Clinical Investigation
Dose Escalation for Prostate Adenocarcinoma: A Long-Term Update on the Outcomes of a Phase 3, Single Institution Randomized Clinical Trial

https://doi.org/10.1016/j.ijrobp.2019.02.045Get rights and content

Purpose

To determine the long-term outcomes for prostate adenocarcinoma when escalating radiation dose from 70 Gy to 78 Gy.

Methods and Materials

Between 1993 and 1998, 301 patients with biopsy-proven clinical stage T1b-T3 prostate adenocarcinoma, any prostate-specific antigen level, and any Gleason score were randomized to 70 Gy in 35 fractions versus 78 Gy in 39 fractions of photon radiation therapy using a 4-field box technique without hormone deprivation therapy. The primary outcome was powered to detect a 15% difference in biochemical or clinical failure. Secondary outcomes included survival, prostate cancer mortality, biochemical failure, local failure, nodal failure, distant failure, and secondary malignancy rates.

Results

With a median follow-up of 14.3 years, the cumulative incidence of 15-year biochemical or clinical failure was 18.9% versus 12.0% in the 70 Gy versus 78 Gy arms, respectively (subhazard ratio [sHR], 0.61; 95% confidence interval [CI], 0.38-0.98; Fine-Gray P = .042). The 15-year cumulative incidence of distant metastasis was 3.4% versus 1.1%, respectively (sHR, 0.33; 95% CI, 0.13-0.82; Fine-Gray P = .018). The 15-year cumulative incidence of prostate cancer-specific mortality was 6.2% versus 3.2%, respectively, (sHR, 0.52; 95% CI, 0.27-0.98; Fine-Gray P = .045). There were no differences in overall survival (HR, 1.10; 95% CI, 0.84-1.45; log rank P = .469) or other-cause survival (sHR, 1.33; 95% CI, 0.99-1.79; Fine-Gray P = .061). Salvage therapy was more common in the 70 Gy arm, at 38.7% versus 21.9% in the 78 Gy arm (P = .002). There was a 2.3% secondary solid malignancy rate (1 bladder, 6 rectal) within the radiation treatment field, which was not significantly different between treatment arms.

Conclusions

Dose escalation by 8 Gy (78 Gy vs 70 Gy) provided a sustained improvement in biochemical and clinical failure, which translated into lower salvage rates and improved prostate cancer-specific mortality, but not overall survival. Long-term follow-up demonstrated a low incidence of potential solid tumor secondary malignancies.

Introduction

External beam radiation therapy is a curative treatment option for localized prostate cancer and is used in roughly a quarter of all treated cases in the United States.1 Based on quantitative biological modeling studies2, 3 and supported by clinical observations,4 it is well established that high doses of radiation are necessary for adequate prostate cancer cell killing to achieve cure. However, until 3-dimensional conformal radiation therapy (3DCRT) and intensity modulated radiation therapy (IMRT) techniques could be implemented clinically, dose escalation to the prostate was limited out of concern for toxicity to surrounding organs at risk. Although several randomized controlled trials have examined dose escalation in prostate cancer,5, 6, 7, 8, 9 none report median follow-up beyond 10 years. Moreover, these trials had heterogeneous use of concurrent androgen deprivation therapy, which is now the standard of care for many patients. Given the frequently indolent nature of the disease and protracted time to failure, extensive follow-up may provide unique and valuable insight. Here, we present long-term follow-up of a prospective trial involving patients with localized prostate adenocarcinoma treated without hormonal therapy, randomized to standard versus dose escalated radiation therapy.

Section snippets

Protocol eligibility and participants

Between 1993 and 1998, patients at our high-volume academic institution were enrolled in an institutional review board–approved phase 3 randomized trial (CRT 93-001). Informed consent was obtained from each participant. Eligibility criteria included clinical stage T1-T3, N0, M0 prostate cancer based on the 1992 American Joint Commission on Cancer staging system; a documented pretreatment serum prostate-specific antigen (PSA) measurement ≤30 ng/mL; histopathologic confirmation of diagnosis and

Results

As of January 2018, the median follow-up was 14.3 years and median time since last contact among living patients was 1 month (range, 0-43 months). Of the 301 patients, 71% (214) were confirmed to be deceased and 7.3% (22) requested to stop contact and/or were lost to follow-up (>48 months since last contact). Examining the patients lost to follow-up more closely, 8 versus 14 were in the 70 Gy versus 78 Gy arm, respectively, which was not significantly different (P = .682). On subgroup analysis,

Discussion

The long-term results of this phase 3 randomized, single institution trial found that increasing the radiation dose from 70 to 78 Gy without androgen deprivation resulted in a significant improvement in the primary endpoint of biochemical or clinical failure, with significant reductions in the development of distant metastases, the need for subsequent therapy, and death from prostate cancer at a median follow-up of 14 years. Radiation therapy was associated with a 2.3% incidence of in-field

Conclusions

Moderate dose escalation from 70 to 78 Gy demonstrates sustained improvement in clinical or biochemical disease control, which translated into lower salvage rates and prostate cancer mortality. Long-term follow-up also shows a low incidence of related solid tumor secondary malignancies.

References (28)

Cited by (0)

Supported in part by grants CA 06294 and CA 16672 awarded by the National Cancer Institute, U.S. Department of Health and Human Services; DOD Grant DAMD 17-98-1-8483; and the Prostate Cancer Research Program at MD Anderson Cancer Center.

Disclosures: A.P., S.J.F., and C.T. disclose funding support by Varian Medical Systems.

View full text