Three discipline collaborative radiation therapy (3DCRT) special debate: We should treat all cancer patients with hypofractionation

Radiation Oncology is a highly multidisciplinary medical specialty, drawing significantly from three scientific disciplines — medicine, physics, and biology. As a result, discussion of controversies or changes in practice within radiation oncology must involve input from all three disciplines. For this reason, significant effort has been expended recently to foster collaborative multidisciplinary research in radiation oncology, with substantial demonstrated benefit.1-3 In light of these results, we endeavor here to adopt this “team-science” approach to the traditional debates featured in this journal. This article is part of a series of special debates entitled “Three Discipline Collaborative Radiation Therapy (3DCRT)” in which each debate team will include a radiation oncologist, medical physicist, and radiobiologist. We hope that this format will not only be engaging for the readership but will also foster further collaboration in the science and clinical practice of radiation oncology. Better Physics, just within this 21st century, now enables us to deliver radiation to a target volume with accuracy better than 1 mm. Given this accuracy, why fractionate at all? If we can put dose only on the cancer, and extremely little on critical normal tissue, then surely just give a high single dose to that cancer, and job done. Local tumor control is 100% with minimal toxicity. If only. Two linked issues keep Biology (radiobiology) in the clinical game. First, our ability to identify, localize, and immobilize anatomy and pathology does not yet correspond with this submillimeter accuracy of radiotherapy delivery. Second, even if that imaging resolution is reached it could still not detect occult disease. Consequently, unless the cancer is truly isolated, which it sometimes may be, for example, in organ-confined early-stage prostate cancer, it is always necessary to “degrade” the treatment plan by defining a CTV and PTV into which the radiation delivery is expanded. This inevitably imposes a risk of normal-tissue radiotoxicity, therefore we must use fractionation to minimize that risk. Traditionally, that fractionation has been carried out with doses close to 2 Gy per fraction. In fractionation, the Linear-Quadratic (LQ) model describes the relationship between total dose and dose per fraction, for isoeffect. A lower α/β value indicates a steeper relationship. Generally late-reacting normal tissues exhibit lower α/β and early-reacting normal tissues exhibit higher α/β. Malignancies can have lower or higher α/β depending on the tumor type. In some malignancies, notably human prostate, clinical data indeed indicate α/β as low as 1.5 and thus in prostate cancers, and likewise in early-stage breast cancers, hypofractionation, arbitrarily defined as a dose per fraction> 2.2 Gy, has become standard of care. In early-stage non-small cell lung cancers a higher α/β is seen, similar to early-reacting normal tissue, but these isolated malignancies can still be more effectively controlled with radical hypofractionation which suggests the story is more complex than a simple LQ picture can paint. So are we moving, and should we be moving, even if slowly but surely, toward giving all patients receiving radiation therapy as hypofractionation? Let us debate! Arguing for the proposition will be Drs. Michael Green, Samantha Van Nest, and Emilie Soisson. Dr. Green is an Assistant Professor at the University of Michigan in the Department of Radiation Oncology. His group utilizes expertise in quantitative immunophenotyping, peripheral tolerance mechanisms, and tumor cell death to define and harness the determinants of inflammation, which shape antitumoral immunity and influence radiotherapy and immunotherapy efficacy. Dr. Van Nest is a Postdoctoral Associate in the Department of Radiation Oncology at Weill Cornell Medicine in New York. Dr. Van Nest's research focuses on developing techniques for the personalization of radiation therapy including Raman spectroscopy and omics-based signatures. She is investigating mechanisms of radiation-induced anticancer immunity with particular focus on patient-based platforms for optimizing immune activation. Dr Soisson is a medical physicist at the University of Vermont Medical Center. She holds faculty appointments at the University of Vermont and McGill University. She earned a PhD in Medical Physics at the University of Wisconsin where she was heavily involved in the clinical implementation of TomoTherapy. Arguing against the proposition will be Drs. Kathryn Huber, Yixiang Liao, and William McBride. Dr. Huber is a Radiation Oncologist at Tufts Medical Center and Assistant Professor at Tufts University School of Medicine, Boston, MA. She specializes in the treatment of thoracic, breast, and head and neck cancers and is the Director of Radiobiology for the residency training program at Tufts. Dr. Liao is a faculty medical physicist at the Rush University Medical Center, Chicago, IL with research interests in brachytherapy, IGRT, SBRT, and treatment planning. Her publications cover various topics including hypofractionation in prostate cancer treatment, and normal tissue tolerance in treatments delivering high dose per fraction such as high-dose rate (HDR) brachytherapy and intraoperative radiation. She also currently serves as the associate director of the medical physics residency program at Rush. Dr. Liao was among the students of the first IBPRO1 (Integrated course in Biology and Physics of Radiation Oncology) held at Wayne State School of Medicine in 2014. Dr. McBride is emeritus professor and former Vice-Chair for Research in the Division of Cellular and Molecular Oncology, Department of Radiation Oncology at UCLA. Most of his extensive research has woven immunological concepts into understanding of radiation responses by normal tissues and tumors, in particular the response of the immune system as it senses “danger” signals from radiation-damaged tissues. Dr. McBride has been honored with an ASTRO Gold Medal and Failla Award from the RRS. Hypofractionated radiotherapy is characterized by the delivery of greater than 2.2 gray (Gy) per fraction and a reduced number of fractions as compared to conventional fractionation. At the turn of the century, now classic radiobiologic experiments showed that fractionated radiotherapy increased tumor control while diminishing acute toxicity. These empirical observations led to the development of one of our fields' most dear beliefs: that fractionated radiotherapy delivered in 1.8 to 2.0 Gy per day is the most efficacious and safest way of delivering radiotherapy.4 In the past decades, transformative improvements in immobilization, target and normal tissue delineation with multiple imaging modalities, treatment planning, and patient alignment have been made. These advances have led to unprecedented potential for safe and effective delivery of high-dose radiotherapy. This has led to the thoughtful and timely re-evaluation of how we provide definitive management and a questioning of our core principles regarding fractionation. The conclusion of this re-evaluation is clear: we should treat all cancer patients with hypofractionation. Multiple randomized trials have suggested that hypofractionated radiotherapy provides superior outcomes in both the definitive and palliative setting. The CHISEL trial demonstrated that ultrahypofractionated radiotherapy was superior to conventional fractionation for Stage I NSCLC.5 Furthermore, ultrahypofractionated approaches have now been shown to provide more durable palliation as compared to standard palliative regimens.6 Moderate hypofractionation has proved noninferior in randomized phase III trials for localized prostate7-10 and breast cancer.11 Long follow-up of these trials as well as meta-analyses have not demonstrated the hypothesized increase in late toxicity with hypofractionated regimens.12-14 Together, these data support hypofractionation in the management of many diseases. Hypofractionation has only been made possible by improvements in tumor localization through advances in image-guided radiation therapy (IGRT). Traditional stereotactic localization, which relied on external targeting frames and specialized equipment, has been replaced by volumetric image guidance (CT, CBCT, MVCT) and stereoscopic imaging which have become accessories on standard accelerators and are now generally available in all clinics. In addition, a wide variety of motion management strategies are routinely employed to quantify, measure, and track intrafraction tumor motion. Daily 3D alignment and motion management have provided an opportunity to explore dose escalation through reduced tumor margins and moderate hypofractionation in sites where tumor dose was previously limited by normal tissue tolerances. Intriguingly, margins have not been shrinking as much as they could be based on localization ability alone. Numerous studies have shown improved geometric accuracy is achievable with IGRT which should go hand in hand with reduced margins, but surveys of practice patterns showed no relationship between the frequency of image guidance and PTV margins.15 Practice change as a result of improved technology is lagging and future clinical trials are still needed to realize the potential of improved localization. The superiority of conventional fractionation is supported by linear-quadratic (LQ) modeling of radiation effects. These models assume that the alpha/beta (α/β) value in tumor is higher than that of the surrounding normal tissue, but re-evaluations have found some tumors actually have an α/β value lower than normal tumors.16, 17 Moreover, the LQ model can break down at the doses used in ultrahypofractionation.18 AAPM has initiated efforts to revise the LQ model (Hypofractionation Treatment Effects in the Clinic, www.aapm.org/pubs/hytec). Thus, prior theoretical concerns have given way to the rapid study and clinical adoption of hypofractionation. The universal benefit of hypofractionation (and possible source of breakdown of the LQ model) rests in the potential role of novel radiobiological factors that may become relevant at higher doses per fraction. Hypofractionation challenges the long-held understanding of how RT controls tumors, redefining its role in immune activation, reoxygenation, and repopulation. Hypofractionation is particularly effective at inducing immunogenic cell death (ICD)19, 20 leading to antitumor immunity.21, 22 In contrast, conventional fractionation promotes more immunosuppressive cell death pathways.23, 24 Dose-dependent increases in tumor antigen presentation further improve opportunity for antitumor immunity with hypofractionation.24, 25 Evidence suggests the inflammatory effects of RT are activated only above a threshold dose of around 6-8 Gy26, 27 leading to increased local secretion of key cytokines, chemokines, and other molecules that initiate and support an adaptive immune response.28 Furthermore, the steep dose falloff typical in hypofractionated regimens may establish a cytokine gradient that promotes increased tumor infiltrating lymphocytes (TILs).28, 29 Hypofractionation has been shown to enhance TILs,30 increase DC recruitment/maturation,19, 29, 31 and activates peripheral CD8+ T cells in several cancer models.20, 32, 33 Tumors with increased levels of active lymphocytes may benefit from increased spacing between fractions, which can be facilitated by hypofractionation.30, 33, 34 The immunogenic effects of hypofractionation can be further exploited through combination with immune checkpoint blockade (ICB). Hypofractionation has been recommended as the optimal strategy for combination with ICB,35 showing systemic tumor reduction and abscopal response at the preclinical and clinical level in a variety of tumor types.34-42 Hypofractionation may enhance antitumor immunity by increasing neoantigen exposure and broadening the T-cell receptor repertoire.27, 33, 43, 44 These findings support the adoption of hypofractionation to improve immune stimulation and potentially induce an abscopal response.24 In addition to promoting immune infiltration, hypofractionation can modulate tumor vasculature.24, 45 Higher doses per fraction (5–10 Gy) applied more than once have been shown to cause reduced blood flow to the tumor and vascular deterioration.46 While some reoxygenation may occur following hypofractionation, the hypoxic fraction is further reduced through ischemic cell death to a subpopulation that would have been inherently radioresistant.47 Hypofractionation also reduces the time to achieve the prescribed dose, possibly countering the role of accelerated tumor repopulation during later stages of RT.48-50 A shortened course of therapy is not only beneficial from a radiobiological but also it provides significant both to the and is that significantly to the of medical and a in As we to improve the of we we must that hypofractionation effective care. clinical physics and radiobiological to a simple all patients should hypofractionated radiotherapy. from a of radiation treatment of cancer is that dose is delivered fractionated in a course to use hypofractionation to treatment time into a more and generally As a result, radiation to associate high dose per fraction with more effects. was by radiobiological experiments showing the of tissue in effects of of dose per fraction and treatment In fractionation tissues with more than tissues that are of rapid these are by during In other as dose per fraction the total dose for an increases more for late than tissues. 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The is clear: all patients should be with hypofractionated radiotherapy. We with Drs. 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