|Year : 2018 | Volume
| Issue : 2 | Page : 73-79
Influencing factors while prescribing androgen deprivation therapy for carcinoma prostate in clinical practice: When literature is not enough!
Kuldeep Sharma, Subodh C Pande, Kamal Verma, Sandeep Goel
Department of Radiation Oncology, Artemis Hospitals, Gurugram, Haryana, India
|Date of Web Publication||31-Dec-2018|
153, Sargodha Apartments, Plot No. 13, Sector 7, Dwarka, New Delhi 110075
Source of Support: None, Conflict of Interest: None
Objective: Androgen deprivation therapy (ADT) is an integral part of prostate cancer management but its clinical use remains controversial. Materials and Methods: We retrospectively analyzed 91 patients with prostate cancer treated between 2007 and 2014 to determine the factors that influenced our physician’s decisions regarding ADT prescription. Results: Of the 55 radically treated cases, the mean age was found to be 67 years with comorbidities present in 67% cases. Overall, 26% patients were symptomatic at presentation with 0%, 19%, and 81% cases in low-, intermediate-, and high-risk (HR) category, respectively. When divided into two groups, ADT (41 cases) and NADT (non-ADT, 14 cases), more HR cases (80% vs. 20%, P = 0.05) and all patients with positive nodes fell in ADT group (P = 0.05). Patients in ADT group had a significantly higher mean initial prostate-specific antigen (iPSA) than that of NADT group (54.2 vs. 13.9ng/mL; P = 0.02). Treatment outcomes and toxicities remained comparable between the two groups. Overall, 74% patients obtained response to primary treatment (75.6% in ADT and 71.4% in NADT) with 10 patients experiencing disease progression during follow-up (FU). Mean progression-free survival was 43 and 32 months in ADT and NADT group, respectively (P = 0.24). Median FU was 54.9 and 35.5 months in ADT and NADT group, respectively (P = 0.29). At last FU, 91% patients were alive (88% in ADT and 100% in NADT) with 67% in disease-free status. Conclusion: Prognostic risk grouping, node positivity, and high iPSA emerged as significant factors that influenced decisions regarding ADT prescription. Other factors such as age, comorbidities, symptoms, Gleason score, and T-stage were found to be insignificant.
Keywords: Androgen, cancer, controversies, deprivation, prostate
|How to cite this article:|
Sharma K, Pande SC, Verma K, Goel S. Influencing factors while prescribing androgen deprivation therapy for carcinoma prostate in clinical practice: When literature is not enough!. J Curr Oncol 2018;1:73-9
| Introduction|| |
Prostate cancer is the second most common cancer among the male population worldwide. Approximately 1.1 million cases were diagnosed in 2012. Radical prostatectomy (RP) and radiotherapy (RT) are the standard treatment options for early-stage, low-risk disease. Androgen deprivation therapy (ADT) is added in intermediate-risk (IR) and high-risk (HR) cases. Although randomized trials, and systematic reviews, have reported an improved disease-free survival (DFS) and overall survival (OS) for RT combined with ADT compared to RT alone, several controversies still persist in ADT use regarding the types of blockade (central, peripheral, or combined), its sequence (neoadjuvant [NA], adjuvant, or both), duration, and agents. The majority of the controversy is regarding the sequence of use (as it influences the timing of the other definite treatment) and the duration (as it influence the overall health of the patient in the presence of cardiac comorbidity).
ADT or no ADT
The benefit of adding ADT to radical treatment remains the prime controversy. Widmark et al. examined ADT alone versus RT in locally advanced prostate cancer (LAPC). Men with LAPC received ADT for 3 months followed by RT or the continuation of ADT. At 10 years, RT arm had reduced the relative risk for mortality (P = 0.004) and prostate-specific antigen (PSA) recurrence (75% vs. 26%). Although ADT with RT is now considered as the standard treatment for locally advanced or HR localized disease, the results are equivocal in IR disease. Evidence for using ADT with RP is less convincing than that with radical RT. A systematic review including LAPC showed that NA-ADT before RP reduced positive margin rates (P < 0.00001) and lymph node invasion (P < 0.02) versus RP alone, but had no effect on OS or DFS. Adjuvant ADT following RP improved DFS (P = 0.0004) in one study with no effect on OS. According to the European Association of Urology (EAU) guidelines, further studies are needed to investigate the application of NA-ADT before RP.
The role of ADT with adjuvant RT after RP is another controversial area. In Radiation Therapy Oncology Group (RTOG9601) trial, patients with rising PSA post-RP received RT alone or RT with bicalutamide for 24 months. Bicalutamide showed significant improvements in biochemical control and freedom from metastases.
The variation in the results of different trials or the results of same trial at different time points further complicates the controversy as shown by a trial where 206 men with IR or HR disease were randomized to RT with or without 6 months of ADT. Although its initial publication in 2004 showed an OS benefit of short-course ADT, its 2015 update refuted the OS benefit. Men with favorable IR disease may do better without ADT with dose-escalated RT. The RTOG0815 randomized trial of dose-escalated RT with or without short-course ADT will ultimately guide this issue.
Sequencing and duration of ADT
Although literature suggests the benefits of NA-ADT, controversies persist. A trial comparing 3 versus 8 months of NA-ADT in localized disease did not show significant difference in biochemical DFS or OS between treatment arms (except HR group), highlighting the complex relationship between the risk status and duration of ADT. RTOG8610 trial showed that NA-ADT for 4 months (NA and concomitant, 2 months each) in LAPC (T2–T4) was beneficial regarding disease-specific mortality, metastases, and biochemical failure. In TROG 96.01, 6 months of NA-ADT improved distant-progression, cancer-specific, and all-cause mortality at 10 years, but 3 months of NA-ADT had no effect on these variables. At present, no data are available to establish if IR patients benefit from ADT similar to HR patients and whether its duration could be reduced in this group.
Regarding adjuvant ADT, European organization for research and treatment of Cancer trial involving LAPC showed that 6 months of adjuvant ADT was inferior to 3 years of ADT regarding 5-year OS. However, another data concluded that 85% of the benefit obtainable with adjuvant ADT at 3 years is achieved in the first year itself; thus, questioning the recommendations for 3 years. The timing of ADT in LAPC is another controversy. Eastern cooperative oncology group3886 trial showed that immediate ADT in node-positive cancer after RP significantly improved OS and progression-free survival (PFS) compared to watchful waiting until disease progression. EAU also recommends immediate use of long-term ADT for LAPC.
Although long-term ADT with RT is the standard treatment for HR patients, a study showed that biochemical response to NA-ADT was a stronger predictor of benefit than its duration. Consequently, for patients achieving a rapid fall in PSA after NA-ADT, the duration may be minimized. Despite marked differences in the ADT duration in various trials, current data showed an OS benefit with long course, suggesting that it may not yet be advisable to reduce the duration below 2 years.
Without direct comparative studies, it is unclear which agent is superior. Although agonists of gonadotropin-releasing hormone (GnRH) have consistently shown satisfactory results, their use is associated with drawbacks such as flaring effects (bone pain, cord compression, ureteral obstruction, and possibly death). Furthermore, desirable testosterone levels (<50ng/dL) are achieved after 4 weeks that too in up to 88% patients. Moreover, a testosterone surge is reported in approximately 25% patients after long-term use.
Antiandrogen, bicalutamide, is another commonly used agent. In LAPC, RT followed by adjuvant bicalutamide significantly improved OS compared to RT alone (70% vs. 58%) with potential advantages regarding potency, libido, and bone preservation.
The newer GnRH antagonist, degarelix, offers faster and more effective control of testosterone, rapid PSA control, and improved biochemical PFS compared with agonists. This is associated with delayed progression to hormone-refractory disease and improved OS., These advantages are more pronounced in patients with metastatic disease, high baseline PSA (>20ng/mL), and highly symptomatic disease. Preclinical data suggest that tumor reduction may be greater with GnRH antagonist than with agonists, and a phase III study comparing NA degarelix versus goserelin showed better symptomatic relief with degarelix owing to its direct effect on extrapituitary receptors in urinary tract.
Promising results are now available with newer agents such as cytochrome P450 (CYP17) inhibitors, abiraterone and orteronel (TAK-700), and MDV-3100, a second-generation antiandrogen.
| Materials and Methods|| |
This was a retrospective study of patients with prostate cancer treated at the Radiation Oncology Department between August 2007 and July 2014. The analysis included histologically confirmed, nonmetastatic, radically treated, stage T1 through T4, and N0 through N2 cases, as per the International Union against Cancer 2007. Pelvic RT was delivered using intensity-modulated RT, and ADT consisted of bilateral orchiectomy or GnRH agonists and antiandrogens.
These patients were divided into two groups: ADT (received ADT) and NADT (received no ADT) and were then analyzed and compared with respect to demographic, clinical, biochemical, and treatment-related characteristics.
The primary objective was to analyze the factors that influenced the physicians to consider ADT for these patients. The secondary objective was to compare the two groups with respect to treatment outcome, treatment toxicity, and survival. Patient factors such as age, comorbidities (hypertension, diabetes mellitus, and coronary artery disease), and presentation (symptomatic or incidental) were noted. Patients were stratified into low, intermediate, and high prognostic risk groups, that is, based on the initial stage, initial PSA (iPSA), and Gleason score (GS) as per the American Urological Association and EAU criterion. Treatment details such as definitive treatment (surgery or RT), RT dose, and its acute and late toxicities were noted. Likewise, ADT details, that is, regimen, sequencing, duration, and toxicity were noted. Treatment outcomes were measured as response to primary treatment (6 months after treatment completion), disease progression (DP), PFS, and duration of follow-up (DOFU). All intervals were calculated from the date of histopathological diagnosis. Complete response (CR) was defined as the reduction of PSA to undetectable level, that is, <0.02ng/mL, with the resolution of lower urinary tract symptoms (LUTS). Partial response (PR) was defined as PSA reduction to <4ng/mL but in detectable range with symptomatic improvement. DP was defined as any biochemical or radiological evidence of local or metastatic progression or death after documented CR, PR, or stable disease. Biochemical progression was defined according to the ASTRO Phoenix criteria. PFS was calculated from diagnosis to the date when DP was first documented. Patients without DP were censored at the date of last follow-up or death for calculating PFS. DOFU was calculated from diagnosis till the last follow-up or death. Thus, DOFU was an indicator of OS and could serve as a surrogate for it.
Acute and late RT toxicities were defined as those occurring within 90 or after 90 days of starting RT, respectively, and were scored using RTOG grading.
Only grade 3 or higher toxicities were considered as low-grade reactions, which were easily manageable without affecting the treatment outcome.
Statistical analysis was carried out using Minitab® and Microsoft Excel 2007, Minitab for data analysis. For continuous data, Kolmogorov–Smirnov tests were performed to assess normality, and where appropriate, the data were analyzed with the two-tailed Student’s t-test. Nonparametric data were analyzed with the Mann–Whitney U test. Categorical data were compared using x2 and Fisher’s exact tests. To observe the significant differences between the mean values of two or more independent groups, we used analysis of variance.
| Results|| |
Patient and disease characteristics
Overall, there were 91 patients during the study period, although four consultant radiation oncologists with different academic and clinical experience remained involved in the decision-making. Thirty-six (40%) cases were metastatic and were excluded from further analysis. Of the 55 radical cases, 41 were placed in ADT and 14 in NADT group. Mean age at presentation was 67 years, and comorbidities were present in 67% patients [Table 1]. Overall, 26% patients were diagnosed at presymptomatic stage with raised PSA only. Patients in ADT group had a higher mean iPSA than that in the NADT group (P = 0.02). When stratified according to risk groups, the majority (81%) fell in the HR category with significantly more HR cases in ADT group (P = 0.02). Likewise, all patients with nodal disease received ADT during treatment; hence, they fell in the ADT group (P = 0.05).
Majority (93% patients) received RT as part of primary treatment with 84% receiving radical RT and the remaining receiving adjuvant RT. Remaining 7% underwent radical surgery alone [Table 2]. More patients in ADT group received RT as compared to NADT group (97% vs. 78%). On the other hand, more patients from the NADT group underwent surgery compared to ADT group (36% vs. 10%). This follows the fact that more advanced cases go for RT and Hormonal Therapy rather than surgery.
In ADT group, majority of the patients (33 of 41) received complete hormonal blockade, that is, GnRH agonist with antiandrogen, whereas four received GnRH agonist alone and four underwent orchiectomy. Twenty nine of 41 patients received long-course ADT (median, 24 months), that is, before, during, and after primary treatment. The remaining 12 patients received short-course ADT (median, 6 months), that is, before and/or during primary treatment.
Overall, 74% patients obtained response (CR or PR) to primary treatment. Overall, 16% patients developed acute and 16% developed late RT toxicity with nonsignificant difference between the two groups. The most common acute toxicity was of rectum (13%), whereas the most common late toxicity was of bladder (13%). In the ADT group, 14% patients experienced toxicities related to ADT, the most common being the hot flashes followed by disturbed sexual functions. It remained unknown in remaining 42% patients.
Overall disease outcomes
Overall, 10 patients experienced DP during follow-up [Table 3]. Two patients presented with radiological progression (one with pelvic node and another with bony lesion) with normal PSA levels. Three patients developed a pure biochemical progression, whereas the remaining five developed combined DP (detectable disease with raised PSA). All patients with DP received salvage treatment with majority (70%) of them receiving ADT as a part of it. Salvage RT was received by 60% cases, whereas salvage chemotherapy was received by one patient with nodal failure.
The median DOFU, which is also an indicator of OS, was 54.9 and 35.5 months in the ADT and NADT group, respectively. At last follow-up, 91% patients (88% in ADT and 100% in NADT group) were alive with 67% being disease free.
| Discussion|| |
In spite of limited sample size and the inherent limitations of a retrospective study, this study provided some interesting results. In this study, 40% patients presenting at stage IV reflect the general trend of late presentation in developing countries in the absence of PSA screening programs. The patient’s age and comorbidities were not found to influence a physician’s decision regarding ADT. LUTS were more common in ADT group, but the difference was statistically nonsignificant (P = 0.75). This reflects the higher stage disease in the ADT group and the fact that physicians are usually more inclined to add ADT in symptomatic patients, which seems reasonable but is not recommended in guidelines. Although 63% patients in ADT group had PSA >20, only 21% patients in NADT group had this level. Thus, iPSA emerged as a strong factor influencing the decision for prescribing ADT. Although more patients in the ADT group had GS 7 or more as compared to NADT group (73% vs. 43%), the difference was nonsignificant. Likewise, although ADT group had more advanced T-stage as compared to NADT group, the difference was nonsignificant (P = 0.20).
All node-positive patients were treated using ADT, and the nodal status emerged as another significant influencing factor for prescribing ADT. Risk grouping also emerged as a highly significant factor for deciding the use of ADT where 80% patients of HR category and 50% patients of IR category were prescribed ADT. No patient was present in the low-risk category in our study although 26% patients presented in asymptomatic stage. A possible reason apart from late presentation could be the presence of poor-risk factors such as higher GS (median 7) and higher iPSA level (mean 42.5ng/mL) in our patients, which pushed them into the IR or HR category. This observation reflects the inadequacy of the current risk stratification system where it is difficult to find patients belonging to low-risk category. Thus, there is a need to modify the existing risk stratification system where the presence of symptoms along with ethnicity should be considered as important factors. Moreover, assigning differential weightage to each factor rather than their mere presence would be more meaningful for stratifying patients in risk groups.
A total of 27 patients received NA-ADT (without adjuvant ADT) with a median duration of 2 months, which is in sync with the literature, which suggests that a longer NA blockade bears no additional benefit and instead delays definitive treatment. Overall, a similar number of patients in the two groups achieved response to radical treatment. More patients experienced DP in NADT group as compared to ADT group (29% vs. 15%). Although statistically nonsignificant, the mean PFS was longer in ADT (43 months) as compared to NADT group (32 months). The similar response rate and better PFS in ADT group, which otherwise had more advanced and HR patients, suggest the beneficial effect of ADT in prostate cancer. No significant difference in toxicities was observed between the two groups, which was consistent with Feigenberg et al. who reported 5-year actuarial risk of grade 2 or higher gastrointestinal morbidity as 17% for NADT versus 18% and 26% for short- and long-course ADT group, respectively.
The mean DOFU was longer in ADT as compared to NADT group (51 vs. 41 months). Although the longer DOFU in ADT group suggests a longer OS, it may also be attributed to the more consistent hospital visits by the ADT patients for taking hormonal injections resulting in improved follow-up data. At DOFU of 4 years, four (10%) patients in the ADT group, whereas none in the NADT group died. This may question the survival advantage of ADT and is in accordance with RTOG92-02, which showed significant improvements in DFS, local and biochemical failure, and distant metastasis at 10 years except OS. These results are difficult to interpret because of differential follow-up between the two groups acting as a confounding factor. As the patients with prostate cancer have a relatively good survival rate and tend to be elderly with multiple comorbidities and competitive risks of death, a benefit in terms of PFS is associated with discordant results regarding OS benefit.
Thus, in this study, risk grouping, nodal status, and high iPSA emerged as the strongest factors influencing physician’s decision while considering ADT. Other factors such as age, comorbidities, presence of LUTS, GS, and T-stage individually were not found contributory in this regard. Existing risk stratification system, especially the IR group, needs modification by including more descriptive factors such as the presence of symptom and ethnicity. Ongoing and future trials will further clarify the issues regarding indications, sequencing, and choice of agents for ADT.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]