Genitourinary Cancer followed by RT, versus RT alone.51 After a median follow-up of about
eight years, the neoadjuvant arm had higher disease-free survival (33 versus 21%; p=0.004), but not overall survival (53 versus 44%; p=0.10), compared with the RT alone arm. Similarly, the neoadjuvant arm had a higher local control rate (42 versus 30%; p=0.016) and a lower incidence of distant metastases (34 versus 45%; p=0.04). Other clinical trials have also reported improved disease-free survival52 survival53
but not improved overall with neoadjuvant ADT before RT.
Eligible men received ADT (goserelin 3.6mg monthly and flutamide 250mg three times/day) for two months before and two months during RT, and were then randomized to receive no additional therapy (short-term ADT) versus two years of LHRH agonist therapy (long-term ADT). After a median follow-up of 5.8 years, the authors reported that the men in the long-term ADT arm had higher five-year disease-free survival (five-year rate 46.4 versus 28.1%; p<0.0001) but not overall survival (80 versus 78.5%; p=0.73). However, sensitivity analysis revealed that among men with Gleason 8–10 prostate cancer, but not Gleason 7 or lower, men in the long-term ADT arm had higher overall survival as well (81.0 versus 70.7%; p=0.044). Thus, ADT before and/or after RT should be considered for men with high-risk prostate cancer, such as our patient (NCCN).
Neoadjuvant and Adjuvant Androgen Deprivation Therapy A large randomized clinical trial (Radiation Therapy Oncology Group [RTOG] Protocol 92-02) tested the efficacy of short-term versus long-term ADT among 1,554 men with locally advanced prostate cancer (T2c–T4).54
Duration
While adjuvant ADT appears to be beneficial after RT among select patients with intermediate- or high-risk prostate cancer, the next question is how long the therapy should be continued for. The EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group reported results on an RCT in which men with locally advanced prostate cancer (T1c–T2a–b and N1 or N2, or T2c–T4 and N0–N2, M0) receiving RT (n=970) were randomized to short- or long-term ADT (six months of LHRH agonist and anti-androgen agent + an additional 2.5 years of LHRH analog).55
After a median follow-up of 6.4 years, while there was no difference in the five-year overall mortality rate for short- and long-term suppression (HR 1.42; p=0.65), the five-year prostate cancer mortality rate was higher in the short-term ADT group compared with the long-term ADT group (HR 1.71; p=0.002). However, the incidence of hot flashes and sexual dysfunction was higher in the long-term ADT group.
Summary for Case Study 2
In summary, adjuvant ADT (LHRH agonist with/without anti-androgen therapy) before, during, and/or after RT is associated with better outcomes among selected men with high-risk, locally advanced prostate cancer, such as this patient. While long-term ADT (two to three years) is associated with better outcomes among men with high-risk disease, long-term ADT is also associated with increased adverse effects. The use of shorter-course (four to six months) adjuvant ADT before/after RT may be appropriate among men with intermediate-risk prostate cancer. We reviewed the benefits and adverse effects of ADT with this patient, and he agreed to receive long-term ADT (two to three years) after his RT.
54 Case Study 3
A 55-year-old attorney was seen by a urologist for localized prostate carcinoma involving eight of the 12 cores, Gleason 4+5, and >50% of cores positive. PSA was 23ng/ml. CT scans of the chest/abdomen/pelvis were unremarkable, except for borderline lymph-node enlargement. He then underwent RP and pelvic lymphadenectomy. Surgical pathology showed the presence of adenocarcinoma of the prostate, Gleason 4+5=9, involving both lobes, no seminal vesicle invasion, and negative surgical margins. However, five pelvic lymph nodes were noted to be positive. Given the presence of positive lymph nodes, he was then referred by his urologist to a medical oncologist for consideration of adjuvant hormonal and/or chemotherapy.
Androgen Deprivation Therapy for Lymph-node-positive Localized Prostate Cancer
Given the success of adjuvant therapies in other cancers such as colon cancer and breast cancer, there has been interest in adjuvant therapies for prostate cancer, particularly high-risk types. In the RCT Eastern Cooperative Oncology Group (ECOG) 3886, men with lymph- node-positive prostate cancer after RP and pelvic lymphadenectomy were randomized to immediate ADT (bilateral orchiectomy, or goserelin continually) versus deferred ADT, i.e. ADT only on detection of distant metastases or symptomatic recurrences.56
After a median
follow-up of 11.9 years, the authors reported that men assigned to immediate ADT (n=47) had a significant improvement in overall survival (HR 1.84; p=0.04) and prostate-cancer-specific survival (HR 4.09; p=0.0004) compared with those assigned to deferred ADT (n=51). It should be noted that the duration of ADT was not optimally defined in the study (goserelin was recommended to be used continually), and the study results do not address the appropriateness of adjuvant ADT in lymph-node-negative, high-risk localized prostate cancer. When first published, this study received criticism for its small sample size and poor methodology.57
Moreover, the long-term effects of ADT on
bone or cardiovascular risk were not ascertained prospectively in a systematic fashion, as the trial was conceived in the 1980s and at that time these adverse effects (osteopenia and cardiovascular risk) were not well recognized.
A subsequent publication did address some of the major concerns.56 It should be recognized that this is the only RCT on adjuvant ADT for lymph-node-positive prostate cancer after RP.56
Moreover, the treatment
of biochemical recurrence (rise in PSA) after RP (or even RT) without radiologic evidence of metastatic disease is currently controversial.58
Thus, long-term ADT should be considered among men with lymph-node-positive prostate cancer after RP.
Neoadjuvant Androgen Deprivation Therapy Before Radical Prostatectomy
A few studies have also evaluated the role of neoadjuvant ADT before RP. In a large clinical trial, 402 men with localized prostate cancer (T2–T3) were randomized to neoadjuvant ADT in the form of LHRH analog (goserelin) plus flutamide for three months followed by RP, versus RP alone.59
After
four years of follow-up, the authors reported no difference in survival between the two arms. However, the neoadjuvant ADT arm had higher clinical and pathologic downstaging (p<0.01), a lower number of positive margins (p=0.01), and a lower local recurrence for cT2 tumors (p=0.03) but
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