Abstract: Secondary cancer risk following radiotherapy is an increasingly important topic in clinical oncology with impact on treatment decision making and on patient management. Much of the evidence that underlies our understanding of secondary cancer risks and our risk estimates are derived from large epidemiologic studies and predictive models of earlier decades with large uncertainties. The modern era is characterized by more conformal radiotherapy technologies, molecular and genetic marker approaches, genome-wide studies and risk stratifications, and sophisticated biologically based predictive models of the carcinogenesis process. Four key areas that have strong evidence toward affecting secondary cancer risks are 1) the patient age at time of radiation treatment, 2) genetic risk factors, 3) the organ and tissue site receiving radiation, and 4) the dose and volume of tissue being irradiated by a particular radiation technology. This review attempts to summarize our current understanding on the impact on secondary cancer risks for each of these known risk factors. We review the recent advances in genetic studies and carcinogenesis models that are providing insight into the biologic processes that occur from tissue irradiation to the development of a secondary malignancy. Finally, we discuss current approaches toward minimizing the risk of radiation-associated secondary malignancies, an important goal of clinical radiation oncology.
Keywords: radiation, secondary carcinogenesis, radiation toxicities, radiation techniques, second cancer risk, genetic biomarkers, radiobiology modeling
The risk of secondary malignancies associated with radiation treatment for cancer patients is an area of controversy in clinical radiation oncology. While the prevalence of second malignancies after radiotherapy for pediatric and young adult populations is well established as one of the significant long-term sequelae of radiation treatment, it is uncertain as to whether secondary malignancy estimates from studies on patients treated using older radiation techniques are reliable or directly applicable toward the broader populations of patients receiving radiotherapy today with contemporary modern radiation techniques. Despite this uncertainty, it is generally agreed that a major goal in modern radiotherapy is to minimize its late effects, which include secondary cancer risks.
The greatest challenge in determining risk is that second cancers after radiotherapy have a latency of onset of 10 years or greater after the initial treatment.1–4 This long interval between treatment and secondary malignancy development makes the risk difficult to measure and impractical to test through large prospective clinical trials. The latency length also makes it difficult to feasibly demonstrate the efficacy of any proposed interventions to reduce secondary carcinogenesis risk, whether by a novel radiotherapy technology or with a potential drug. To date, most of the data that are used to estimate secondary cancer risks come from large epidemiology studies with limited follow-up information and inherent uncertainties.
The other major challenge in determining radiation associated secondary cancer risk is the limited understanding of the complex biological processes involved in radiation carcinogenesis. Advances in molecular biology and genomics have brought a deeper understanding of the underlying mechanisms that may predispose or determine malignant transformation after radiotherapy. Other advances include the incorporation of modern genomics and bioinformatics to determine cancer risks for subpopulations carrying specific genetic markers. Over the past decade, we have begun to characterize specific signaling pathways involved in radiation-associated carcinogenesis that may better stratify risks for patients based on their genetic markers.5,6
Further insights have been gained from the advances in carcinogenesis modeling, a field which is moving from its traditional epidemiology base toward integrating biologically based principles within its framework.7–9 Different risk models can show a broad range of predicted absolute risks when applied to organ-specific dosimetry models.10 Modern advances in carcinogenesis modeling include work to integrate short-term processes and long-term factors into a coherent complex model.7,8 Despite this increasing sophistication, much remains unknown about the underlying mechanisms and events leading from tissue irradiation to secondary carcinogenesis.
Yet it is more important than ever for clinicians and patients to have accurate risk estimates of secondary cancers after radiotherapy. Cancer patients are living longer, and more patients are receiving radiation therapy as part of their treatments. The 5-year survival rate for all cancer patients in the United States has steadily and significantly increased in the past several decades.11 The populations in many countries are aging, leading to a higher prevalence of cancers needing radiation treatment, while radiation therapy equipment and technologies are becoming increasingly available worldwide. For many malignancies treated with radiotherapy, it is common to have long-term survivors and late radiation toxicities that were once considered unlikely are now of relevant concern. For example, secondary cancers have emerged to the forefront of management concerns for patients with pediatric malignancies or lymphomas. After disease recurrence, second cancers are the most common cause of treatment-related death in long-term survivors of pediatric malignancies.12 What are the risks of developing secondary cancers after radiotherapy for different treated sites and how are they affected by the ever-changing technologies used? How can we optimize their risks without sacrificing the therapeutic benefits of radiotherapy?
The goal of this review article is to summarize the existing literature regarding secondary malignancy risks for patients treated with radiotherapy. The primary, traditional source of evidence comes from large epidemiology, registry, and cohort studies. Genomic and biomarker studies are increasingly reshaping our views in this field. We will also summarize the history and recent advances in the field of carcinogenesis modeling, which integrates biological processes within a mathematical framework to better explain the current incidence and predict future risks.
We will organize our discussion into four major areas that are known to impact second cancer risks – 1) age, 2) genetics, 3) tissue/organ treatment site, and 4) volume of irradiated tissue for a given radiation technology/technique. Our discussion will interweave results seen from the epidemiologic studies and discuss aspects of current biological and quantitative modeling to predict future risks. We will discuss the impact of the increased utilization of modern radiotherapy technologies for treating cancers – such as intensity-modulated radiation therapy (IMRT), stereotactic body radiotherapy, and proton radiotherapy – and their potential implications regarding future second malignancy risks. Finally, we will also discuss future directions toward optimizing second cancer risks from radiation treatment.