Clinical Investigation
A Phase II Trial of Arc-Based Hypofractionated Intensity-Modulated Radiotherapy in Localized Prostate Cancer

https://doi.org/10.1016/j.ijrobp.2010.04.054Get rights and content

Purpose

To evaluate acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and biochemical control of hypofractionated, image-guided (fiducial markers or ultrasound guidance), simplified intensity-modulated arc therapy for localized prostate cancer.

Methods and Materials

This Phase II prospective clinical trial for T1a–2cNXM0 prostate cancer enrolled 66 patients who received 63.2 Gy in 20 fractions over 4 weeks. Fiducial markers were used for image guidance in 30 patients and daily ultrasound for the remainder. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Results

Median follow-up was 36 months. Acute Phase Grade 2 and 3 toxicity was 34% and 9% for GU vs. 25% and 10% for GI symptoms. One Grade 4 acute GI toxicity occurred in a patient with unrecognized Crohn's disease. Late Grade 2 and 3 toxicity for GU was 14% and 5%, and GI toxicity was 25% and 3%. One late GI Grade 4 toxicity was observed in a patient with significant comorbidities (anticoagulation, vascular disease). Acute GI toxicity ≥Grade 2 was shown to be a predictor for late toxicity Grade ≥2 (p < 0.001). The biochemical disease-free survival at 3 years was 95%.

Conclusions

Hypofractionated simplified intensity-modulated arc therapy radiotherapy given as 63.2 Gy in 20 fractions demonstrated promising biochemical control rates; however, higher rates of acute Grade 3 GU and GI toxicity and higher late Grade 2 GU and GI toxicity were noted. Ongoing randomized controlled trials should ultimately clarify issues regarding patient selection and the true rate of severe toxicity that can be directly attributed to hypofractionated radiotherapy.

Introduction

Prostate cancer is the most commonly diagnosed male cancer, and radical external beam radiotherapy is an accepted treatment modality (1). However, the biochemical failure-free rate with conventional non–dose-escalated external beam radiotherapy remains below 50% 2, 3, 4, 5. Research to improve biochemical control has included the addition of adjuvant hormones and dose escalation. Dose escalation trials with conventional (1.8–2 Gy/day) fractionation to doses in excess of 75 Gy are associated with prolonged treatment times of more than 2 months 3, 6, 7, 8, 9, 10. These trials have shown reduced biochemical and distant failures 1, 11, 12, 13, 14, 15, 16, 17. The associated prolonged treatment time of more than 2 months 3, 6, 7, 8, 9, 10 has raised the issues of patient convenience, image guidance, and resource management (18). In addition, despite these escalated doses, failure rates of up to 33% for patients treated to 78 Gy have been reported (8).

Recent studies have examined the use of hypofractionated treatment using fractional doses greater than 2 Gy based on the rationale that the predicted α/β for prostate cancer is approximately two 3, 4, 19, 20, 21, 22, 23, 24, 25, 26. Early data from hypofractionation studies suggest that hypofractionated radiotherapy up to 60 Gy in 20 fractions is safe, is effective, and holds similar long-term bowel and bladder sequelae compared to conventional treatment while permitting the treatment to be delivered over a shorter time 27, 28, 29.

Arc radiotherapy techniques such as intensity-modulated arc therapy, helical tomotherapy, and volumetric arc therapy have been proposed as alternatives to existing intensity-modulated radiotherapy (IMRT) delivery techniques 30, 31. One advantage of arc therapy is the ability to optimize the beam delivery over a large number of beam angles for better conformality. In the first intensity-modulate arc therapy proposal, a beam fluence pattern using inverse treatment planning is generated (32). The fluence pattern is decomposed into a series of conformally shaped arcs (moving beam) treatments. Wong et al. have proposed a simplification of this technique: simplified intensity modulated arc therapy (SIMAT) (11). The SIMAT technique involves a series of dynamically shaped arcs that are used to treat the target volume with the option of dynamic shielding of critical organs as the gantry rotates. By varying the relative importance (weights) of the arcs, an optimal plan with concave dose distributions can be obtained, satisfying the desired treatment dose prescriptions and normal tissue constraints. We have shown that SIMAT is similar to other IMRT techniques and produces better dose distributions than three-dimensional (3D) conformal therapy 33, 34.

In this article we report on a Phase I/II trial of image-guided, hypofractionated radiotherapy for localized prostate cancer with an emphasis on acute and late toxicities and early biochemical control rates.

Section snippets

Study design

This was a Phase II, single-institution, prospective clinical trial carried out at the London Regional Cancer Program for patients with biopsy-proven localized adenocarcinoma of the prostate. Pretreatment evaluation included baseline history, physical examination, determination of prostate-specific antigen (PSA), and pathology review. A negative bone scan before treatment was required for PSA values greater than 10, a Gleason score greater than 7, or staging of T2B or greater. Estimated nodal

Results

The trial was conducted between October 2003 and July 2006, during which 66 patients were enrolled. All patients were treated according to protocol, with no observed target or normal tissue dose–volume histogram deviations. Toxicity data were analyzed as of August 2009 on all 66 patients. Two patients were lost to follow-up. One received all posttreatment follow-up at a separate center; another was followed up by his family physician after his 3-month posttreatment follow-up. These 2 patients

Discussion

We previously reported on a study of SIMAT for conventionally fractionated radiotherapy with toxicity comparable to that of reported 3D and intensity-modulated techniques 34, 38. The present study, which enrolled 66 patients with a median follow-up of 36 months, gave 63 Gy in 3.16-Gy fractions (biologically effective dose2Gy of 81.5Gy). The acute GU Grade 2 toxicity observed (33.8%) was within the findings of previous IMRT-based hypofractionated studies (9–48%) (Table 7). For acute Grade 3 GU

Conclusions

Hypofractionation using daily localization with fiducial markers or ultrasound and arc-based SIMAT delivery in this Phase II trial was associated with acute Grade 2 and late Grade 3 toxicity similar to previously reported IMRT-based hypofractionated trials. However, the acute Grade 3 and late Grade 2 toxicity was higher than previously published hypofractionation and dose escalation trials, suggesting this method may require caution with its use. Randomized trials of hypofractionation (RTOG

References (48)

  • J. Livsey et al.

    Hypofractionated conformal radiotherapy in carcinoma of the prostate: Five-year outcome analysis

    Int J Radiat Oncol Biol Phys

    (2003)
  • A. Pollack et al.

    Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial

    Int J Radiat Oncol Biol Phys

    (2006)
  • A. Dasu

    Is the α/β value for prostate tumors low enough to be safely used in clinical trials?

    Clin Oncol

    (2007)
  • S.M. Bentzen et al.

    The α/β ratio for prostate cancer: What is it, really? [editorial]

    Radiother Oncol

    (2005)
  • E.E. Yeoh et al.

    Evidence for efficacy without increased toxicity of hypofractionated radiotherapy for prostate carcinoma: Early results of a Phase III randomized trial

    Int J Radiat Oncol Biol Phys

    (2003)
  • E.E. Yeoh et al.

    Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: Updated results of a phase III randomized trial

    Int J Radiat Oncol Biol Phys

    (2006)
  • D. Palma et al.

    Volumetric modulated arc therapy for delivery of prostate cancer radiotherapy: Comparison with intensity-modulated radiotherapy and three-dimensional conformal radiotherapy

    Int J Radiat Oncol Biol Phys

    (2008)
  • T.R. Mackie et al.

    Tomotherapy. Semin Radiat Oncol

    (1999)
  • G. Bauman et al.

    Simplified intensity-modulated arc therapy for dose escalated prostate cancer radiotherapy

    Med Dosim

    (2004)
  • M. Roach et al.

    Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO phoenix consensus conference

    Int J Radiat Oncol Biol Phys

    (2006)
  • M. Lock et al.

    Hypofractionated prostate arc radiotherapy using ultrasound localization

    Radiother Oncol

    (2006)
  • P. Cheung et al.

    Individualized planning target volumes for intrafraction motion during hypofractionated intensity-modulated radiotherapy boost for prostate cancer

    Int J Radiat Oncol Biol Phys

    (2005)
  • P.A. Kupelian et al.

    Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Long term outcomes

    Int J Radiat Oncol Biol Phys

    (2005)
  • P.A. Kupelian et al.

    Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience

    Int J Radiat Oncol Biol Phys

    (2007)
  • Cited by (0)

    Conflict of interest: none.

    View full text