Long-Term Results of a Randomized Trial Comparing Iridium Implant Plus External Beam Radiation Therapy With External Beam Radiation Therapy: Beyond the Abstract

Over the past decade, a number of randomized trials have shown improved biochemical control resulting from escalated doses of radiotherapy for men with prostate cancer.  Some of these trials have employed a brachytherapy boost, resulting in reductions of biochemical relapse in the order of 31-58% (Sathya, 2005; Hoskin, 2012; Morris, 2017).  Despite these clinically significant improvements in biochemical control, none of these studies have, to date, reported any benefit with respect to subsequent development of metastatic disease, prostate cancer-specific mortality or overall survival.  The study by Sathya et al began enrollment in 1992 in a single center, providing an opportunity for extended follow up of these patients. 

The initial study randomized 104 patients with locally advanced, surgically node-negative prostate cancer between external beam radiation alone (66 Gy delivered in 33 fractions over 6 ½ weeks) or medium dose rate brachytherapy by iridium implant (35 Gy delivered over 48 hours) followed by external beam radiation (40 Gy delivered in 20 fractions over 4 weeks).  Patients did not receive any androgen ablation.  After a median follow up of 8.2 years, the initial report revealed a hazard ratio of 0.42 for a combined outcome of either biochemical or clinical failure, in favour of the implant group.

The updated report (Dayes, 2017) collected additional data on study subjects with respect to PSA, use of LHRH agonists, development of metastases, clinical recurrences, second cancers and dates and causes of death. No additional toxicity data was collected.

Data was available for all but 5 patients with a median follow up length of 14 years.  Nearly half of all patients were followed beyond 15 years (46 patients), while 4 patients were followed to at least 20 years.

Since the initial analysis over ten years ago, a further 12 recurrences have occurred with 4 in the implant group and 8 in the EBRT group, maintaining the significant benefit seen in the initial report (Figure 1. HR=0.53; 95% CI=0.31 to 0.88; p=0.01).  This translated in to significantly more patients in the EBRT group being placed on LHRH agonists (58% vs. 31%, Risk difference=-27%; 95% CI=-44 to -8; p=0.007).




A total of 75 deaths have now occurred: 21 from prostate cancer, 25 from a second, unrelated cancer and 25 from non-malignant causes.  The cause of the remaining deaths is unknown.  No patients developing a second cancer died from prostate cancer.  There were no differences between the two groups with respect to overall deaths (Figure 2. HR=1.00; 95% CI = 0.63 to 1.59; p=0.99) or prostate cancer-specific deaths (HR=0.91; 95% CI=0.25 to 1.39; p=0.83).  



One quarter of patients developed metastatic disease with no significant difference between the two treatment groups (HR= 0.70, 95% CI = 0.32 to 1.57; p=0.32).  Of the 25 men who developed metastatic disease, 19 eventually died of prostate cancer, with 2 dying from a second cancer, 2 dying from non-malignant causes and 2 remaining alive.

Despite ongoing benefit with respect to biochemical disease control, long term follow up out to 2 decades failed to demonstrate improvements in other important outcomes such as development of metastatic disease, deaths from prostate cancer and deaths from any cause. Large differences in absolute biochemical control failed to give any indication of any treatment effect on overall mortality with a hazard ratio of 1.00, although the initial study was not powered for this outcome .  With the majority of patients now dead, longer follow up is unlikely to change these findings.  However, other randomized studies of brachytherapy were approximately two (Hoskin, 2012) and four (Morris, 2017) times larger and may, with time, have the statistical power to reveal such differences.  Our findings are, however, consistent with a number of dose escalation studies in which external beam treatments alone were used.

Reasons for the lack of translation from disease control to survival may be a reflection of the prolonged natural history of prostate cancer and the growing number of options for patients experiencing biochemical relapse.

All three randomized brachytherapy boost trials have suggested (at a minimum) a trend toward a greater risk of late GU toxicity associated with implant.  This risk must be balanced against a greater risk of requiring future LHRH agonists in the salvage setting, bringing its own risk of toxicity.

Additional findings highlighted by this trial include the observation that patients developing metastatic disease following a recurrence are most likely (19/25, 76%) to die of prostate cancer.  Conversely, patients developing a recurrence without distant disease, are very unlikely (2/36, 6%) to die of prostate cancer.  Also, men developing a second, unrelated cancer are similarly very likely (25/30, 83%) to die of their subsequent diagnosis and very unlikely (0/30) to die of prostate cancer.  Highlighting the need for ongoing primary care of these patients, 13 patients died from cardiac or vascular causes and 3 patients died as a result of falls.

Due to the often very prolonged natural history of prostate cancer, even in the recurrent setting, extended follow up of randomized trials is crucial to help patients, physicians and policy-makers navigate the growing number of treatment options for patients with prostate cancer.  Although limited by relatively small numbers, this further analysis of a previously reported randomized trial provides extended follow up, illustrating long term implications of the study’s initial findings.  Long term reports of other trials are eagerly awaited.

Written by: Ian Dayes

Read the Abstract

References:


Sathya JR, Davis IR, Julian JA, Guo Q, Daya D, Dayes IS, Lukka HR, Levine M. Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate. Journal of Clinical Oncology. 2005 Feb 20;23(6):1192-9.

Morris WJ, Tyldesley S, Rodda S, Halperin R, Pai H, McKenzie M, Duncan G, Morton G, Hamm J, Murray N. Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An analysis of survival endpoints for a randomized trial comparing a low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high-and intermediate-risk prostate cancer. International Journal of Radiation Oncology* Biology* Physics. 2017 Jun 1;98(2):275-85.

Hoskin PJ, Rojas AM, Bownes PJ, Lowe GJ, Ostler PJ, Bryant L. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiotherapy and Oncology. 2012 May 31;103(2):217-22.

Dayes IS, Parpia S, Gilbert J, Julian JA, Davis IR, Levine MN, Sathya J.  Long-Term Results of a Randomized Trial Comparing Iridium Implant Plus External Beam Radiation Therapy With External Beam Radiation Therapy Alone in Node-Negative Locally Advanced Cancer of the Prostate. International Journal of Radiation Oncology* Biology* Physics. 2017 Sep 1;99(1):90-93. 
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