New Radiation Therapy Guidelines for Prostate Cancer Lowers Treatment Burden and Cost

For clinicians who treat men with early-stage prostate cancer in their clinical practice, a new clinical guideline on the use of external beam radiation therapy (EBRT) has been developed by a panel of experts representing the American Society of Clinical Oncology (ASCO), American Society for Radiation Oncology, and American Urological Association.¹Incorporating these guidelines into practice may make treatment shorter and more convenient for patients with localized disease.

Scott Morgan, MD, an assistant professor of radiation oncology at the University of Ottawa and cochair of the guideline panel, said in an ASCO press release, “Men who opt to receive hypofractionated radiation therapy will be able to receive a shorter course of treatment, which is a welcome benefit to many men. When clinicians can reduce overall treatment time while maintaining outcomes, it’s to our patients’ benefit, as they can spend less time away from family and less time traveling to and from treatment.”

Motivation for Hypofractionation Guidelines

Prostate cancer is the most frequently diagnosed cancer and contributes to the second most cancer-related deaths in men in the United States.²Furthermore, the number of patients diagnosed with early-stage disease is increasing.³

Current treatment options for early-stage localized prostate cancer include active surveillance, in carefully selected patients; radical prostatectomy; or radiation therapy, which consists of EBRT and/or low-dose—rate or high-dose–rate brachytherapy, with or without androgen deprivation therapy.

EBRT is a definitive treatment option for men who have localized prostate cancer, and it has been shown to lead to long-term cancer control outcomes that are equivalent to those seen with radical prostatectomy.⁴With improved imaging over the past 20 years, there have been technical advances related to the planning and delivery of prostate EBRT. The technical advances include the ability to use cross-sectional imaging during the treatment planning process and the use of intensity modulation and daily image guidance to enhance treatment delivery.^5-7These technical advances allow for more precise delivery of high radiation doses to the prostate.

In hypofractionated EBRT, the radiation dose delivered per fraction is increased while total fractions are decreased. A higher bioequivalent dose can be delivered to the prostate in fewer treatments. Conventional fractionation is defined as EBRT with fraction sizes between 180 and 200 centigray (cGy), moderate hypofractionation consists of EBRT with fraction sizes between 240 and 340 cGy, and ultrahypofractionation is EBRT with fraction sizes that are 500 cGy or larger.¹

Howard M. Sandler, MD, chair of the Department of Radiation Oncology and director of the Samuel Oschin Comprehensive Cancer Institute of Cedars-Sinai Medical Center and co-chair of the guideline panel, said in an ASCO press release, “Conclusive evidence from several large, well-designed randomized trials now confirms that dose escalation can almost universally benefit men with early-stage prostate cancer who choose to manage their disease with external radiation. Significant advances in treatment planning and delivery have enabled oncologists to deliver more powerful, life-saving doses of radiation in fewer visits and without compromising quality of life.”

To date, hypofractionated EBRT has been studied in prospective trials of men with localized prostate cancer by many cooperative groups and institutions. The results of population-based studies demonstrate an increased use of ultrahypofractionated EBRT in routine practice, and several randomized controlled trials have compared the use of conventional fractionation with moderate fractionation.⁸Therefore, the development of an evidence-based guideline on the clinical practice of hypofractionated EBRT in localized prostate cancer was initiated.

Hypofractionation Determinations for Localized Prostate Cancer

A detailed systematic literature review was conducted, using an analytic framework that incorporated population, intervention(s), comparator(s), and outcome(s) to develop search strategies in MEDLINE PubMed related to the key questions developed by the task force.

A modified Grading of Recommendations Assessment, Development, and Evaluation methodology was used to develop guideline recommendation statements from the literature. High-quality data contributed to the basis of statements according to National Academy of Medicine standards, when data were available. Expert opinion was used to supplement evidence if necessary.

A strong recommendation indicates that the task force was confident in the risk-benefit ratio of the intervention and that “all or almost all informed people would make the recommended choice for or against an intervention.” A conditional recommendation suggests an uncertain risk-benefit ratio of an intervention and that “most informed people would choose the recommended course of action, but a substantial number would not.” These situations call for further evaluation of whether informed choices reflect individual values and preferences through extended shared decision making.

In addition, the quality of evidence for each recommendation was categorized as very low, low, moderate, or high, and consensus of task force members for each recommendation was evaluated through a rating on a 5-point Likert scale, from strongly agree to strongly disagree. A threshold of ≥75% agreement was needed to indicate consensus.

The joint guidelines were published online in October 2018 in the Journal of Clinical Oncology, Practical Radiation Oncology, and The Journal of Urology, and included a total of 61 articles that were addressed in the final analysis.

Key Recommendations for Moderate Hypofractionation:

• Moderate hypofractionation should be offered to men who decline active surveillance and receive EBRT to the prostate regardless of cancer risk stratification group, patient age, comorbidity, anatomy, or baseline urinary function. Recommendation strength, strong; quality of evidence, high; consensus, 94% to 100%.

• Men require counseling regarding the small increased risk of acute gastrointestinal toxicity with moderate hypofractionation. This risk is similar to conventionally fractionated EBRT; however, most RCTs have limited follow-up beyond 5 years. Recommendation strength, strong; quality of evidence, high; consensus, 100%.

• Suggested regimens of hypofractionated EBRT include 6000 cGy delivered in 20 fractions of 300 cGy or 7000 cGy delivered in 28 fractions of 250 cGy. There is no optimal choice of regimen, as the efficacy of moderately hypofractionated EBRT is not based on patient age, comorbidity, anatomy, or urinary function. Recommendation strength, strong; quality of evidence, high; consensus, 100%.

Key Recommendations for Ultrahypofractionation:

• Ultrahypofractionation may be offered as an alternative to conventional fractionation in men with low-risk prostate cancer who decline active surveillance and choose active treatment with EBRT. Recommendation strength, conditional; quality of evidence, moderate; consensus, 88%.
  • EBRT ultrahypofractionation may be offered as an alternative to conventional fractionation in men with intermediate-risk prostate cancer; however, the task force strongly recommends that these patients receive treatment as part of a clinical trial or multi-institutional registry. Recommendation strength, conditional; quality of evidence, low; consensus, 94%.
  • EBRT ultrahypofractionation is not suggested for men with high-risk prostate cancer outside of a clinical trial or multi-institutional registry based on insufficient comparative evidence. Recommendation strength, conditional; quality of evidence, low; consensus, 94%.
• The suggested regimen of ultrahypofractionated prostate EBRT is 3500 to 3625 cGy in 5 fractions of 700 to 725 cGy for low- and intermediate-risk patients with prostate sizes <100 cm3. Recommendation strength, conditional; quality of evidence, moderate; consensus, 88%.
  • Doses above 3625 cGy for 5-fraction prostate ultrahypofractionation are not suggested outside a trial or multi-institutional registry based on late toxicity risk. Recommendation strength, conditional; quality of evidence, moderate; consensus, 100%.
  • Daily consecutive treatments for 5-fraction prostate ultrahypofractionation are not suggested based on the potentially increased risk of late rectal and urinary toxicity. Recommendation strength, conditional; quality of evidence, very low; consensus, 100%.

Key Recommendations for Technical Considerations:

• At least 2 dose-volume constraint points for the rectum and bladder should be used for moderately or ultrahypofractionated EBRT, with 1 near the total dose prescribed and 1 near the midpoint of the total dose. Recommendation strength, strong; quality of evidence, moderate; consensus, 100%.
  • Use of normal tissue constraints for moderately or ultrahypofractionated EBRT that differ from those of a published reference study is not recommended based on the risk of acute and late toxicity. Recommendation strength, strong; quality of evidence, low; consensus, 100%.
• Uses of target volume and associated margin definitions for hypofractionated EBRT that deviate from those of a published reference study are not recommended, especially for hypofractionated regimens. Recommendation strength, strong; quality of evidence, low; consensus, 100%.
• Image-guided radiation therapy is universally recommended when delivering moderately or ultrahypofractionated EBRT. Recommendation strength, strong; quality of evidence, moderate; consensus, 100%.
• Nonmodulated 3-D conformal radiation therapy techniques are not recommended when delivering moderately or ultrahypofractionated prostate EBRT. Recommendation strength, strong; quality of evidence, moderate; consensus, 100%.

In this study, Morgan and the other task force members developed a clinical practice guideline with recommendations for the use of hypo-fractionated EBRT in the treatment of localized prostate cancer. The recommendations cover moderate and ultrahypofractionation, as well as technical recommendations. The task force is in strong agreement that, based on high-quality evidence, moderately hypofractionated EBRT should be offered to men of all risk groups who choose EBRT for treatment of their prostate cancer.

Current evidence on the use of ultrahypofractionated EBRT primarily consists of prospective single-arm trials conducted in low-risk disease with limited follow-up and no efficacy data from randomized trials. This emphasizes the need for further large-scale randomized clinical trials designed to evaluate EBRT hypofractionation. Importantly, the task force views the enrollment in prospective randomized clinical trials as a preferred approach for radiotherapeutic management in men with localized prostate cancer. This guideline will be updated to incorporate efficacy and toxicity results as they emerge from these trials. Furthermore, the conditional recommendations regarding ultrahypofractionation demonstrate the need for shared decision making between patients and clinicians, including a discussion of the risk-benefit ratio that considers the patient&rsquo;s values and preferences.

In an ASCO press release, Daniel A. Barocas, MD, MPH, an associate professor of urologic surgery at Vanderbilt University Medical Center and co-author of the guideline, said, &ldquo;Image guidance and other advances in radiation therapy delivery have enabled radiation oncologists to treat prostate cancer with a therapeutic dose of radiation in a shorter treatment period than was previously possible. Results so far show comparable early control to conventional fractionation, while maintaining an acceptable [adverse] effect profile. This has benefits to the patient in terms of reducing the treatment burden and cost and may increase the acceptability of external beam radiation therapy.

References:

1. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated radiation therapy for localized prostate cancer: an ASTRO, ASCO, and AUA evidence-based guideline [published online October 11, 2018]. J Clin Oncol. doi: 10.1200/ JCO.18.01097.
2. Key statistics for prostate cancer. American Cancer Society website. cancer.org/cancer/prostate-cancer/about/key-statistics.html. Updated January 4, 2018. Accessed October 24, 2018.
3. Pashayan N, Pharoah P, Neal DE, et al. Stage shift in PSA-detected prostate cancers - effect modification by Gleason score. J Med Screen. 2009;16(2):98-101. doi: 10.1258/jms.2009.009037.
4. Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375(15):1415-1424. doi: 10.1056/NEJMoa1606220.
5. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet. 1999;353(9149):267-272. doi: 10.1016/S0140- 6736(98)05180-0.
6. Viani GA, Viana BS, Martin JE, Rossi BT, Zuliani G, Stefano EJ. Intensity-modulated radiotherapy reduces toxicity with similar biochemical control compared with 3-dimensional conformal radiotherapy for prostate cancer: a randomized clinical trial. Cancer. 2016;122(13):2004-2011. doi: 10.1002/ cncr.29983.
7. Kupelian PA, Langen KM, Willoughby TR, Zeidan OA, Meeks SL.. Image-guided radiotherapy for localized prostate cancer: treating a moving target. Semin Radiat Oncol. 2008;18(1):58-66. doi: 10.1016/j.semradonc.2007.09.008.
8. Yu JB, Cramer LD, Herrin J, Soulos PR, Potosky AL, Gross CP. Stereotactic body radiation therapy versus intensity-modulated radiation therapy for prostate cancer: comparison of toxicity. J Clin Oncol. 2014;32(12):1195- 1201. doi: 10.1200/JCO.2013.53.8652.