Prospective Randomized Trial Comparing External Beam Radiotherapy versus Watchful Waiting in Early Prostate Cancer (T1b-T2, pN0, Grade 1-2, M0)

Reporter: Abigail Berman Milby
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 3, 2011

Presenting Author: A. Widmark
Affiliation: Department of Radiation Sciences, Oncology, Umeå University, Umeo, Sweden


  • In the mid-eighties, watchful waiting was an acceptable standard of care but radical prostatectomy and definitive radiotherapy became increasingly used.
  • Watchful waiting is an attractive option for patients with early-stage prostate cancer, as some cancers are slow-growing and do not contribute significantly to morbidity or mortality, particularly in the elderly population.
  • Bill Axelson et al. (NEJM, 2005) published a randomized trial of radical prostatectomy versus watchful waiting in early prostate cancer; they identified a 5% difference in overall survival after 10 years.
  • This randomized trial was started in 1986 to evaluate progression free survival and overall survival in early localized prostate cancer (LPC) randomized to external beam radiotherapy (EBRT) or watchful waiting (WW).


  • Eligible patients included:
    • newly diagnosed LPC, T1b-T2, surgically staged node negative, grade 1-2
    • no metastatic disease as assessed by bone scan and CXR
    • no previous treatment
    • life expectancy equal to an age matched population
  • The primary end point was progression free survival and overall mortality
  • The goal accrual was 260 patients and later increased to 320 based on achieving a 10% difference in 5 year survival (85 vs. 95%) with ?=0.05 and ?=90%
    • not reached due to recruitment difficulties
    • patients were mainly recruited from North Sweden (177), Denmark (40), and Norway
  • Radiotherapy was administered via 3D conformal radiotherapy
    • four-field-box EBRT, starting with 50 Gy to the pelvis then approximately 15 Gy to the prostate)
      • From 1986-93, 64 Gy in 32 fractions with a 2 cm margin
      • From 1986-93, 64-68 Gy with 1.5 cm margin
  • On objective progression, hormonal treatment was given in both arms. Some patients in the WW arm received EBRT.
  • Patients were followed every six months for the first two years then annually with PSA and general chemistries.


  • Between April 1986 and January 1997, 214 patients were enrolled.
  • This analysis is based on 138 deaths
    • 74 patients (69%) in the WW group and 64 (60%) in the EBRT group
  • Minimum follow up of 16 years
  • 20 year OS of 0.31 (95% CI, 0.22-0.42) and 0.35 (95% CI, 0.25-0.48) respectively (p=0.26).
  • 15 year prostate cancer specific deaths was 25 (23%) and 19 (18%) respectively giving a prostate cancer-specific survival of 0.71 (0.62-0.82) and 0.79 (0.71-0.89), respectively (p =0.51).
  • Distant progression was 33/107 (31%) in the WW and 18/107 (17%) in the EBRT
    • 15 year recurrence free survival of 0.66 (95% CI, 0.57-0.77) and 0.81 (95% CI, 0.74-0.90), (p=0.022).
  • Clinical progression (defined as biochemical or local that made the treating doctor change treatment) was 58% in the WW arm and 29% in the EBRT arm
    • 15 years recurrence free survival of 0.40 (95% CI, 00.31-0.51) and 0.67 (95% CI, 00.58-0.78) respectively, (p <0.0001).
  • Biochemical and local progression independently were both significantly in favor of EBRT.

Author's Conclusions

  • EBRT significantly reduced distant progression and clinical progression compared to WW
    • no significant difference in prostate cancer-specific survival or overall survival

Clinical Implications

  • This trial shows that definitive therapy for localized prostate cancer with EBRT decreases distant progression and clinical progression compared to WW without an effect on survival.
    • Many studies have shown survival benefits in low-risk prostate cancer with longer follow-up than seen in this study.
  • Notably, this is in the pre-PSA era; with PSA screening, we identify prostate cancer not evident on digital rectal examination that may contribute even less to morbidity and mortality than these patients. Therefore, the difference in distant and clinical progression may not be seen if this study were performed in the PSA era due to lag time and stage migration.
  • Strengths of this study include a minimum of 16 years of follow-up and selecting patients with a life expectancy similar to that of a matched population.
  • A separate publication on the quality of life analysis of this study (Fransson Scand J Urol Neph 2009) showed no differences in QOL, bowel symptoms, or erectile function. Weak stream, fatigue, nocturia was more common in the RT group. Erections decreased in the WW patients over time. Overall, they found very few differences in QOL.
  • Watchful waiting has largely been replaced in the United States by active surveillance, where patients are closely monitored with repeat PSA, DRE, and serial biopsy and treated at progression of any one of those metrics.
    • First, this population does not necessarily match the accepted criteria for active surveillance (AS), including cT1-T2, GS <=6 (sometimes <=7), PSA <10 (sometimes PSA <15 or <20), low PSA velocity (PSA DT >4 years).
    • Second, we would expect even less of a difference when comparing AS to EBRT than WW to EBRT given the closer monitoring.
  • Interesting subset analyses would be different age cohorts and comorbidity indices; we would anticipate that older patients with more comorbidities would benefit less from definitive therapy.
    • We also anticipate learning how many patients in WW group received EBRT and any difference in the results utilizing intention-to-treat analyses versus including patients who ultimately received EBRT into the EBRT.