1ASTRO Whole Breast Irradiation Guideline Practical Radiation Oncology

1ASTRO Whole Breast Irradiation Guideline Practical Radiation Oncology

Practical Radiation Oncology (2018)

Radiation Therapy for the Whole Breast: An American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline

Benjamin D. Smith, MD,a* Jennifer R. Bellon, MD,b Rachel Blitzblau, MD, PhD,c Gary Freedman, MD,d Bruce Haffty, MD,e Carol Hahn, MD,f Francine Halberg, MD,g Karen Hoffman, MD,a Kathleen Horst, MD,h Jean M. Moran, PhD,i Caroline Patton, MA,j Jane Perlmutter, PhD,k Laura Warren, MD,b Timothy Whelan, BM, BCH,l Jean L. Wright, MD,m Reshma Jagsi, MD, DPhili

1. Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX
2. Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA
3. Department of Radiation Oncology, Duke University Medical Center, Durham, NC
4. Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA
5. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
6. Department of Radiation Oncology, Duke Cancer Center Wake County, Raleigh, NC
7. Department of Radiation Oncology, Marin Cancer Institute, Greenbrae, CA
8. Department of Radiation Oncology, Stanford University, Stanford, CA
9. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
10. American Society for Radiation Oncology, Arlington, VA
11. Ann Arbor, MI
12. Department of Oncology, McMaster University, Hamilton, ON Canada
13. Department of Radiation Oncology, Johns Hopkins University, Baltimore, MD

* Corresponding author:Benjamin Smith, MD, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1202, Houston, TX 77030

Email address:

Conflict of Interest Disclosure Statement

Before initiating work on this guideline, all task force members completed disclosure statements and pertinent disclosures are published within this report. Where potential conflicts are detected, remedial measures to address them are taken and noted here.

Jennifer Bellon: honoraria and travel expenses from ASTRO, paid author for UptoDate, previous honoraria from EMMC Partridge Foundation Breast Cancer Symposium, Oncoclinicas, American Society of Breast Surgeons, Harvard University, and Eastern Maine Medical Center; Gary Freedman: travel expenses from American Board of Radiology; Bruce Haffty: research funding from Breast Cancer Research Foundation; Carol Hahn: travel expenses and honoraria from ASTRO, travel expenses from American College of Surgeons Commission on Cancer, previous travel expenses from National Cancer Policy Forum, previous honoraria and travel expenses from University of Rochester CMCR; Karen Hoffman: consultant for Vanderbilt University; Reshma Jagsi: research funding from NIH and Breast Cancer Research Foundation, previous research funding from Abbott Pharmaceuticals and Abbvie, previous advisory board for Eviti; Jean Moran: research funding from Varian, National Institutes of Health, and Blue Cross Blue Shield of Michigan, consultant for Chartrounds, and VA National Center for Patient Safety, travel expenses from AAPM, consultant and travel expenses for St. Jude Children’s Research Hospital, research collaboration with Modus Medical Devices testing gel dosimetry; previous travel expenses from Sun Nuclear and Wayne State University; Jane Perlmutter: President and Founder of Gemini Group; Benjamin Smith: research funding from Varian and MD Anderson Cancer Center, consultant for Global Oncology One, relationship with Oncora Medical, previous research funding from Conquer Cancer Foundation, previous research funding from Cancer Prevention and Research Institute of Texas.

These disclosures were reviewed by the Guidelines Subcommittee chairs (for the task force chairs), the task force chairs (for task force members), and the Conflict of Interest Review Committee. They were determined to be sufficiently managed by disclosure to the task force and in this publication and no other remedial measures were considered necessary.

Acknowledgements

The authors thank the expert reviewers: Thomas Buchholz, MD, Anthony Fyles, MD, Lori Pierce, MD, Frank Vicini, MD, Julia White, MD, and John Yarnold, MD. They also acknowledge Sokny Lim, MPH, for literature review and administrative support and Margaret Amankwa-Sakyi, MPH, Shushan Rana, MD, Xiao Zhao, MD, Fiori Alite, MD for literature review assistance.

ASTRO guidelines present scientific, health, and safety information and may reflect scientific or medical opinion. They are available to ASTRO members and the public for educational and informational purposes only. Commercial use of any content in this guideline without the prior written consent of ASTRO is strictly prohibited. Adherence to this guideline will not ensure successful treatment in every situation. This guideline should not be deemed inclusive of all proper methods of care or exclusive of other methods reasonably directed to obtaining the same results. The physician must make the ultimate judgment regarding any specific therapy in light of all circumstances presented by the patient. ASTRO assumes no liability for the information, conclusions, and findings contained in its guidelines. This guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials. This guideline was prepared on the basis of information available at the time the task force was conducting its research and discussions on this topic. There may be new developments that are not reflected in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline.

Introduction

Breast cancer is the most common malignancy treated with radiation therapy (RT) in the United States, and whole breast irradiation (WBI) is the most common type of RT prescribed for breast cancer.1 Historically, the standard of care for WBI in the United States has been conventional fractionation (CF), defined as daily doses of 180-200 cGy to a total breast dose of approximately 4500-5000 cGy, with or without a sequential tumor bed boost. This approach was utilized in most of the randomized trials that established the appropriateness of breast conservation in the majority of women with early breast cancer, defining the standard of care for a generation of patients and physicians.

Recognizing the limitations of this approach with respect to patient convenience and health system costs, randomized trials were initiated in the 1990s and 2000s to determine if moderate hypofractionation (HF), defined as daily doses ranging from 265 to 330 cGy, with accompanying total dose reduction, could yield oncologic and functional/cosmetic outcomes similar to CF-WBI. Initial reports of these trials, published from 2002 to 2008, supported the safety and effectiveness of HF-WBI.2-6 In response, the American Society for Radiation Oncology (ASTRO) published an evidence-based guideline in 2011 which concluded that the evidence supports the equivalence of HF-WBI to CF-WBI for patients ≥50 years of age with pT1-2 N0 breast cancer, treated with breast conserving therapy without systemic chemotherapy, in whom the central axis dose homogeneity is within ±7% of the prescription dose.7

Subsequent to the publication of the 2011 ASTRO guideline, the evidence supporting HF-WBI has grown substantially stronger, with the two largest clinical trials reporting 10-year outcome data in 20138 and the first randomized controlled trial from the United States reporting acute toxicity and quality of life data,9 along with large observational studies extending the approach to patients with ductal carcinoma in situ (DCIS) and examining the generalizability of trial outcomes to populations treated in community practice. Despite even stronger evidence supporting HF-WBI, a growing body of literature demonstrated that adoption of HF-WBI among appropriate patients remained low, with approximately 30% of appropriate patients in the United States receiving HF-WBI in 2013.10-14 Additionally, patterns of care research indicated that nearly three-quarters of the variation in use of HF-WBI was attributable to the treating radiation oncology practice and physician, rather than the patient.12 Although variations in care at the time of many of these studies (2013 and earlier) may reflect reasonable reluctance to implement changes without robust, long-term data from confirmatory trials, evidence has accumulated over time that merits reconsideration of the original guideline in an attempt to further support thoughtful individualization of radiation oncology care for patients.

Recognizing the growing literature evaluating HF-WBI, ASTRO convened this guideline to replace the prior ASTRO guideline on fractionation for WBI. The purpose of this new guideline is not only to provide clear guidance regarding fractionation for WBI but also to provide general recommendations on treatment planning and delivery for WBI and a sequential tumor bed boost when indicated. By providing guidance to physicians on the most appropriate application of the available evidence to clinical decision-making for WBI and a boost, it is hoped that the physician contribution to care variability may be decreased and that decisions may be more appropriately individualized based on tumor factors, anatomic considerations, and patient preferences. Of note, this guideline only covers the subjects specified in the key questions, which pertain to WBI and the use of a tumor bed boost. Outside the scope of this guideline are many other important questions that may be subjects of other guidelines, including whether WBI should be pursued, treatment of patients who have undergone mastectomy, or treatment decisions in patients who will receive directed regional nodal RT—including dose and fractionation decisions in these cases.

This guideline is endorsed by the Royal Australian and New Zealand College of Radiologists and the Society of Surgical Oncology.

Methods and Materials

Process

In June 2015, the ASTRO Guidelines Subcommittee convened a work group to review new evidence published after completion of the systematic review for the prior ASTRO WBI guideline and to recommend whether the guideline should be withdrawn completely, updated, replaced, or reaffirmed. The group comprised one co-lead of the original guideline, two guidelines subcommittee members, and two additional topic experts (one not involved in the original guideline). After review of new literature, the work group recommended development of a new guideline that would replace the prior ASTRO WBI guideline and address a broader array of issues related to whole breast radiation. The work group also specifically recommended that discussion of regional nodal treatment not be included in this work product as this topic was felt to merit its own guideline. The proposal was approved by the ASTRO Board of Directors in October 2015. A task force of radiation oncologists specializing in breast cancer was recruited, as well as a medical physicist and a patient representative. The members were drawn from academic settings, community practice, and residency.

Through calls and emails, the task force formulated recommendation statements and narratives based on the literature review. The draft manuscript was reviewed by six expert reviewers (see Acknowledgments) and ASTRO legal counsel. The update was posted online for public comment in May and June 2017. The Board of Directors approved the final document in November 2017. Going forward, the ASTRO Guidelines Subcommittee will monitor this guideline beginning at two years after publication and initiate updates according to ASTRO policies.

Literature Review

A systematic literature review formed the basis of the guideline. An analytic framework incorporating the population, interventions, comparators, and outcomes (PICO) was used to develop search strategies in MEDLINE PubMed for each key question (KQ). The searches identified English-language studies between January 2009 and January 2016 for KQs 1-3 and between January 2000 and May 2016 for KQs 4-5. The included trials evaluated adults with invasive or in situ breast cancer receiving breast conserving surgery and WBI with or without a tumor bed boost. Both MeSH terms and text words were utilized and terms common to all searches included: breast cancer; breast neoplasms/radiotherapy; early stage; stage I; stage II; whole breast irradiation;and intensity modulated radiation therapy. Additional terms specific to each KQ were also incorporated. The outcomes of interest were overall and disease-free survival, recurrence rates, acute and late toxicity, and quality of life. The electronic searches were supplemented by hand searches.

A total of 528 abstracts were retrieved and screened. Subsequently, 428 articles were eliminated based on the inclusion and exclusion criteria. The exclusion criteria were: post-mastectomy radiation, concurrent chemoradiation, stage III or IV patients, recurrent disease, pre-clinical or non-human studies, non-English language, available in abstract only, and otherwise not relevant to the KQs. Ultimately, 100 articles were included and abstracted into detailed tables to provide supporting evidence for the guideline recommendations.

Grading of Evidence, Recommendations, and Consensus Methodology

Guideline recommendation statements were developed based on the current literature using a modified GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) methodology. GRADE is an explicit, systematic approach to defining the recommendation strength and quality of evidence.15,16When available, high-quality data formed the basis of the statements in accordance with the National Academies of Science, Engineering, and Medicine’s Health and Medicine Division (formerly Institute of Medicine) standards.17 When necessary, expert opinion supplemented the evidence.

Recommendations were classified as “strong” or “conditional.” A strong recommendation indicated the task force was confident the benefits of the intervention clearly outweighed the harms, or vice-versa, and “all or almost all informed people would make the recommended choice for or against an intervention.”16 Conditional recommendations were made when the balance between risks and benefits was more even or was uncertain. In these cases, the task force believed “most informed people would choose the recommended course of action, but a substantial number would not” and, therefore, “clinicians and other health care providers need to devote more time to the process of shared decision-making by which they ensure that the informed choice reflects individual values and preferences.”16

The quality of evidence underlying each recommendation statement was categorized as either high, moderate, or low. These quality levels indicated:

• “High: We are very confident that the true effect lies close to that of the estimate of the effect.
• Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
• Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.”15

Consensus within the task force on the recommendation statements was evaluated through a modified Delphi approach adapted from the American Society of Clinical Oncology (ASCO) process.18 Task force members (except the patient representative) completed an online survey to rate their agreement with the recommendations on a five-point Likert scale, ranging from strongly disagree to strongly agree. The medical physics representative abstained from rating some clinically-focused recommendations, which are designated by an asterisk beside the consensus percentage. A pre-specified threshold of ≥75% of raters selecting “agree” or “strongly agree” indicated when consensus was achieved. If a recommendation statement did not meet this threshold, it was modified and re-surveyed or excluded from the guideline.

Results

Key Question 1: For patients receiving WBI without additional fields to cover the regional lymph nodes, what is/are the preferred dose-fractionation scheme(s) and how should these vary as a function of:

• Grade
• Margins
• ER/PR/HER2-neu status and other assessments of tumor biology
• Normal tissue exposure
• Systemic therapy receipt (including prior chemotherapy, concurrent endocrine, or targeted therapies)
• Age
• Stage (including DCIS versus invasive disease)
• Histology
• Breast size and dose homogeneity
• Collagen vascular disease and other relative contraindications to radiation
• Intent to cover the low axilla

See Table 1 for a comparison of the recommendations from this guideline to those of the 2011 ASTRO Guideline.

Overall statement

Statement KQ1A: For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is HF-WBI to a dose of4000 cGy in 15 fractions or 4250 cGy in 16 fractions.

• Recommendation strength: Strong
• Quality of evidence: High
• Consensus: 100%

Narrative

In the context of CF-WBI serving as the historical standard of care, decisions between CF-WBI and HF-WBI should be shared with the patient and individualized based on considerations of relevant tumor and host characteristics, as well as patient values and preferences. To help guide these discussions, the task force felt that HF-WBI is generally the preferred dose-fractionation scheme when delivering WBI without regional nodal irradiation based on the results of multiple clinical trials which have demonstrated equivalent tumor control, improved acute toxicity, and similar or improved late toxicity with certain HF-WBI regimens as compared to CF-WBI. Four prospective randomized phase III clinical trials comparing HF-WBI to CF-WBI have reported 10-year outcomes data and serve as the evidentiary basis for this recommendation (Table 2).3,4,8,19 The Ontario Clinical Oncology Group (OCOG) trial randomized patients to 4250 cGy in 16 fractions over 22 days versus 5000 cGy in 25 fractions over 35 days.2,19 No tumor bed boost was delivered. Eligibility factors included breast-conserving surgery, invasive breast cancer, size ≤5 cm, pathologically node-negative, and negative margins defined as no tumor on ink. These two radiation schedules were associated with equivalent 10-year invasive cancer local recurrence risks of 6.2% and 6.7%, respectively. HF-WBI was not inferior to CF-WBI in terms of cancer mortality, death from other causes, or overall survival. The late cosmetic appearance was considered good or excellent in approximately 70% of women in both groups. There were similarly no reported differences in 10-year skin and subcutaneous tissue complications.

The Royal Marsden Hospital and Gloucestershire Oncology Centre (RMH/GOC), or Standardization of Breast Radiotherapy (START) pilot trial, was a three-arm trial that used 3900 cGy or 4290 cGy in 13 fractions, compared to 5000 cGy in 25 fractions, all delivered in 5 weeks.3,4 Eligibility was T1-3, N0-1, age <75 years, invasive breast cancer treated with breast-conserving surgery with a macroscopic negative margin. A tumor bed boost was allowed. The local recurrence rates at 10 years were 12.1% for 5000 cGy, 14.8% for 3900 cGy, and 9.6% for 4290 cGy (p=0.027).3 The 4290 cGy arm conferred a statistically inferior change in breast appearance, so the dose for this arm was reduced to 4160 cGy for the START A trial. The United Kingdom START A and B trials consisted of two separate studies of hypofractionation.5,6,8 START A compared 5000 cGy in 25 fractions, 4160 cGy in 13 fractions, or 3900 cGy in 13 fractions, all delivered in 5 weeks. START B compared 5000 cGy in 25 fractions over 5 weeks versus 4000 cGy in 15 fractions over 3 weeks. Eligibility included T1-3a, N0-1, invasive breast cancer treated with breast-conserving surgery or mastectomy with a margin >1 mm. A tumor bed boost was permitted and administered in 61% of patients in START A and 39% of patients in START B. Local-regional recurrence rates were not significantly different by treatment arm for both START A (7.4%, 6.3%, and 8.8%, respectively) and START B (5.5% and 4.3%, respectively). No differences were observed in rates of disease-free and overall survival between treatment arms in START A. In START B, disease-free and overall survival were better for patients treated with HF-WBI than CF-WBI. The late effects of breast appearance, breast edema or hardness, or skin changes were generally equal or better with hypofractionation, and there were no significant differences in late effects of rib fracture or ischemic heart disease.