <0.05 for all tests. Analyses were performed using the SAS 9.2 statistical software package (SAS Institute Inc., Cary, NC).

The distribution of the clinical characteristics and treatment modalities for the overall cohort (n=379), the organ-confined cohort (n=251), and the FFbF analysis cohort (n=52) groups are presented in Tables 1 and 2. The median age at diagnosis among Ghanaian men was 65 years. Of all patients referred to KBTH for treatment, 69.6% had initial PSA > 20 ng/mL with a median initial PSA of 39.0 ng/mL. As shown in Table 3, there was a significant association between higher iPSA level and advanced Gleason score (8–10 vs. ≤7, p < 0.001) and clinical T stage (T3/4 vs. T1/2, p < 0.001). There was no significant association between initial PSA and age at presentation (<65 vs. 65+) (p= 0.099). A total of 128 men, representing 33.8% of the overall cohort, were diagnosed with metastatic disease at time of referral and were excluded from further analysis.

Among 251 patients with organ-confined disease, eligible for definitive radiation therapy (RT), 135 patients (53.8%) received EBRT without brachytherapy at the KBTH (Table 2). Reasons recognized by KBTH clinicians for patients declining EBRT included: the prohibitive cost of treatment, fear of radiation, and a state of denial based on their perception of disease originating solely from spiritual causes rather than biologic processes. Patients treated with EBRT received a median dose of 70 Gy, delivered in 2 Gy daily fractions. Among the organ-confined cohort, 16 patients received orchiectomy, including 7 patients who also received EBRT. At least 214 patients (85%) with organ-confined disease presented with intermediate-to-high risk disease (Table 1). Six patients with low risk prostate cancer were started on ADT by their referring urologist prior to evaluation at KBTH. Seventeen patients in the intermediate- and high-risk groups did not receive ADT during EBRT, due to Gleason score of 5 or less (8 patients) or unaffordable out-of-pocket costs and other socioeconomic factors (9 patients).

All members of the FFbF analysis cohort (n=52) received EBRT +/− ADT and had at least 2 years of follow up data after treatment (Table 1). Median ADT time was 24 months. Median follow up time in this group was 38.9 months. The 3- and 5-year actuarial FFbF was 73.8% and 65.1% respectively (Figure 1). The 5-year FFbF rates for patients with PSA < 30 ng/mL and PSA > 30 ng/mL were 67.0% and 63.2%, respectively (log-rank, p= 0.586). Acute toxicity during treatment included increased fatigue, urinary frequency, nocturia and bowel frequency, but the rates of these events could not be assessed in the available records. None of the patients on treatment were known to require any surgical intervention or inpatient hospitalization from treatment related causes.

In our study population of Ghanaian men with prostate cancer, >90% of patients with available data presented with intermediate- or high-risk disease, >95% with clinically T2 or greater disease, and 70% with PSA > 20 ng/ml. In contrast, in the US population, 40-60% of prostate cancer patients present with clinically inapparent disease, mostly diagnosed as T1c upon trans-rectal ultrasound guided (TRUS) biopsy [32, 33]. Furthermore, less than 15% of prostate cancer patients in the US population present with PSA > 20 ng/ml [34]. This may be attributed to PSA screening efforts and more frequent TRUS biopsies of prostate in developed countries. Currently, routine yearly PSA screening is a source of controversy in the United States [35], but this approach is not feasible in Ghana where the costs would be prohibitive. Moreover, the effect of PSA screening on prostate cancer mortality in the United States and Europe has been inconclusive. Data from the Prostate Lung Colorectal and Ovarian (PLCO) trial did not show a survival benefit from screening, however the European Randomized Study of Prostate Cancer (ERSPC) trial demonstrated a 31% reduction in the risk of death from prostate cancer in men that had PSA screening [36].

There are major concerns that PSA screening leads to over-diagnosis and overtreatment of indolent prostate cancer in men which if left untreated would have little or no impact on life expectancy [37]. However, in men of African descent who may demonstrate more aggressive disease, the lack of screening could result in an increased number of patients presenting with high risk disease, which would adversely impact prostate cancer mortality rates. This is exemplified in the analysis of our patient cohort showing a strong correlation between PSA levels at diagnosis and advanced clinical T stage as well as Gleason score. Based on trends of prostate cancer mortality in Ghana and the vast majority of patients presenting with high risk disease, it would be advantageous to develop a healthcare policy that will allow for PSA screening along with DRE in a selected cohort of men. Although annual PSA screening would likely exceed financial constraints in Ghana, it may be worthwhile to consider a program that includes less frequent screening. Determining the appropriate initial age for screening and the appropriate time interval for PSA screening in Ghana is beyond the scope of this study, but future studies should address these considerations.

Out of 251 patients eligible for definitive radiation treatment with curative intent only 141 patients (56.2%) actually received EBRT. A number of factors acting as barriers to treatment delivery include the use of alternative medicines and traditional healing methods coupled with inadequate health education, which often delays correct diagnosis and initiation of treatment. Furthermore, taboos, stigmas, and false beliefs that cancer is a “curse” often lead to delayed diagnosis and non-adherence to treatment. Other barriers specific to radiation treatment delivery among Ghanaian men included fear of radiation, inflated perception of the cost of treatment, difficulty with access to transportation to and from daily treatments, and loss of income due to absence or inability to work.

Ghana has a population of 24 million serviced by only two megavoltage machines in two radiation treatment centers 250 kilometers (180 miles) apart. The lack of accessibility to treatment centers as well as time loss and costs incurred by patient transportation presents a huge barrier for compliance to daily treatments. Furthermore, the national health insurance re-imbursements payment rate to the health care facilities is very low, which in turn renders the out of pocket cost per treatment course per patient enormously expensive for the average working-class Ghanaian man. Currently, shorter course (“hypofractionated”) treatment schedules are being explored for prostate cancer, in an effort to improve patient convenience, reduce costs, and to take advantage of unique radiobiological characteristics of prostate cancer that make large fractions potentially more effective [38]. The adaptation of a hypofractionated schedule for treatment in Ghana would offer a profound advantage in not only decreasing healthcare delivery costs but also improve access to treatment by reducing transportation time and expense for patients during radiation therapy. This represents a potential for implementing tailored prostate cancer treatment schemes for developing countries, an important focus for future studies. To this end, we propose to develop and conduct clinical trials of shorter course radiation therapy schedules tailored to the needs of Ghanaian prostate cancer patients.

To date, the data presented in this article provides the only source of published information on outcomes for prostate cancer treatment in the West African region. Our results showed that the 3- and 5-year FFbF for Ghanaian men with mostly intermediate to high risk prostate cancer receiving EBRT +/− ADT was 73.8% and 65.1% respectively. In light of differences in patient disease characteristics at diagnosis and older treatment techniques one must consider whether to evaluate these outcomes with respect to the latest published data using dose escalation as reported by Zietman et al. [21] that demonstrated a 80-90% biochemical control as opposed to older experiences from randomized trials such as RTOG 9202 [39] and EORTC 22863 [40] showing biochemical failure rates as high as 50-76% for patients with advanced tumors. A major drawback to this retrospective study is the limited ability to assess important end points such as impact of treatment on cause-specific survival and distant metastases free survival due to a median follow up data of only 3 years. Nevertheless, there is valuable information presented in this article that will aid in the strategic development of a roadmap for prostate cancer research in Ghana, with a focus on improving therapeutic approach as well as fostering a prudent allocation of scarce resources.

Results presented in this study have demonstrated that the majority of Ghanaian men diagnosed with prostate cancer present with very advanced stage disease. Current treatment recommendations for advanced stage prostate disease are based on clinical trials that include conventionally-fractionated radiation therapy and long-term ADT [39‐41]. However, the availability of modern treatment technologies and the more recent interest in hypofractionation for prostate cancer offer an opportunity to develop studies aimed at improving the treatment and outcomes for Ghanaian patients with advanced stage prostate disease. The Ghanaian prostate cancer patient population is in need of clinical trials that seek to develop novel, shorter course treatment regimens for locally-advanced prostate cancer. We have established collaboration between two institutions with the hope of improving prostate cancer treatment in Ghana and plan to develop clinical trials that can be conducted in tandem between our two institutions. Our group encourages approaching the design of clinical trials in a way that includes perspective of the public health burden of prostate cancer in Ghana and the specific barriers to care. We hope to achieve progress by involving stakeholders in a coordinated fashion to develop tailored radiation treatment techniques that are cost-effective and well-suited for the needs of Ghanaian men.