Update of the Results of the Dutch Multicenter Dose Escalation Trial of Radiotherapy for Localized Prostate Cancer

Reviewer: Charles B. Simone, II, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 2, 2007

Share article


Presenter: Abrahim Al-Mamgani, MD
Presenter's Affiliation: Erasmus Medical Center, Rotterdam, The Netherlands
Type of Session: Scientific

Background

  • With the increased use of three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT), radiation oncologists have been able to treat patients with prostate cancer to higher doses than had previously been tolerated with conventional external beam radiation therapy. Dose escalation has been possible with these newer radiation techniques through their ability to reduce dose to normal tissues. Researchers have investigated freedom from failure (FFF) and local control in trials with dose escalation.
  • The Dutch Multicenter Dose Escalation Trial investigated whether a dose of 78 Gy improved outcomes when compared with a conventional dose of 68 Gy for patients with prostate cancer.
  • Previously published results after a median follow-up of 51 months demonstrated that a higher dose of external beam radiation therapy improves FFF. The rate of FFF in patients who received 78 Gy was 64%, compared with 54% in patients receiving 68 Gy (p=0.02). No statistically significant differences in freedom from clinical failure (FFCF) or overall survival were demonstrated between dose groups (Peeters ST, et al. J Clin Oncol. 2006;24(13):1990-6.).
  • This investigation serves to update the randomized Dutch Multicenter Dose Escalation Trial and reports outcomes after a median follow-up of 69 months.

Materials and Methods

  • Between June of 1997 and February of 2003, 669 patients with prostate cancer enrolled in this trial and were randomized to receive external beam radiation therapy to doses of 68 Gy or 78 Gy. Patients were eligible for accrual with stages T1b to T4 prostate adenocarcinoma and PSA levels less than 60 ng/ml, except for patients with T1b to T1c tumors and PSA levels less than 4 ng/ml. Patients with metastases or pathologically proven regional lymph node involvement were excluded. Mean age of study participants was 69 years.
  • Patients were stratified by age, institution, use of hormonal therapy, and treatment group.
  • Patients were categorized as low risk (PSA ≤10 ng/ml, Gleason 2 to 6, T1 to T2), intermediate risk (patients who did not fulfill criteria for the low risk or high risk), or high risk (any one of PSA >20 ng/ml, Gleason 8 to 10, T3 to T4).
  • FFF served as the primary study endpoint and was defined as clinical or biochemical failure, which was evaluated independently for both three consecutive increases in PSA level after a nadir (American Society of Therapeutic Radiation Oncology definition) and a PSA nadir plus 2.0 ng/mL (Phoenix definition).
  • Secondary end points included FFCF and overall survival, as well as gastrointestinal and genitourinary toxicities.

Results

  • Patients who received radiation doses of 78 Gy had significantly better FFF when compared to those who received 68 Gy (57% vs. 45%, p = 0.015).
  • Subset analysis based on risk stratification demonstrated that the benefit in FFF with higher radiation doses was most strongly correlated with intermediate risk patients, although no statistically significant benefits was seen when comparing doses within each risk group. 
  • There was no difference in FFCF (70% vs. 69%, p = 0.96) or overall survival (75% vs. 74%, p = 0.66) between patients in the two arms of the study. 
  • There was no difference in frequency of RTOG/EORTC grade 2 or higher late genitourinary toxicity between treatment arms, and the cumulative incidence of toxicity increased from 36% at five years to 40% at seven years.
  • More patients in the 78 Gy arm reported RTOG/EORTC grade 2 of higher late gastrointestinal toxicity (36% vs. 25%, p = 0.04).

Author's Conclusions

  • Patients with prostate cancer experience significant improvements in FFF when treated with external beam radiation therapy to 78 Gy when compared to patients treated to 68 Gy.
  • Patients with intermediate risk prostate cancer benefited most from dose escalation, although a benefit to low risk patients can not be excluded.
  • There is no statistically significant difference in FFCF and overall survival between dose groups at a median follow-up of 69 months.
  • While no difference was demonstrated in rates of late genitourinary toxicity, patients receiving higher doses of radiation had significantly higher rates of late gastrointestinal toxicity.

Clinical/Scientific Implications

As a definitive treatment option for patients with localized prostate cancer, external beam radiation therapy can achieve 10-year biochemical progression-free survival (bPFS) rates greater than 80% in patients with low-risk disease. bPFS rates decrease with time from treatment and increasing gleason score, PSA level, and tumor stage. In an attempt to further improve FFF rates, researchers have investigated the benefits of dose escalation on FFF and local control. Prior research suggestions that higher doses of irradiation are often superior for patients with localized disease, although total doses are often limited by toxicity. This trial employs 3D-CRT to achieve higher doses to the target volume while minimizing normal tissue doses, and it demonstrates that dose escalation does improve FFF. At a median follow-up of 69 months, no benefit to dose escalation was demonstrated in FFCF or overall survival. Larger trials with longer follow-up are needed to determine if such a benefit in FFF will result in improvements in the rates of clinical failure and overall survival. Larger trials are also needed to determine definitely which risk group of patients should receive dose escalation, as no statistically significant difference was seen in this study when comparing doses within each risk group, likely due to the small sample size of this subset analysis. Additionally, the use of adjuvant hormonal therapy in conjunction with dose escalation for higher risk patients is also warranted. One concern with dose escalation demonstrated in this trial is the increased rate of late gastrointestinal toxicity among patients treated to higher radiation doses. However, all patients in this trial were treated with 3D-CRT. Rates of gastrointestinal toxicity would have been expected to be lower with the delivery of IMRT. 

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.