ANDROGEN DEPRIVATION THERAPY
ADT: Less May Be More — shorter duration; better quality of life.

Ed Weber, M.D., Editor
September – October, 2014

The goal of androgen deprivation is controlling progression of prostate cancer while minimizing the considerable adverse effects of decreased testosterone. This review will cite studies in which the duration of ADT has been shortened as compared to standard regimens while achieving comparable outcomes.

Briefly stated, the adverse events associated with diminished testosterone are:

• decreased bone mineral density and increased risk of fractures;
• a metabolic syndrome ( increased cholesterol, triglycerides, and insulin resistance );
• increased risk of myocardial infarction, strokes, congestive heart failure (especially in men with prior cardiovascular morbidity), and diabetes;
• muscle loss and weight gain; muscle weakness and easier fatigability;
• diminished erectile function and reduced sexual interest;
• and possibly some extent of cognitive decline.

These may occur to variable extents in different men, and their severity increases with longer testosterone suppression.

INTERMITTENT ANDROGEN DEPRIVATION (IAD):

Through the clinical trials process IAD has become the accepted and a recommended regimen for reducing the duration of exposure to low testosterone in men with a rising PSA following primary therapy and also for men with metastatic disease.

The most informative review of this subject was offered by Dr. Laurence Klotz (Toronto): Intermittent Androgen Deprivation Therapy: Clarity from Confusion,” European Urology, 64 (2013). Dr. Klotz has been researching, administering, and frequently publishing articles about IAD since 1986. His analyses of trials of IAD in non-metastatic and metastatic prostate cancer has led him to the conclusion that, when applied appropriately, IAD achieves outcomes comparable to continuous therapy in both stages of the disease. He felt data supported his opinion despite the conclusion in the recently published Southwest Oncology Group (SWOG) study (Hussain,JCO,2012) that in minimal metastatic disease IAD “showed a nonsignificant trend of a benefit of continuous therapy.”

Although there are many various regimens for IAD and the optimal regimen is under active investigation, his recommendation is as follows:

1. Initiate therapy with an LHRH agonist (usually Lupron but may become Firmagon) combined with bicalutamide (2 weeks to cover the T flare or continuous are both accepted).
2. Continue therapy for 6 – 9 months, and if the PSA has decreased to <0.2 - 0.4 ng/ml discontinue IAD; otherwise continue treatment.
3. Check serum testosterone every 3 months [to insure desired T levels of < 20 - 32 ng/dl is maintained].
4. Treatment should be reinstituted when when the PSA reaches 10 – 20 ng/ml.
5. “One phase 2 study suggests that the off-treatment interval is doubled by 5-alpha reductase inhibitor use [Avodart, Proscar], but this has not been confirmed … .”

“Patients with bulky tumors, a massive burden of nodal and bone metastases, hepatic metastases, PSA >100 ng/ml, rapidly rising PSA (>5 ng/ml per month), or persistent pain from bone metastases are not good candidates for IAD. Selected high-risk patients who demonstrate an excellent PSA response may still be considered.”

Klotz’s conclusion: “Few treatment approaches offer improved quality of life, reduced comorbidity, decreased cost, and no adverse survival effect.”

INTERMEDIATE-RISK DISEASE:

In a comprehensive review article, “Current Trend for the Use of Androgen Deprivation Therapy in Conjunction with Radiotherapy for Patients With Unfavorable Intermediate-risk, High-Risk, Localized, and Locally Advanced  Prostate Cancer,” Cancer. June 1,2014, Dr. Mack Roach summarizes that “In patients with an intermediate-risk of disease, short-term ADT typically is used for a duration of 4 months to 6 months with RT.”

1. Intermediate-risk prostate cancer (NCCN: T2b-2c or Gleason 7 or PSA 10-20 ng/ml) is a heterogeneous mix, just as is the case with the NCCN “high-risk” category. Acknowledging this heterogeneity, D’Amico et al. propose subdividing the category, as described in “The Likelihood of Death From Prostate Cancer in Men with Favorable or Unfavorable Intermediate-Risk Disease,” Cancer. June 15, 2014.

   The regimen of interest in their study was the comparative outcome of [the then] high-dose radiation therapy (70 Gy) with up to 6 months of ADT for the RT/ADT group (97 men) v. RT alone (100). The 197 men were balanced between risk groups:

   • ~25% were low-risk,
   • ~50% intermediate, and
   • ~22% high-risk.

   Unfavorable intermediate-risk: “Men who had unfavorable intermediate-risk PC included those with primary Gleason 4+3 disease, >2 intermediate-risk factors, or a ppb [percent positive biopsy cores] >50%.  A PSA velocity >2 ng/ml in the year prior to diagnosis or tertiary Gleason pattern 5 were additional unfavorable markers.

   Favorable intermediate-risk: Men with favorable intermediate-risk disease included those with a less than 50% cancer in any one biopsy core of <50% and at most 1 intermediate-risk factor, either Gleason pattern 3+4 disease, or a PSA level from 10-20 ng/ml, or AJCC T2b tumors.”

   D’Amico’s findings: “After a median follow-up of 14.3 years in surviving patients … . there were no PC deaths in the favorable intermediate risk-group.”  This observation led the authors to suggest that this group “might not require ADT to reduce their risk of prostate cancer specific mortality.” The unfavorable intermediate-risk group experienced a worse outcome, nearly similar to that of men with high-risk PC in their study. For this group, the authors suggest a targeted mpMRI biopsy to assess whether they might harbor undiagnosed “high-risk” disease and were candidates for ADT longer than 6 months.

   As with any important new finding, these observations will require validation. RTOG 8015 (NCT00936390 – initiated 2009) is testing this concept in an ongoing phase 3 trial with intermediate-risk patients randomized to escalated dose RT (79.2 Gy) with or without 6 months of ADT (including Bicalutamide, 50 qd for 6 months). 

   If D’Amico’s findings are confirmed, this regimen will allow a portion of intermediate-risk men to avoid ADT.

HIGH-RISK DISEASE:

Individualizing duration of ADT in association with radiation therapy (RT) in men diagnosed with intermediate-risk or high-risk (“locally advanced”) prostate cancer.

NCCN Definitions of high-risk disease –

• High risk: T3a or Gleason 8-10 or PSA >20 ng/ml;
• Very high risk: T3b-T4. D’Amico high-risk group includes T2c disease.

The current guidelines for ADT therapy in men with high-risk prostate cancer is 2-3 years as summarized in the review by Dr. Roach (ibid). Although most studies cited showed a survival benefit for prostate cancer related deaths for long-term ADT,  in many trials there was no gain in all-cause survival (ACS) for 2-3 years of treatment.

In his web slide presentation at the American Society of Therapeutic Radiology Dr. D’Amico generalized that the benefit for long-term ADT was in the range of 4% (Full Article Here). In his opinion ADT duration should be personalized on the basis of PSA nadir and the patient’s comorbidities.

D’Amico et al. (Cancer. 2013) states that “The optimal duration of hormone therapy is a function of the patient’s age and the number of cardiovascular risk factors. In regimens of ADT for 6 months or 2-3 years those men with a prior MI or substantial cardiac risk factors experience a decrease in quality of life compared with no hormone therapy in both durations of treatment.”

In the conclusion of his article, Dr. Roach states that ADT “appears to provide survival benefit in selected patients,” but without further clarification. The three models discussed below attempt to address this important issue of patient selection.

1. ADT 18 versus 36 months: At the 2013 Genitourinary Cancers Symposium, Abstract 3 was presented by Nabid et al. (Montreal): “High-risk prostate cancer treated with pelvic radiotherapy and 36 months versus 18 months of androgen blockade: Results of a phase III randomized study.” Treatment consisted of RT to whole pelvis and prostate; and ADT — bicalutamide (for one month) and goserelin [an LHRH agonist] every three months. 320 men were treated for 18 months and 310 men for 36. Median figures were: for age, 71;  PSA ,16 ng/ml;  and Gleason score 8. Follow-up was 77 months.

   Study findings: At 10 years the outcome for 18 v. 36 months were essentially identical for the two therapy durations: 63% overall survival and 87.2% disease specific survival. In the same symposium in 2014 a quality of life analysis of the trial found significant improvement in domains of sexual interest,  activity and enjoyment for the shorter ADT duration and more hot flushes in the longer treatment.

   Study conclusion: In men with high-risk PC, “Long term androgen blockade can be safely reduced from 36 to 18 months without compromising outcomes”

2. PSA nadir > 0.5 ng/ml as a surrogate for prognosis:  D’Amico et al. reported another relevant model for limiting the exposure of men treated with RT and ADT: “Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen suppression therapy in men with localized and locally advanced prostate cancer: analysis of two randomized trials (Lancet Oncology. 2012).

   The authors at the onset offer the summary statement regarding long-term ADT regimens for RT/ADT:  “3 years of androgen suppression confers a small survival benefit compared to 6 months in this [high-risk] setting.”

   Their study aimed to determine in which men 6 months of treatment was sufficient and who might need the longer ADT.

   Their interpretation: “After radiotherapy and 6 months of androgen suppression, men with PSA values exceeding 0.5 ng/ml should be considered for long-term androgen suppression; additionally, those with localized and locally advanced prostate cancer with PSA nadir values exceeding 0.5 ng/ml should be considered for inclusion in randomized trials investigating the use of drugs [i.e. Xtandi or Zytiga], which have extended survival in castration-resistant metastatic prostate cancer.”

3. Limiting ADT to 6 months in men with high-risk prostate cancer treated with brachytherapy and external beam radiotherapy (EBRT).

   Drs. Nelson Stone and Richard Stock reported a thought provoking study in support of their recommendation for the 6 month duration, “15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-Term Hormonal therapy,” J Urol. March 2014; also presented at the 2013 AUA meeting.

   The study was comprised of 1669 men with T1-T3 cancer and a median age of 66. “Treatments were implant alone; implants plus hormone therapy (HT) or EBRT; or implant plus HT plus EBRT. Study cohorts were divided in the three NCCN risk categories. HT was administered in 897 (53.8%) men for a median duration of 6 months (range 1-34). ”When BT and EBRT were combined the median biologic effective dose was 198 Gy. In the study 45.4% were low-risk; 38.6% intermediate; and 15.9% high-risk.

   In the background of their study is the acknowledgment that high-risk men customarily receive 2-3 years of ADT and the awareness that some data suggest that “longer term HT itself induces morbidity and it possibly may increase mortality [references provided].”

Their findings: 
The 15 year prostate cancer specific survival in the low, intermediate, and high-risk groups was 96.3%, 97.5% and 85.2% (p<0.001). Hormone therapy for high-risk men reduced the all-cause survival (ACS) at 10 years from 89.8% to 84.2%, and at 15 years from 60.3% to 54.9.  “ACS was not reduced if HT was limited to <6 months.”
“… older age, higher PSA, Gleason score and stage, use of HT, and the presence of diabetes and heart disease were associated with decreased 15 years survival. However, even excluding men with significant health factors the additional of HT still had a negative influence on ACS (p=0.008).”

Their conclusion:

“Prostate irradiation delivered by brachytherapy [combined with EBRT in appropriate cases] results in favorable all-cause specific survival for all risk groups.” “Hormonal therapy, when given for longer that 6 months in the neoadjuvant/adjuvant setting … impacts ACS and warrants further investigation for any benefit in high risk patients.”

BOTTOM LINE: The studies cited above are only a very small sampling of the extensive literature addressing the optimal balance between the duration of adjuvant ADT and RT. This issue is under active investigation, reflecting a concerted desire to reduce the adverse effects of ADT while maintaining favorable outcomes.