Late Sequelae of Radiotherapy
The Effect of Technical and Conceptual Innovations in Radiation Oncology
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Background: Approximately half of all patients with tumors need radiotherapy. Long-term survivors may suffer from late sequelae of the treatment. The existing radiotherapeutic techniques are being refined so that radiation can be applied more precisely, with the goal of limiting the radiation exposure of normal tissue and reducing late sequelae.
Methods: This review is based on the findings of a selective search in PubMed for publications on late sequelae of conventional percutaneous radiotherapy, January 2000 to May 2020. Late sequelae affecting the central nervous system, lungs, and heart and the development of second tumors are presented, and radiobiological mechanisms and the relevant technical and conceptual considerations are discussed.
Results: The current standard of treatment involves the use of linear accelerators, intensity-modulated radiotherapy (IMRT), image-guided and respiratory-gated radiotherapy, and the integration of positron emission tomography combined with computed tomography (PET-CT) in radiation treatment planning. Cardiotoxicity has been reduced with regard to the risk of coronary heart disease after radiotherapy for Hodgkin’s lymphoma (hazard ratio [HR] 0.44 [0.23; 0.85]). It was also found that the rate of radiation-induced pneumonitis dropped from 7.9% with conformal treatment to 3.5% with IMRT in a phase III lung cancer trial. It is hoped that neurocognitive functional impairment will be reduced by hippocampal avoidance in modern treatment planning: an initial phase III trial yielded a hazard ratio of 0.74 [0.58; 0.94]. It is estimated that 8% of second solid tumors in adults are induced by radiotherapy (3 additional tumors per 1000 patients at 10 years).
Conclusion: Special challenges for research in this field arise from the long latency of radiation sequelae and the need for large-scale, well-documented patient collectives in order to discern dose–effect relationships, and take account of cofactors, when the overall number of events is small. It is hoped that further technical and conceptual advances will be made in the areas of adaptive radiotherapy, proton and heavy-ion therapy, and personalized therapy.
Now that the number of long-term cancer survivors is increasing, the late sequelae of cancer treatment have taken on new importance, and about half of all patients with cancer are treated with radiotherapy (1, e1).
The late sequelae of radiotherapy manifest themselves with a latency of three months to several decades after the completion of treatment; unlike acute sequelae, they are generally irreversible (1, e2). Their latency and severity depend on the nature of the affected organ or tissue, the applied radiation dose (total and per fraction), and the irradiated volume and are modulated by concomitant treatments and other characteristics of the patient.
There have been recent advances in radiotherapeutic techniques, treatment planning, and the integration of modern imaging methods with the goal of limiting the radiation exposure of normal tissue in order to lessen toxicity, or else enable raising the dose delivered to the tumor without increasing toxicity (1, 2). These developments include linear accelerators with intensity-modulated radiotherapy or volumetrically modulated arc therapy (VMAT) (e3), image-guided radiotherapy, and stereotactic radiotherapy (Box). Modern imaging techniques are also being increasingly applied in order to delimit tumors more precisely in the planning and execution of radiotherapy (2, e4). The ideal goal of zero radiation exposure of the normal tissue is not attainable even in principle. The dose distribution always represents a compromise, where the physicians and radiation physicists must collaborate in weighing the probability of late sequelae against the tumor control rate for each individual patient.
In this review, we present current clinical and biological data on the late sequelae of percutaneous radiotherapy for selected organs at risk and discuss the implications of recent technical developments with regard to these sequelae. For more information on treatment and prevention of radiation side effects, the reader is referred to the German S3 guideline on supportive therapy for cancer patients (Supportive Therapie bei onkologischen PatientInnen, Ref. 3).
Radiation biological principles of the late sequelae of radiotherapy
The late sequelae of radiotherapy reflect changes in organ parenchyma, in the vasculature, or in the connective tissue, which lead to a loss of function within the irradiated volume. The immune system participates in this process with inflammatory reactions, the degradation of damaged cells, and the generation of pro-inflammatory and pro-fibrogenic cytokines (4). The sequelae of radiotherapy depend on tissue architecture. In serially constructed organs, such as the gastrointestinal tract and the vascular system, radiation exposure at any site in the system affects the function of distally located compartments as well. In organs that are constructed in parallel, such as the liver or lung, the radiation exposure must affect a significant portion of the overall volume to have any adverse clinical effects. Late sequelae arise after at least a few months, with the latency being inversely related to the biologically effective dose (e5). Relative biological effectiveness (RBE) is a parameter that can be used to predict what doses of two different types of ionizing radiation (e.g., electrons and protons) will be equally biologically effective (5).
Late sequelae in normal tissue arise in 5–10% of patients who undergo radiotherapy (6, 7). Multiple factors, including cellular composition, degree of differentiation, cell replication capacity, and cellular radiation sensitivity, determine the extent of the sequelae. Patient-related factors, too, are important co-determinants of the risk (8). The reaction of human beings to ionizing radiation is individual and variable and is affected by age, smoking behavior, illnesses such as diabetes mellitus, collagenoses, and vascular diseases, and the genotype (8). The molecular basis of individual sensitivity to radiation is complex and poorly understood. There is currently no reliable biological marker that can predict severe radiation sequelae. Only in the case of breast and prostate cancer is there an observed, significant association between the nucleotide polymorphism (SNP) rs1801516 of the ataxia-telangiectasia gene, which is found in ca. 10% of the population, and the severity of late sequelae (odds ratio [OR] 1.2; 95% confidence interval [0.81; 2.27]) (9, 10). Further SNPs are also of predictive value in prostate cancer. Other epigenetic changes in relevant genes are being studied as well. Genetic factors such as DNA repair, oxidative stress, radiofibrogenesis, and endothelial cell damage all play a role in the late sequelae of radiotherapy (11).
In this review, we present the late sequelae of conventional percutaneous radiotherapy in the central nervous system (CNS), lungs, and heart, as well as the generation of second tumors. A selective literature search was carried out in PubMed covering the period from 2000 to May 2020. Publications of the following kinds were considered: systematic reviews, meta-analyses, and population-based studies with late toxicity as a primary endpoint. We also considered relevant phase III trials of dose escalation and/or de-escalation in which data on the patient population, applied dose/technique, and classification of toxicity were reported. Empirical documentation of the clinical effects of recent technical and conceptual innovations will only be possible many years after their introduction; thus, model calculations will be used as a surrogate and will be presented for a number of illustrative situations.
Specific late sequelae of radiotherapy
The types of damage to the heart that can arise after mediastinal irradiation include coronary heart disease (CHD), cardiomyopathy, valvular disease, disturbances of the intracardiac conducting system, and pericardial disease (1, 12). They are caused by diffuse interstitial fibrosis and collagen deposition, as well as by narrowing of the lumen of arteries and arterioles through the accumulation of myofibroblasts. The site and magnitude of the applied dose determine the type, extent, and latency of the clinical sequelae. Individual substructures display different dose–response relationships: the risk of coronary heart disease depends linearly on the median cardiac dose (relative risk [RR]: 7.4%/Gy [2.9; 14.5]) (13). The rate of additional events (excess rate ratio, ERR) compared to cohorts from the general population is 0.04 [0.02; 0.06] after radiotherapy for breast cancer or Hodgkin’s lymphoma (13, 14, 15). In contrast, the rate of radiation-induced valvular disease rises exponentially beyond an exposure of 30 Gy (cumulative incidence figures at 30 years: 3.0% [≤ 30 Gy], 6.4% [31–35 Gy], 9.3% [36–40 Gy], 12.4% [≥ 40 Gy]) (14, e6).
Current consensus recommendations stratify risk categories according to the median cardiac dose and urge the avoidance of dose maxima in the coronary arteries (16, 17, 18). Measures that were implemented over the period 1970–1999 to lower the radiation exposure of patients with Hodgkin’s lymphoma and thereby lessen cardiotoxicity were indeed accompanied by a significant lowering of the 20-year incidence of CHD: cumulative incidence 0.99% [0.67; 1.48] in the 1970s, versus 0.42% [0.20; 0.88] with hazard ratio (HR) 0.44 [0.23; 0.85] in the 1990s (12).
Similar developments can be seen in adjuvant radiotherapy for patients with breast cancer who were treated in the period 2000–2012. They did not have a higher risk than the general population for acute coronary events or cardiac death (19, 20). Developments such as the possibility of irradiating only during deep inspiration have lowered the cardiac dose still further (e7, e8). The German Society for Radiation Oncology recommends this technique for the treatment of left-sided breast cancer (17). Comparative dosimetric evaluations have shown that this technique lowers the median cardiac dose by 1.3–3.45 Gy in lymphoma treatment as well (21, 22, 23).
Subacute pneumonitis and chronic pulmonary fibrosis are potential side effects of radiotherapy in the chest. Pneumonitis arises 1–6 months after treatment, with manifestations ranging from asymptomatic changes visible on a chest CT, to moderately severe cough, dyspnea, and sometimes fever, to rare severe courses with respiratory insufficiency. Pulmonary fibrosis can arise as a long-term complication (1).
Irradiation initiates a complex mechanism involving damage to the alveolar epithelium through inflammation, DNS damage, cell senescence, and subsequent fibrosis (24). Pneumonitis can lead to pulmonary fibrosis through a mechanism that has yet to be fully explained, but is thought to involve radiation-induced oxidative stress and free-radical production, leading to an inflammatory reaction and DNA injury. A resulting high concentration of circulating growth factors may induce fibroblast proliferation and migration, leading to collagen deposition (25). The incidence and severity of pneumonitis depend on the magnitude of the applied dose, the volume of lung tissue irradiated, and the dose per fraction (26).
A meta-analysis of studies on the prediction of symptomatic pneumonitis that were published over the period 1993–2010 contained an evaluation of individual data on 836 patients who had undergone radiotherapy (and sometimes chemotherapy as well) with curative intent for non-small-cell lung cancer, at a median dose of 60 Gy (IMRT or conformal technique). After a median follow-up time of 2.3 years, pneumonitis of grade 2 or worse was seen in 29% of the patients (26). In contrast, in the phase III trials of conventional radiotherapy for lung cancer that were published in the period 2016–2020 (27)—partly with simultaneous dose escalation (2, 28)—grade 3 pneumonitis was seen in only 0–7.5% of the patients. The follow-up times were 21–29 months and thus similar to those of the previous studies included in the meta-analysis mentioned above (26).
The risk of pneumonitis is increased by advanced patient age, simultaneous chemotherapy (particularly if it includes taxanes), and a positive smoking history (26, 29). In contrast, it is probably lowered by smoking during radiotherapy (30, 31, e9, e10).
Various technical developments have enabled a lowering of radiation exposure. In one of the phase III trials mentioned above, pneumonitis of grade 3 or worse arose significantly less commonly after IMRT than after conformal radiotherapy (3.5% vs. 7.9%; p = 0.039) (28). In the technique of PET-CT, the morphological display of anatomy with CT is combined with a nuclear-medical study revealing tissue functionality. Usually, radioactively labeled glucose is injected to demonstrate intratumoral metabolic activity. The integration of PET-CT in radiation planning to reduce the target volume has enabled isotoxic dose escalation (2). In radiotherapy planning studies involving patients with lymphoma, the breath-hold technique lowered median pulmonary exposure by 1.5–2.4 Gy (21, 22, 23). Moreover, with the aid of an imaging unit combined with the linear accelerator for the generation of verification images during radiotherapy (so-called on-board imaging), day-to-day anatomical changes such as tumor remission, atelectasis, or pleural effusions can be visualized and the volume to be irradiated can be tailored during treatment (adaptive planning) (32). Daily adaptation of the treatment plan to generate a “plan of the day” requires not only rapid on-board imaging, but also precise fusion of these images with the planning images, as well as the availability of appropriate staff to carry out the re-planning. This technique is currently under development (32).
The late sequelae of radiotherapy in the CNS include, above all, neurocognitive functional impairment and, rarely, brain necrosis.
The risk of neurocognitive functional impairment after radiotherapy of the brain is particularly disturbing for patients and for the specialists who treat them. Such problems tend to affect the domains of verbal and nonverbal memory, problem-solving ability, attention, and information-processing speed. Changes that are demonstrable in neuropsychological tests are not always clinically relevant (33), and a dementia syndrome is rare. Neurocognitive impairment arising from four months to several years after radiotherapy (with or without chemotherapy) is generally irreversible (e11, e12) (Table 1). Reliable data on the frequency of neurocognitive impairment after radiotherapy are hard to obtain because of the small patient collectives, short follow-up times, cross-sectional studies without reporting of baseline data, inappropriate test instruments (e.g., the Mini Mental Status Test), poor test compliance, and the confounders tumor progression and treatment with antiepileptic drugs (33, e13, e14, e15). Patients whose glioma was well controlled suffered more often from neurocognitive functional impairment if they had received radiotherapy than if they had not (17/32 patients [53%] versus 4/17 [24%]). However, tumor recurrence is the main risk factor for functional impairment, in patients with brain metastases as well (e11, e12, e16).
The risk of toxicity is increased by fraction doses > 2 Gy (in conventional radiotherapy), antiepileptic drugs (e11, e12, e17), chemotherapy, the administration of BRAF inhibitors (e18), and either very young or very old age (e11, e12, e17, e19). The risk of neurocognitive impairment after prophylactic whole-brain radiotherapy in patients with lung cancer is of particular clinical significance. Neurocognitive impairment is already present in 23–95% of patients before radiotherapy and worsens in 8–89% after radiotherapy, compared to 3–42% after observation alone (e19).
Some memory tasks are thought to be localized to the hippocampus. The IMRT and VMAT techniques enable reduction of the radiation dose that is delivered to the hippocampus. In the first phase III trial of whole-brain radiotherapy for brain metastases with or without hippocampal sparing, the frequency of cognitive impairment (memory/language) at four months was significantly lower in the group with hippocampal sparing than in the control group (52% versus 65%, 211/517 patients studied, HR 0.74 ([0.58; 0.94]) (34). Further study findings on the functional effect of hippocampal sparing, and on tumor control despite dose reduction, are currently pending.
Brain necrosis in tumor-free brain tissue has become a rare event (<1%) since the introduction of IMRT/VMAT and stereotactic radiotherapy. Necrosis arises in high-dose regions of radiotherapy for brain tumors or metastases from 10 months to approximately 3 years after treatment in 1–12% of patients, with the frequency depending on the total dose, fraction dose, and treatment volume (e20, e21). Patients present with focal symptoms that depend on the neuroanantomical location of the necrosis; large areas of necrosis can also exert mass effect, producing symptoms of intracranial hypertension. The differential diagnosis of tumor progression versus “pseudoprogression” (i.e., radionecrosis) can be made by magnetic resonance tomography with perfusion and diffusion studies and spectroscopy, supplemented, if indicated, by combined positron emission tomography and computed tomography (PET-CT) employing an amino-acid tracer such as 18F-fluoroethyl-L-tyrosine (sensitivity 83–87%, specificity 81–85%) (e22). The clinical course of cerebral radionecrosis varies, ranging from spontaneous remission, to stable clinical manifestations and magnetic resonance findings, to continuing progression.
Technical innovations such as stereotactic radiotherapy now enable escalation of the dose delivered to the tumor without any increase in toxicity. For brain metastases, tumor control rates above 80% have been achieved (e20).
The induction of second tumors
After the successful treatment of the primary tumor, a small number of patients develop second tumors (or multiple further tumors) later on in life (Table 2, eTable). The incidence of such tumors can be estimated from the findings of cohort studies (with large, heterogeneous patient groups) or meta-analyses of randomized, controlled trials (with narrowly defined but small patient groups); it is reported as a standardized incidence rate (SIR) compared to the normal population, as an absolute excess rate (AER) of cases per 10 000 patient-years, or as a relative risk in comparison to a control group. Aside from the radiotherapy undergone by the patient, the risk factors for a second tumor include the same factors that likely played a role in the development of the primary tumor:
- lifestyle (35% of second malignancies are in patients who consume alcohol, tobacco, or both)
- environmental factors
- genetic factors (hereditary ovarian carcinoma, hereditary non-polypoid colorectal carcinoma, breast cancer (BRCA) 1/2 mutation (35, 36, 37).
Patients who have had a first cancer have an elevated risk of developing a second cancer with or without radiotherapy (SIR after cancer of the rectum or endometrium 2.98 , after breast cancer 1.08 ). An estimated 8% of solid second tumors in adults, corresponding to 3 additional tumors per 1000 patients in 10 years, are thought to be induced by radiotherapy (35).
Tumors induced by radiotherapy (e23) are mainly solid tumors arising after a latency of at least 5–10 years, with an incidence that never reaches a plateau (35, 39). Critical factors for the development of second tumors include both the irradiated volume in and immediately adjacent to the tumor and the volume of tissue outside the tumor that is irradiated at a much lower dose. After radiotherapy for prostate cancer, 50% of the second tumors in the low-dose region (doses less than 1–3 Gy) arise in the lung and the other 50% in the bone marrow, while the tumors in the high-dose region arise in portions of the bladder and rectum that are adjacent to the prostate (e24). The underlying radiobiological processes that give rise to cancer are chronic inflammatory reactions in the high-dose region and an elevated mutation rate and epigenetic changes in the low-dose region.
Second tumors arise more frequently in patients with genetic syndromes, Li-Fraumeni syndrome, hereditary retinoblastoma, Gorlin syndrome, and Wilms tumor (36). Women who have undergone radiotherapy for breast cancer have a higher risk of a second tumor compared to the general population if they carry a missense mutation with loss of function of the ataxia-telangiectasia mutated (ATM) gene; on the other hand, no elevation of the risk is demonstrable in women carrying mutations of the BRCA1/2 genes (e25). Lifestyle factors potentiate the risk: the RR of developing lung cancer after chemo- or radiotherapy for Hodgkin’s lymphoma is five times higher in intense smokers than in nonsmokers or persons who smoke very little (37). For patients who underwent radiotherapy in childhood or adolescence, the risk of a second tumor is greater in those who were irradiated at younger ages (especially under the age of 5 years) (e26). Radiotherapy involving or confined to the CNS elevates the risk of glioma (AER 3, compared to chemotherapy with AER 2.6) and meningioma, while mediastinal radiotherapy for Hodgkin’s lymphoma elevates the risk of breast cancer (SIR 13–55) (40) (eTable, e27, e28, e29). It follows that all persons who underwent radiotherapy in childhood or adolescence should have annual follow-up examinations by a multidisciplinary team for the rest of their lives, including, among other things, lifestyle counseling and, in women who underwent radiotherapy of the chest, intensified screening for breast cancer (e30).
The dose-response curve for the induction of second tumors is linear (except in the case of thyroid cancer), with an excess relative risk per Gy of 0.01–0.2 for adults, and, for children, excess relative risks ranging from 0.08–0.33 (highly malignant glioma) to 1.06 (meningioma) (40).
The calculated estimate of the hazard ratio for carcinoma of the rectum after radiotherapy for prostate cancer in the years 1973–2010 is 1.43 for irradiated versus non-irradiated patients (e31), or an additional two carcinomas of the rectum per 1000 patients (e32). In contrast, phase III trials conducted in the period 1990–2006 in which modern, conformal radiotherapy was used, did not reveal any elevation of the rate of second tumors in a small group of patients who had undergone pelvic radiotherapy (38).
In an analysis of clinical cohort studies of patients with breast cancer, conducted from 1935 to 2007, the standardized incidence rate of second tumors ten years after treatment, compared to the normal population, was 1.5 in patients who had undergone radiotherapy of the breast, and 1.16 in patients who had not (39). The variables radiation dose, radiation technique, and smoking could not be considered in the analysis. A lower risk of second tumor can be expected with the types of normal-tissue-sparing radiotherapy that are available today. Because of the long latency, however, the effect can only be estimated with models for the time being. For women with breast cancer, the estimated mortality from lung cancer is 0.8% with radiotherapy vs. 0.5% without (in never-smokers), and 13% vs. 9% (in active smokers) (15). The expected effect cannot yet be seen in the German studies on Hodgkin’s lymphoma, in which the radiation dose and volume were systematically reduced.
Conclusion and overview
Conceptual and technical advances in radiotherapy over the past twenty years have enabled reduction of the radiation dose delivered to normal tissue and/or escalation of the dose delivered to the tumor. Further improvements are expected from advances in proton and heavy-ion beam therapy and adaptive radiotherapy, and from the integration of tumor-biological predictive tests. Special challenges for research are posed by the long latency of sequelae and the need (because these sequelae are fairly rare) to collect data from large, well-documented patient cohorts to be able to evaluate cofactors such as systemic tumor therapy, patient-related risk factors, and the primary malignancy itself.
Conflict of interest statement
The authors state that they have no conflict of interest.
Manuscript submitted on 25 March 2020, revised version accepted on 20 November 2020.
Translated from the original German by Ethan Taub, M.D.
PD Dr. med. Ulrike Höller
MVZ Charité Vivantes
Landsberger Allee 49,
10249 Berlin, Germany
Cite this as:
Hoeller U, Borgmann K, Oertel M, Haverkamp U, Budach V, Eich HT: Late sequelae of radiotherapy—the effect of technical and conceptual innovations in radiation oncology. Dtsch Arztebl Int 2021; 118: 205–12. DOI: 10.3238/arztebl.m2021.0024
Department of Radiation Oncology, Charité—University Medicine Berlin: Prof. Dr. med. Dr. h. c. Volker Budach
Laboratory for Radiobiology & Experimental Radiooncology, Department for Radiotherapy and Radiation Oncology, Center of Oncology, University Medical Center Hamburg-Eppendorf: Prof. Dr. rer. nat. Kerstin Borgmann
Department of Radiation Oncology, University Hospital Münster: Dr. med. Michael Oertel, Prof. Dr. rer. medic. Uwe Haverkamp, Prof. Dr. med. Hans Theodor Eich
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