Addition of Focal Boost to Intraprostatic Lesions in EBRT Improves Biochemical DFS in Localized Prostate Cancer

Article

The addition of a focal boost to the intraprostatic lesion was found to improve biochemical disease-free survival in patients undergoing treatment with external beam radiotherapy for localized intermediate- and high-risk prostate cancer.

Linda G.W. Kerkmeijer, MD, PhD

Linda G.W. Kerkmeijer, MD, PhD

The addition of a focal boost to the intraprostatic lesion was found to improve biochemical disease-free survival (bDFS) in patients undergoing treatment with external beam radiotherapy (EBRT) for localized intermediate- and high-risk prostate cancer, according to results from the phase 3 FLAME trial (NCT01168479) published in the Journal of Clinical Oncology.1

At a median follow-up of 72 months, patients who received a focal boost in addition to conventionally fractionated EBRT experienced a significantly higher bDFS vs those who received EBRT alone (hazard ratio [HR], 0.45; 95% CI, 0.28-0.71; P <.001).

At 5 years of follow-up, the bDFS rates in the investigative and control arms were 92% (95% CI, 87%-94%) and 85% (95% CI, 80%-89%), respectively. Moreover, Kaplan-Meier curves indicated a significant improvement in bDFS (log-rank, P <.001) and DFS (log-rank, P <.001) up to 7 years in the cohort of patients who received the focal boost.

However, no major differences were observed between the arms with regard to distant metastases-free survival (log-rank P = .26), overall survival (OS; log-rank P = .50), or prostate cancer–specific survival (PCSS; log-rank P = .49).

“The FLAME trial is the first phase 3 randomized controlled trial showing that the addition of a focal boost to the intraprostatic lesion(s) in EBRT for prostate cancer significantly improves 5-year bDFS,” lead study author Linda G.W. Kerkmeijer, MD, PhD, of the University Medical Center of Utrecht and Radboud University Medical Center, and colleagues, wrote. “Differences in toxicity were small and not statistically significant. However, to adequately assess late genitourinary [GU; urethra-related] toxicity, longer follow-up is required.”

As post-radiotherapy local recurrences of prostate cancer have been known to often originate from the primary tumor site, investigators have hypothesized that focal boosting may help to increase bDFS without increased toxicity.2,3

In the phase 3 FLAME trial, investigators set out to confirm the hypothesis that focal dose-escalation would result in improved biochemical DFS for patients with intermediate- and high-risk prostate cancer. Because the benefit of focal boosting has been unproven historically, the trial was designed to avoid increased toxicity with the addition of this approach.

To be eligible for enrollment, patients with intermediate- and high-risk localized prostate cancer originally had to meet ASH criteria. However, because that criteria is no longer used in clinical practice, investigators utilized European Association of Urology risk classification for additional analyses.

Patients who had a World Health Organization performance status of greater than 2, an International Prostate Symptom score of 20 or greater, and evidence of lymph node involvement or distant metastases, were excluded. Additional exclusion criteria included a history of pelvic radiation, prostatectomy, transurethral resection of the prostate (TURP) less than 3 months prior to radiotherapy, and the inability to undergo magnetic resonance imaging (MRI).

Study participants were randomized 1:1 to either the standard treatment arm or the investigative focal boost arm. Those on the control arm received conventionally fractionated EBRT that was comprised of 77 Gy, given in 35 fractions of 2.2 Gy, to the prostate. Those in the investigative arm received a simultaneous integrated focal boost of up to 95 Gy to the macroscopic tumor, which resulted in 35 fractions of up to 2.7 Gy. If required, the boost dose was reduced.

“Although the Prostate Imaging Reporting and Data System [PI-RADS] guidelines were published after the start of the FLAME trial, the multiparametric MRI protocols were conformed to the PI-RADS recommendations,” the study authors noted.

The primary end point of the study was 5-year bDFS, which was defined as the time from random assignment to biochemical recurrence. Recurrence was defined to be the lowest prostate-specific antigen (PSA) value after treatment plus 2 ng/mL. Key secondary end points included PCSS, OS, toxicity, and health-related quality of life (HRQoL).

Between November 2009 and February 2015, a total of 571 patients with localized intermediate- and high-risk disease were enrolled to the trial; 287 of patients received standard EBRT and 284 were given EBRT with the focal boost.

Patient and treatment characteristics at baseline were observed to be well balanced between the arms. Across the arms, the mean age of study participants was 70 years. Eighty-four percent of patients had high-risk disease, 15% had intermediate-risk disease, and 1% had low-risk disease.

The mean intact PSA of patients enrolled to the investigative arm was 16.3 ng/mL vs 15.2 ng/mL in the control arm. Additionally, 7% of patients in the focal-boost cohort received neoadjuvant hormonal therapy vs 8% of those in the standard cohort; 93% vs 92% of patients received adjuvant hormonal therapy.

Thirty-four percent of patients in the investigative arm received 18 to 36 months of hormonal therapy, 12% received 6 to 18 months, 18% received 6 months, and 35% received none; these rates were 29%, 11%, 20%, and 35%, respectively, in the control arm. Moreover, 13% and 14% of patients in the investigative and control arms, respectively, had underwent TURP.

Additional data from an adjusted Cox regression analysis indicated that biochemical failures were reduced by 55% with the addition of a focal boost vs standard treatment (HR, 0.45; 95% CI, 0.29-0.71; P <.001). The analyses demonstrated similar results with regard to DFS (HR, 0.48; 95% CI, 0.32-0.74; P <.001), with no statistically significant difference in DMFS observed between the arms (HR, 0.72; 95% CI, 0.43-1.22; P = .22). Data from an adjusted Cox regression analysis revealed an HR for OS of 1.26 (95% CI, 0.83-1.93; P = .27) and an HR for PCSS of 0.69 (95% CI, 0.27-1.79; P = .45). Notably, data from a per-protocol analysis that was also conducted did not differ from the intention-to-treat analysis. A competing risk analysis indicated similar results.

No statistically significant differences in HRQoL domains were observed between the 2 treatment arms. Urinary HRQoL was found to deteriorate 1 month following treatment and then to improve within 1 year in both arms. Bowl HRQoL was noted to deteriorate less than 5 points from baseline in both arms, and to remain at a similar level during follow-up. Additionally, sexual activity in patients who did not receive hormonal therapy never deteriorated by more than 5 points from baseline in either of the arms.

Differences in grade 2 and higher or 3 and higher GU and gastrointestinal (GI) toxicities were small and not determined to be statistically significant between the arms. Only 1 patient in the focal-boost arm experienced a grade 4 GU toxicity following 3 years of treatment. The patient developed severe urinary incontinence and underwent a permanent urinary diversion. Notably, no grade 4 GI toxicities were observed.

“In conclusion, the FLAME trial showed that a focal boost to a high dose improves biochemical DFS in intermediate- and high-risk localized prostate cancer, without additional toxicity,” the study authors concluded. “Focal dose escalation in (extreme) hypofractionated schedules should be further explored. As we observed a clear dose response relation, further improvement of tumor control may be feasible when more advanced techniques allow a higher boost dose.”

References

  1. Kerkmeijer LGW, Groen V, Pos FJ, et al. Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: results from the FLAME randomized phase III trial. J Clin Oncol. 2021;39(7):787-796. doi:10.1200/JCO.20.02873
  2. Cellini N, Morganti AG, Mattiucci GC, et al. Analysis of intraprostatic failures in patients treated with hormonal therapy and radiotherapy: implications for conformal therapy planning. Int J Radiat Oncol Biol Phys. 2002;53(3):595-599. doi:10.1016/s0360-3016(02)02795-5
  3. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys. 1999;44(4):921-929. doi:10.1016/s0360-3016(98)00502-1
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