Impact of radiotherapy (RT) combined with androgen deprivation (ADT) versus ADT alone for local control in clinically locally advanced prostate cancer

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 6 de junio del 2010

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Background

  • In locally advanced prostate cancer, the combination of radiation therapy (RT) and androgen deprivation therapy (ADT) has been demonstrated to provide superior outcomes when compared to RT or ADT alone (Bolla, Lancet, 2002).
  • Indications and methodology for delivery of ADT remain uncertain and at times controversial. Outstanding questions may include duration of ADT, coordination with other treatment modalities, and type of ADT employed (androgen receptor agonist versus leutonizing hormone releasing hormone (LHRH) agonist, versus total androgen blockade using a combination of the two.
  • At the time when this study was designed, ADT alone was often used in locally advanced disease, especially in Europe.
  • Another recently published Phase III study (Widmark, Lancet, 2009) demonstrated a significant reduction in prostate-cancer-specific mortality with the addition of RT to ADT alone; however, this study used a long term androgen receptor antagonist (Flutamide) rather than an LHRH agonist
  • Clear results with long-term administration of a LHRH agonist with or without RT had not been reported until now.
  • Here, the authors report the results of a phase III trial in locally advanced prostate cancer, comparing combined modality (ADT + RT) to ADT alone.

Methods

  • The study was a multicenter, randomized Phase III trial
  • Inclusion criteria:
    • Patients < 80 years of age
    • Histologically confirmed prostate cancer, clinical stage T3 - T4, or pathologic stage T3 (on biopsy)
    • N0 by CT abdomen/pelvis and M0 by bone scan
  • Patients were randomized to one of 2 parallel groups:
    • ADT alone (Leuprorelin subcutaneous injection every 3 months) for 3 years, with Flutamide during the first month, or
    • The same ADT regimen combined with RT (starting within 3 months) as follows:
      • 48 ± 2 Gy to the whole pelvis using a 4-field technique, followed by:
      • A cone-down to the prostate only using a 3D conformal technique, to a total dose of 70 ± 4 Gy, in 200 cGy fractions.
  • The primary endpoint was 5-year overall progression free survival (PFS), either biological (using the ASTRO definition of a PSA level equal to or greater than nadir + 2) or clinical.
  • Secondary end points included:
    • Clinical PFS, with clinical progression defined as an increase of > 50% prostatic volume from its nadir on ultrasound, new regional lymph nodes, or distant lesions on CT or bone scan.
    • Loco-regional progression
    • Metastatic progression
    • Overall survival
    • Quality of life measures.
  • Analysis was by intent to treat.

Results

  • 263 patients were randomized (130 to ADT, 133 to the combined group).
  • Baseline characteristics were evenly distributed between the 2 groups:
    • Mean age was 70 years,
    • 93% had a T3 disease,
    • Mean baseline PSA: 52 ng/mL (ADT alone) vs. 42 ng/mL (combined group) (p = 0.79).
    • The mean Gleason score was 6.4 and 6.6, respectively.
  • Median follow up of 67 months
  • Primary endpoint:
    • The 5-year PFS was 60.9% (combined group) vs. 8.5% (ADT alone group) (RR: 5.9 [4.19; 8.42]; p<0.001).
    • The median overall PFS was 7.7 years (combined group) vs. 1.7 years (ADT alone)
  • Secondary endpoints:
    • The 5-year clinical PFS was 88.7% (combined group) vs. 62.3% (ADT group) (p<0.001).
    • The cumulative incidence of loco-regional progression at 5 years was 9.7% (combined group) versus 29% (ADT group) (p = 0.0002)
    • The cumulative incidence of metastatic progression at 5 years was 3% (combined) vs. 10.8% (ADT alone), (p = 0.018).
    • When stratified by PSA level, there was no benefit with combined treatment observed in patients with a PSA < 20, a benefit to combined treatment in patients with a PSA between 20-50, and a more pronounced benefit to combined treatment when the PSA was > 50 ng/mL.
    • There was no observed difference in overall survival, and a trend towards improvement in cancer-specific survival (92% in combined arm versus 86% in ADT alone) that did not reach significance.

Authors’ Conclusions

  • In patients with locally advanced prostate cancer (in this study mainly T3N0M0), addition of RT to 3 years of ADT with a LHRH agonist significantly reduces the risk of clinical progression.
  • The follow-up is relatively limited at this point (median follow-up of 5.5 years), so the observed benefit is mainly seen in terms of loco-regional progression and not overall survival.
  • For distant metastases a prolonged follow up is needed to see a larger benefit.
  • This reduction of progression confirms that combined modality (ADT and RT) should be the standard of care for patients with a significant life expectancy diagnosed with locally advanced prostate cancer.

Clinical Implications

  • This trial is an important addition to a number of studies demonstrating that combined modality treatment with long-term androgen deprivation and radiation therapy is the standard of care for patients with locally advanced prostate cancer.
  • This study complements several other randomized Phase III data that analyze this question in slightly different ways:
    • The Bolla EORTC study (Lancet 2002) demonstrated that the addition of long-term hormonal therapy to RT improved overall survival in this subset of patients. The magnitude of the treatment effect in the Bolla study was greater than the magnitude in the present study, potentially supporting an argument that the incremental benefit of hormonal therapy may be greater than that of radiation therapy in these patients.
    • As mentioned previously, another recent study (Widmark, Lancet, 2009) demonstrated a significant reduction in prostate-cancer-specific mortality with the addition of RT to ADT alone, but in this study long-term androgen receptor blockade was used instead of an LHRH agonist.
  • The study presented here, somewhat unexpectedly, demonstrated that the benefit of adding RT to ADT in terms of progression-free survival appears to be correlated with baseline PSA level, with a greater benefit seen in patients with a higher baseline PSA (>50 as opposed to PSA between 20 – 50). This is intriguing but the clinical significance remains to be determined.
  • Potential limitations to the applicability of this study to current practice include the relatively low dose of radiation (total dose of 70 Gy) delivered, in light of the fact that dose escalation has been shown to correlate with improved outcomes.
    • This warrants additional investigation into the incremental benefit of combined modality therapy in the setting of RT dose escalation.
  • Finally, in light of recent studies demonstrating an increased risk of all-cause mortality in patients with underlying cardiovascular disease treated with ADT (Nanda, JAMA 2009), additional studies are needed to determine which patients, when stratified by cardiovascular risk factors, are likely to benefit from combined modality treatment for locally advanced prostate cancer.



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