TARGETING AND DELIVERY

For decades, radiographic images have been the standard method of verification, providing localization, displacement, and deformation of tumors and/or OARs in two dimension (2D), three dimension (3D), or 4D to achieve the beam-and-target alignment, dose verification, and adaptation, which are dependent on both image quality and imaging frequency.68 Nowadays, the emerging delta radiomics, a longitudinal fashion for radiomics, can be based on routine images to serve as a biomarker for treatment monitoring and optimization or active surveillance. An increase in the number of images will ensure accurate and precise RT delivery and yield smaller setup errors and CTV-to-PTV margins reducing SMN risks in distant tissues, but add more imaging radiation doses to target and adjacent healthy tissues. About 70% of SMNs occur in those regions.69,70 At some point, a cost/benefit balance needs to be reached, which is highly individualized to RT site and protocol. In fact, geometric precision is only one aspect of treatment, and its desire should be balanced with clinical gains and modest workloads on RT contouring, planning, and delivery.

Besides imaging frequency, the organ-absorbed doses also depend on imaged region, imaging parameters, and techniques provided by different vendors (Figure 4).71 Generally, 2D imaging dose is concentrated at the skin, while 3D/4D tomography dose is distributed nearly uniformly throughout the imaged volume. If imaging parameters are not optimized, out-of-field doses from imaging can be comparable to doses from the scatter and leakage radiation associated with therapeutic beam. There is an estimated probability of 0.08–3.59% of SMN.72 Therefore, the imaging dose and its distribution need to be taken into account in the treatment planning, which results in about 4–5% reduction in MUs and control points,73 or it is appropriate to optimize the image quality and minimize the imaging dose to ≤2% variation of the therapy dose, which is the internationally accepted beam output variation of RT linac, through varying the beam directions, field of view, number of projections per imaging, the tube voltage (kVp), current (mA), or mAs/frame. Especially for pediatric patients, it is necessary to perform personalized imaging according to patient characteristics considering the type of imaging, such as two orthogonal images or cone beam CT (CBCT), and acquisition modes, for example, CBCT head modes can be used to image the thorax, abdomen, or pelvis to selectively avoid irradiation of superficial organs.74

Unlike the diagnostic/planning imaging, radiation targeting adds the additional dose to an already high level of therapeutic radiation except for the first fraction (Figure 2). The joint effect of targeting and delivery, which is additive or not, is not readily tested through randomized clinical trials. In theory, due to enhanced accuracy, the observed reduction in adverse effects of IGRT might in part be due to an adaptive response of normal tissues to the low doses of radiation from the imaging process before the delivery of high therapeutic doses. By coincidence, tumor cell radioresistance triggered by the imaging dose has been verified recently.75 According to the generalized linear–quadratic model, the delay time between imaging and treatment also affects local tumor control while incorporating imaging dose into the therapeutic dose.76 Other modalities such as optical imaging techniques also have an important role in IGRT without exposing the patient to additional radiation dose during RT delivery.77 In conjunction with X-ray systems providing some information about internal anatomical structures such as bones, they can provide continuous monitoring of patients and detect these changes in the soft tissues, where the tumor is located.

Due to higher rates of medication errors among adult (7.1%) and pediatric (18.8%) patients with cancer, numerous programs for workflow-related QA are established and performed to detect errors to ensure that these personalized treatments are delivered safely.78 These errors include unauthorized acts, operative errors, equipment failures, initiating events, accident precursors, near misses, and other mishaps.79 Most of the errors are discovered in setup/treatment and during treatment follow-up phases. There are still errors that are not covered by regular QA checks, so individual clinics should perform a risk analysis of their unique practice, classifying and learning from incidents, and to determine appropriate testing frequencies to maximize physicist time efficiency and patient treatment quality, improving existing processes or implementing new workflows. But manually intensive procedures are more prone to errors. To further minimize human errors, all kinds of applications using state-of-the-art web technologies, data mining, and machine learning, are being designed to automate and model the clinical workflow and IGRT process.

As one of today’s most rapidly growing technical fields, machine learning also brings new treatment technologies via new learning algorithms, such as auto-adaptive margin generation for real-time tracking RT for motion management.80 However, technological innovations themselves can lead to the development of new potential hazards, so it is important to carry out quality evaluation when they are implemented in the clinic. All aspects of the treatment workflow, from imaging to dose calculation and treatment delivery, should be carefully handled and recorded. A large amount of data will be produced. Although these data are available in one RT center or other centers separately, it is difficult to make comparisons of new treatment technologies on a large scale and explore treatment effects. Nowadays, information availability has become more elaborate and widespread. More and more national or international infrastructures are being developed to enable structured and automated data collection and secure sharing of RT data.81 To reach the best patient care, most treatment decisions will be based on gathered relevant data, referred to as big data, while treatments can be further optimized with respect to increased survival, less SMN risk, and less burden on the health care sector.

FOLLOW-UP CARE AND RE-IRRADIATION

The risk of second malignancies after RT is a subject not without controversy. Generally, all cancer survivors should follow applicable national guidelines for cancer screening. But it is more important than ever for clinicians and patients to have accurate risk estimates of secondary cancers after RT to permit the development of individualized follow-up guidelines and prevention and intervention strategies.

To date, there are many investigations of interactions between RT and potential confounding factors such as age, sex, race, tobacco and alcohol use, dietary intake, energy balance, and other cofactors, as well as genetic susceptibility. One of the most important factors correlated with an SMN is the age of the patient at the time of RT. For the same dose, it shows that children are considered to be 3–15 times more sensitive to radiation-induced SMN than adults, and the cancer risk decreases from about 15%/Sv of whole body uniform irradiation for children under 10 years of age to about 1%/Sv for adults exposed at over 60 years of age.82 Greater systematic checkup should be implemented after RT for this higher risk population. Compared to the therapeutic benefit, SMN might not be as significant and should not factor into treatment decisions for the older population.

It has been known that there is a significant dependence of tissue and organ to SMN risk. According to the National Council on Radiation Protection and Measurements (NCRP) report No. 116, stomach, lung, and colon are the most common sites for developing a fatal second cancer after radiation exposure. In addition, the thyroid gland is known to have a low threshold for radiation-induced cancer, especially in children and young adults (a mean organ dose as low as 0.05 Gy).83 For a given dose, females have a higher SMN incidence compared to men due to the increased risk of breast and thyroid cancers in females.84 Therefore, follow-up care should be managed on a case-by-case basis, but the cost to both the health care system and patients need to be evaluated.

The greatest challenge in determining risk is that second cancers after RT have a latency of onset of 5–10 years for leukemia and about 10–60 years for solid tumors after the initial treatment.85 Only longer follow-up will allow a true assessment of the SMN risk. Taking into account what is known with regard to first primary cancers and adding evidence on SMN risks, a detailed survivorship care plan should be made to record the patient’s treatment and anticipated long-term effects.86 In addition, a risk-adapted strategy can be made to optimize the routine follow-up policy such as screening frequency and follow-up duration and to minimize the probability of second cancers according to the follow-up care guidelines.

Indeed, new SMNs now are representing about 16% of all cancers reported to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program.87 Further, SMNs particularly solid tumors are a major cause of mortality among cancer survivors. Fortunately, technological advances in RT and imaging have made treatment of patients with re-irradiation possible. However, re-irradiation with overlapping volumes of previously irradiated tissues is not without risks because of severe toxicity. Due to some disease- and patient-related factors, such as previous treatment, second cancer site, and performance status, the identification of who might derive the most benefit from which technology with what kind of dose and fractionation schedules is of utmost importance.