DÄ internationalArchive12/2021Late Sequelae of Radiotherapy

Review article

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

Hoeller, U; Borgmann, K; Oertel, M; Haverkamp, U; Budach, V; Eich, H T

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.

LNSLNS

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.

Technical developments in radiotherapy
Box
Technical developments in radiotherapy

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).

Methods

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

Cardiotoxicity

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).

Lung toxicity

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).

Neurotoxicity

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).

Overview of studies on neurocognitive functional impairment after radiotherapy (with or without chemotherapy)
Table 1
Overview of studies on neurocognitive functional impairment after radiotherapy (with or without chemotherapy)

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:

Studies on second tumors
Table 2
Studies on second tumors
Overview of studies on second tumors
eTable
Overview of studies on second tumors
  • 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 [38], after breast cancer 1.08 [39]). 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.

2020.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
PD Dr. med. Ulrike Höller
MVZ Charité Vivantes
Landsberger Allee 49,
10249 Berlin, Germany
ulrike.hoeller@charite.de

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

Supplementary material

eReferences, eTable:
www.aerzteblatt-international.de/m2021.0024

1.
De Ruysscher D, Niedermann G, Burnet NG, Siva S, Lee AWM, Hegi-Johnson F: Radiotherapy toxicity. Nat Rev Dis Primers 2019; 5: 13 CrossRef MEDLINE
2.
Nestle U, Schimek-Jasch T, Kremp S, et al.: Imaging-based –target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial. Lancet Oncol 2020; 21: 581–92 CrossRef
3.
Leitlinienprogamm Onkologie: S3 guide line: supportive therapy for patients with cancer (S3-Leitlinie. Supportive Therapie bei onkologischen PatientInnen). 2015. www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie/ (last accessed on 24 January 2021).
4.
Citrin DE, Mitchell JB: Mechanisms of normal tissue injury from irradiation. Semin Radiat Oncol 2017; 27: 316–24 CrossRef MEDLINE PubMed Central
5.
Wolfgang Dörr TH, Herrmann T, Trott KR: Normal tissue tolerance. Translational Cancer Research 2017. 6(S5): 840–51 CrossRef
6.
Burnet NG, Johansen J, Turesson I, Nyman J, Peacock JH: Describing patients‘ normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy. Int J Cancer 1998; 79: 606–13 CrossRef
7.
Azria D, Lapierre A, Gourgou S, et al.: Data-based radiation oncology: design of clinical trials in the toxicity biomarkers era. Front Oncol 2017; 7: 83 CrossRef MEDLINE PubMed Central
8.
Bentzen SM, Overgaard J: Patient-to-patient variability in the expression of radiation-induced normal tissue injury. Semin Radiat Oncol 1994; 4: 68–80 CrossRef
9.
Andreassen CN, Rosenstein BS, Kerns SL, et al.: Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients. Radiother Oncol 2016; 121: 431–9 CrossRef MEDLINE PubMed Central
10.
Gu Y, Shi J, Qiu S, et al.: Association between ATM rs1801516 polymorphism and cancer susceptibility: a meta-analysis involving 12,879 cases and 18,054 controls. BMC Cancer 2018; 18: 1060 CrossRef MEDLINE PubMed Central
11.
Barnett GC, West CM, Dunning AM, et al.: Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9: 134–42 CrossRef MEDLINE PubMed Central
12.
Mulrooney DA, Hyun G, Ness KK, et al.: Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 2020; 368: l6794 CrossRef MEDLINE PubMed Central
13.
Darby SC, Ewertz M, McGale P, et al.: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368: 987–98 CrossRef MEDLINE
14.
van Nimwegen FA, Schaapveld M, Cutter DJ, et al.: Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin Lymphoma. J Clin Oncol 2016; 34: 235–43 CrossRef MEDLINE
15.
Taylor C, Correa C, Duane FK, et al.: Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol 2017; 35: 1641–9 CrossRef MEDLINE PubMed Central
16.
Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 2018; 132: 1635–46 CrossRef MEDLINE PubMed Central
17.
Duma M-N, Baumann R, Budach W, et al.: Heart-sparing radiotherapy techniques in breast cancer patients: a recommendation of the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO). Strahlenther Onkol 2019; 195: 861–71 CrossRef MEDLINE
18.
Piroth MD, Baumann R, Budach W, et al.: Heart toxicity from breast cancer radiotherapy: Current findings, assessment, and prevention. Strahlenther Onkol 2019; 195: 1–12 CrossRef MEDLINE PubMed Central
19.
Weberpals J, Jansen L, Muller OJ, Brenner H: Long-term heart-specific mortality among 347 476 breast cancer patients treated with radiotherapy or chemotherapy: a registry-based cohort study. Eur Heart J 2018; 39: 3896–903 CrossRef MEDLINE
20.
Chang JS, Shin J, Park E-C, Kim YB: Risk of cardiac disease after adjuvant radiation therapy among breast cancer survivors. Breast (Edinburgh, Scotland) 2019; 43: 48–54 CrossRef MEDLINE
21.
Charpentier AM, Conrad T, Sykes J, et al.: Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: impact on normal tissue dose. Pract Radiat Oncol 2014; 4: 174–80 CrossRef MEDLINE
22.
Paumier A, Ghalibafian M, Gilmore J, et al.: Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin‘s lymphoma. Int J Radiat Oncol Biol Phys 2012; 82: 1522–7 CrossRef MEDLINE
23.
Aznar MC, Maraldo MV, Schut DA, et al.: Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92: 169–74 CrossRef MEDLINE
24.
Ghita M, Dunne V, Hanna GG, Prise KM, Williams JP, Butterworth KT: Preclinical models of radiation-induced lung damage: challenges and opportunities for small animal radiotherapy. Br J Radiol 2019; 92: 20180473 CrossRef MEDLINE PubMed Central
25.
Simone CB: Thoracic radiation normal tissue injury. Semin Radiat Oncol 2017; 27: 370–7 CrossRef MEDLINE
26.
Palma DA, Senan S, Tsujino K, et al.: Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2013; 85: 444–50 CrossRef MEDLINE PubMed Central
27.
Flentje M, Huber RM, Engel-Riedel W, et al.: GILT—a randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer. Strahlenther Onkol 2016; 192: 216–22 CrossRef MEDLINE
28.
Chun SG, Hu C, Choy H, et al.: Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017; 35: 56–62 CrossRef MEDLINE PubMed Central
29.
Pinnix CC, Smith GL, Milgrom S, et al.: Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015; 92: 175–82 CrossRef MEDLINE PubMed Central
30.
Bjermer L, Franzén L, Littbrand B, Nilsson K, Angström T, Henriksson R: Effects of smoking and irradiated volume on inflammatory response in the lung of irradiated breast cancer patients evaluated with bronchoalveolar lavage. Cancer Res 1990; 50: 2027–30.
31.
Mörth C, Kafantaris I, Castegren M, Valachis A: Validation and optimization of a predictive model for radiation pneumonitis in patients with lung cancer. Oncol Lett 2016; 12: 1144–8 CrossRef MEDLINE PubMed Central
32.
Sonke J-J, Aznar M, Rasch C: Adaptive radiotherapy for anatomical changes. Semin Radiat Oncol 2019; 29: 245–57 CrossRef MEDLINE
33.
van der Meulen M, Dirven L, Habets EJJ, van den Bent MJ, Taphoorn MJB, Bromberg JEC: Cognitive functioning and health-related quality of life in patients with newly diagnosed primary CNS lymphoma: a systematic review. Lancet Oncol 2018; 19: e407–18 CrossRef MEDLINE
34.
Brown PD, Gondi V, Pugh S, et al.: Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol 2020; 38: 1019–29 CrossRef MEDLINE
35.
Berrington de Gonzalez A, Curtis RE, Kry SF, et al.: Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol 2011; 12: 353–60 CrossRef
36.
Wood ME, Vogel V, Ng A, Foxhall L, Goodwin P, Travis LB: Second malignant neoplasms: assessment and strategies for risk reduction. J Clin Oncol 2012; 30: 3734–45 CrossRef MEDLINE
37.
Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK: Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nature Rev Clin Oncol 2013; 10: 289–301 CrossRef MEDLINE
38.
Wiltink LM, Nout RA, Fiocco M, et al.: No increased risk of second cancer after radiotherapy in patients treated for rectal or endometrial cancer in the randomized TME, PORTEC-1, and PORTEC-2 Trials. J Clin Oncol 2015; 33: 1640–6 CrossRef MEDLINE
39.
Grantzau T, Overgaard J: Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: a systematic review and meta-analysis of population-based studies including 522,739 patients. Radiother Oncol 2016; 121: 402–13 CrossRef MEDLINE
40.
Berrington de Gonzalez A, Gilbert E, Curtis R, et al.: Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys 2013; 86: 224–33 CrossRef MEDLINE PubMed Central
e1.
Yap ML, Zubizarreta E, Bray F, Ferlay J, Barton M: Global access to radiotherapy services: have we made progress during the past decade? J Glob Oncol 2016; 2: 207–15 CrossRef MEDLINE PubMed Central
e2.
Jung H, Beck-Bornholdt HP, Svoboda V, Alberti W, Herrmann T: Quantification of late complications after radiation therapy. Radiother Oncol 2001; 61: 233–464 CrossRef
e3.
Thilmann C, Oelfke U, Sterzing F: Intensitätsmodulierte Strahlentherapie. In: Wannenmacher M, Wenz F, Debus J, (eds.): Strahlentherapie. Springer: Berlin Heidelberg 2013; 271–86 CrossRef
e4.
Finazzi T, Palacios MA, Spoelstra FOB, et al.: Role of on-table plan adaptation in MR-guided ablative radiation therapy for central lung tumors. Int J Radiat Oncol Biol Phys 2019; 104: 933–41 CrossRef MEDLINE
e5.
Joiner M: Linear energy transfer and relative biological effectiveness. In: Joiner M, van der Kogel B (eds.): Basic clinical radiobiology. London: Hodder 2009; 68–78 CrossRef
e6.
Cutter DJ, Schaapveld M, Darby SC, et al.: Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst 2015; 107: djv008 CrossRef MEDLINE PubMed Central
e7.
Aznar MC, Maraldo MV, Schut DA, et al.: Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92: 169–74 CrossRef MEDLINE
e8.
Boda-Heggemann J, Knopf A-C, Simeonova-Chergou A, et al.: Deep inspiration breath hold-based radiation therapy: a clinical review. Int J Radiat Oncol Biol Phys 2016; 94: 478–92 CrossRef MEDLINE
e9.
Vogelius IR, Bentzen SM: A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol 2012; 51: 975–83 CrossRef MEDLINE PubMed Central
e10.
Jin H, Tucker SL, Liu HH, et al.: Dose-volume thresholds and smoking status for the risk of treatment-related pneumonitis in inoperable non-small cell lung cancer treated with definitive radiotherapy. Radiother Oncol 2009; 91: 427–32 CrossRef MEDLINE PubMed Central
e11.
Douw L, Klein M, Fagel SS, et al.: Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 2009; 8: 810–8 CrossRef
e12.
Bosma I, Vos MJ, Heimans JJ, et al.: The course of neurocognitive functioning in high-grade glioma patients. Neuro Oncol 2007; 9: 53–62 CrossRef MEDLINE PubMed Central
e13.
Lawrie TA, Gillespie D, Dowswell T, et al.: Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma. Cochrane Database Syst Rev 2019; 8: CD013047 CrossRef MEDLINE PubMed Central
e14.
Khan L, Soliman H, Sahgal A, Perry J, Xu W, Tsao MN: External beam radiation dose escalation for high grade glioma. Cochrane Database Syst Rev 2020; 5: CD011475 CrossRef MEDLINE
e15.
Tallet AV, Azria D, Barlesi F, et al.: Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol 2012; 7: 77 CrossRef MEDLINE PubMed Central
e16.
Li J, Bentzen SM, Renschler M, Mehta MP: Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007; 25: 1260–6 CrossRef MEDLINE
e17.
Nieder C, Leicht A, Motaref B, Nestle U, Niewald M, Schnabel K: Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs. Am J Clin Oncol 1999; 22: 573–9 CrossRef MEDLINE
e18.
Kroeze SGC, Fritz C, Hoyer M, et al.: Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev 2017; 53: 25–37 CrossRef MEDLINE
e19.
Zeng H, Hendriks LEL, van Geffen WH, Witlox WJA, Eekers DBP, De Ruysscher DKM: Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: a systematic review. Cancer Treat Rev 2020; 88: 102025 CrossRef MEDLINE
e20.
Wiggenraad R, Verbeek-de Kanter A, Kal HB, Taphoorn M, Vissers T, Struikmans H: Dose-effect relation in stereotactic radiotherapy for brain metastases. A systematic review. Radiother Oncol 2011; 98: 292–7 CrossRef MEDLINE
e21.
Akanda ZZ, Hong W, Nahavandi S, Haghighi N, Phillips C, Kok DL: Post-operative stereotactic radiosurgery following excision of brain metastases: a systematic review and meta-analysis. Radiother Oncol 2020; 142: 27–35 CrossRef MEDLINE
e22.
Treglia G, Muoio B, Trevisi G, et al.: Diagnostic performance and prognostic value of PET/CT with different tracers for brain tumors: a systematic review of published meta-analyses. Int J Mol Sci 2019; 20: 4669 CrossRef MEDLINE PubMed Central
e23.
Trott KR: Special radiobiological features of second cancer risk after particle radiotherapy. Phys Med 2017; 42: 221–7 CrossRef MEDLINE
e24.
Brenner DJ, Curtis RE, Hall EJ, Ron E: Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 2000; 88: 398–406 CrossRef
e25.
Vallard A, Magné N, Guy JB, et al.: Is breast-conserving therapy adequate in BRCA 1/2 mutation carriers? The radiation oncologist‘s point of view. Br J Radiol 2019; 92: 20170657 CrossRef MEDLINE PubMed Central
e26.
Bhatti P, Veiga LH, Ronckers CM, et al.: Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 2010; 174: 741–52 CrossRef MEDLINE PubMed Central
e27.
Taylor AJ, Little MP, Winter DL, et al.: Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 2010; 28: 5287–93 CrossRef MEDLINE PubMed Central
e28.
Henderson TO, Amsterdam A, Bhatia S, et al.: Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Inter Med 2010; 152: 444–54 CrossRef MEDLINE
e29.
Bowers DC, Nathan PC, Constine L, et al.: Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol 2013; 14: e321–8 CrossRef
e30.
Gebauer J, Baust K, Bardi E, et al.: Guidelines for long-term follow-up after childhood cancer: practical implications for the daily work. Oncol Res Treat 2020; 43: 61–9 CrossRef MEDLINE
e31.
Rombouts AJM, Hugen N, van Beek JJP, Poortmans PMP, de Wilt JHW, Nagtegaal ID: Does pelvic radiation increase rectal cancer incidence?—a systematic review and meta-analysis. Cancer Treat Rev 2018; 68: 136–44 CrossRef MEDLINE
e32.
Wallis CJD, Mahar AL, Choo R, et al.: Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ 2016; 352: i851 CrossRef MEDLINE PubMed Central
e33.
Liu L, Zhao T, Zhong Q, Cui J, Xiu X, Li G: The role of prophylactic cranial irradiation in patients with non-small cell lung cancer: an updated systematic review and meta-analysis. Front Oncol 2020; 10: 11 CrossRef MEDLINE PubMed Central
e34.
Dhawan S, Patil CG, Chen C, Venteicher AS: Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev 2020; 1: CD009229 CrossRef MEDLINE PubMed Central
e35.
Gehrke AK, Baisley MC, Sonck AL, Wronski SL, Feuerstein M: Neurocognitive deficits following primary brain tumor treatment: systematic review of a decade of comparative studies. J Neurooncol 2013; 115: 135–42 CrossRef MEDLINE
e36.
Zhu Z, Zhao S, Liu Y, et al.: Risk of secondary rectal cancer and colon cancer after radiotherapy for prostate cancer: a meta-analysis. Int J Colorectl Dis 2018; 33: 1149–58 CrossRef MEDLINE
e37.
Franklin JG, Paus MD, Pluetschow A, Specht L: Chemotherapy, radiotherapy and combined modality for Hodgkin‘s disease, with emphasis on second cancer risk. Cochrane Database Syst Rev 2005; 2005: CD003187 CrossRef MEDLINE PubMed Central
e38.
Taylor AJ, Winter DL, Pritchard-Jones K, et al.: Second primary neoplasms in survivors of Wilms‘ tumour—a population-based cohort study from the British Childhood Cancer Survivor Study. Int J Cancer 2008; 122: 2085–93 CrossRef MEDLINE
e39.
Bavle A, Tewari S, Sisson A, Chintagumpala M, Anderson M, Paulino AC: Meta-analysis of the incidence and patterns of second neoplasms after photon craniospinal irradiation in children with medulloblastoma. Pediat Blood Cancer 2018; 65: e27095 CrossRef MEDLINE
MVZ Charité Vivantes Department of Radiation Oncology, Charité—University Medicine Berlin: PD Dr. med. Ulrike Höller
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
Technical developments in radiotherapy
Box
Technical developments in radiotherapy
Overview of studies on neurocognitive functional impairment after radiotherapy (with or without chemotherapy)
Table 1
Overview of studies on neurocognitive functional impairment after radiotherapy (with or without chemotherapy)
Studies on second tumors
Table 2
Studies on second tumors
Overview of studies on second tumors
eTable
Overview of studies on second tumors
1.De Ruysscher D, Niedermann G, Burnet NG, Siva S, Lee AWM, Hegi-Johnson F: Radiotherapy toxicity. Nat Rev Dis Primers 2019; 5: 13 CrossRef MEDLINE
2.Nestle U, Schimek-Jasch T, Kremp S, et al.: Imaging-based –target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial. Lancet Oncol 2020; 21: 581–92 CrossRef
3.Leitlinienprogamm Onkologie: S3 guide line: supportive therapy for patients with cancer (S3-Leitlinie. Supportive Therapie bei onkologischen PatientInnen). 2015. www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie/ (last accessed on 24 January 2021).
4.Citrin DE, Mitchell JB: Mechanisms of normal tissue injury from irradiation. Semin Radiat Oncol 2017; 27: 316–24 CrossRef MEDLINE PubMed Central
5.Wolfgang Dörr TH, Herrmann T, Trott KR: Normal tissue tolerance. Translational Cancer Research 2017. 6(S5): 840–51 CrossRef
6.Burnet NG, Johansen J, Turesson I, Nyman J, Peacock JH: Describing patients‘ normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy. Int J Cancer 1998; 79: 606–13 CrossRef
7.Azria D, Lapierre A, Gourgou S, et al.: Data-based radiation oncology: design of clinical trials in the toxicity biomarkers era. Front Oncol 2017; 7: 83 CrossRef MEDLINE PubMed Central
8.Bentzen SM, Overgaard J: Patient-to-patient variability in the expression of radiation-induced normal tissue injury. Semin Radiat Oncol 1994; 4: 68–80 CrossRef
9.Andreassen CN, Rosenstein BS, Kerns SL, et al.: Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients. Radiother Oncol 2016; 121: 431–9 CrossRef MEDLINE PubMed Central
10.Gu Y, Shi J, Qiu S, et al.: Association between ATM rs1801516 polymorphism and cancer susceptibility: a meta-analysis involving 12,879 cases and 18,054 controls. BMC Cancer 2018; 18: 1060 CrossRef MEDLINE PubMed Central
11.Barnett GC, West CM, Dunning AM, et al.: Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat Rev Cancer 2009; 9: 134–42 CrossRef MEDLINE PubMed Central
12.Mulrooney DA, Hyun G, Ness KK, et al.: Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort. BMJ 2020; 368: l6794 CrossRef MEDLINE PubMed Central
13.Darby SC, Ewertz M, McGale P, et al.: Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368: 987–98 CrossRef MEDLINE
14.van Nimwegen FA, Schaapveld M, Cutter DJ, et al.: Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin Lymphoma. J Clin Oncol 2016; 34: 235–43 CrossRef MEDLINE
15.Taylor C, Correa C, Duane FK, et al.: Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol 2017; 35: 1641–9 CrossRef MEDLINE PubMed Central
16.Dabaja BS, Hoppe BS, Plastaras JP, et al.: Proton therapy for adults with mediastinal lymphomas: the International Lymphoma Radiation Oncology Group guidelines. Blood 2018; 132: 1635–46 CrossRef MEDLINE PubMed Central
17.Duma M-N, Baumann R, Budach W, et al.: Heart-sparing radiotherapy techniques in breast cancer patients: a recommendation of the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO). Strahlenther Onkol 2019; 195: 861–71 CrossRef MEDLINE
18.Piroth MD, Baumann R, Budach W, et al.: Heart toxicity from breast cancer radiotherapy: Current findings, assessment, and prevention. Strahlenther Onkol 2019; 195: 1–12 CrossRef MEDLINE PubMed Central
19.Weberpals J, Jansen L, Muller OJ, Brenner H: Long-term heart-specific mortality among 347 476 breast cancer patients treated with radiotherapy or chemotherapy: a registry-based cohort study. Eur Heart J 2018; 39: 3896–903 CrossRef MEDLINE
20.Chang JS, Shin J, Park E-C, Kim YB: Risk of cardiac disease after adjuvant radiation therapy among breast cancer survivors. Breast (Edinburgh, Scotland) 2019; 43: 48–54 CrossRef MEDLINE
21.Charpentier AM, Conrad T, Sykes J, et al.: Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: impact on normal tissue dose. Pract Radiat Oncol 2014; 4: 174–80 CrossRef MEDLINE
22.Paumier A, Ghalibafian M, Gilmore J, et al.: Dosimetric benefits of intensity-modulated radiotherapy combined with the deep-inspiration breath-hold technique in patients with mediastinal Hodgkin‘s lymphoma. Int J Radiat Oncol Biol Phys 2012; 82: 1522–7 CrossRef MEDLINE
23.Aznar MC, Maraldo MV, Schut DA, et al.: Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92: 169–74 CrossRef MEDLINE
24.Ghita M, Dunne V, Hanna GG, Prise KM, Williams JP, Butterworth KT: Preclinical models of radiation-induced lung damage: challenges and opportunities for small animal radiotherapy. Br J Radiol 2019; 92: 20180473 CrossRef MEDLINE PubMed Central
25.Simone CB: Thoracic radiation normal tissue injury. Semin Radiat Oncol 2017; 27: 370–7 CrossRef MEDLINE
26.Palma DA, Senan S, Tsujino K, et al.: Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2013; 85: 444–50 CrossRef MEDLINE PubMed Central
27.Flentje M, Huber RM, Engel-Riedel W, et al.: GILT—a randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer. Strahlenther Onkol 2016; 192: 216–22 CrossRef MEDLINE
28.Chun SG, Hu C, Choy H, et al.: Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol 2017; 35: 56–62 CrossRef MEDLINE PubMed Central
29.Pinnix CC, Smith GL, Milgrom S, et al.: Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015; 92: 175–82 CrossRef MEDLINE PubMed Central
30.Bjermer L, Franzén L, Littbrand B, Nilsson K, Angström T, Henriksson R: Effects of smoking and irradiated volume on inflammatory response in the lung of irradiated breast cancer patients evaluated with bronchoalveolar lavage. Cancer Res 1990; 50: 2027–30.
31.Mörth C, Kafantaris I, Castegren M, Valachis A: Validation and optimization of a predictive model for radiation pneumonitis in patients with lung cancer. Oncol Lett 2016; 12: 1144–8 CrossRef MEDLINE PubMed Central
32.Sonke J-J, Aznar M, Rasch C: Adaptive radiotherapy for anatomical changes. Semin Radiat Oncol 2019; 29: 245–57 CrossRef MEDLINE
33.van der Meulen M, Dirven L, Habets EJJ, van den Bent MJ, Taphoorn MJB, Bromberg JEC: Cognitive functioning and health-related quality of life in patients with newly diagnosed primary CNS lymphoma: a systematic review. Lancet Oncol 2018; 19: e407–18 CrossRef MEDLINE
34.Brown PD, Gondi V, Pugh S, et al.: Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol 2020; 38: 1019–29 CrossRef MEDLINE
35.Berrington de Gonzalez A, Curtis RE, Kry SF, et al.: Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol 2011; 12: 353–60 CrossRef
36.Wood ME, Vogel V, Ng A, Foxhall L, Goodwin P, Travis LB: Second malignant neoplasms: assessment and strategies for risk reduction. J Clin Oncol 2012; 30: 3734–45 CrossRef MEDLINE
37.Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK: Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nature Rev Clin Oncol 2013; 10: 289–301 CrossRef MEDLINE
38.Wiltink LM, Nout RA, Fiocco M, et al.: No increased risk of second cancer after radiotherapy in patients treated for rectal or endometrial cancer in the randomized TME, PORTEC-1, and PORTEC-2 Trials. J Clin Oncol 2015; 33: 1640–6 CrossRef MEDLINE
39.Grantzau T, Overgaard J: Risk of second non-breast cancer among patients treated with and without postoperative radiotherapy for primary breast cancer: a systematic review and meta-analysis of population-based studies including 522,739 patients. Radiother Oncol 2016; 121: 402–13 CrossRef MEDLINE
40.Berrington de Gonzalez A, Gilbert E, Curtis R, et al.: Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys 2013; 86: 224–33 CrossRef MEDLINE PubMed Central
e1.Yap ML, Zubizarreta E, Bray F, Ferlay J, Barton M: Global access to radiotherapy services: have we made progress during the past decade? J Glob Oncol 2016; 2: 207–15 CrossRef MEDLINE PubMed Central
e2.Jung H, Beck-Bornholdt HP, Svoboda V, Alberti W, Herrmann T: Quantification of late complications after radiation therapy. Radiother Oncol 2001; 61: 233–464 CrossRef
e3.Thilmann C, Oelfke U, Sterzing F: Intensitätsmodulierte Strahlentherapie. In: Wannenmacher M, Wenz F, Debus J, (eds.): Strahlentherapie. Springer: Berlin Heidelberg 2013; 271–86 CrossRef
e4.Finazzi T, Palacios MA, Spoelstra FOB, et al.: Role of on-table plan adaptation in MR-guided ablative radiation therapy for central lung tumors. Int J Radiat Oncol Biol Phys 2019; 104: 933–41 CrossRef MEDLINE
e5.Joiner M: Linear energy transfer and relative biological effectiveness. In: Joiner M, van der Kogel B (eds.): Basic clinical radiobiology. London: Hodder 2009; 68–78 CrossRef
e6.Cutter DJ, Schaapveld M, Darby SC, et al.: Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst 2015; 107: djv008 CrossRef MEDLINE PubMed Central
e7.Aznar MC, Maraldo MV, Schut DA, et al.: Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92: 169–74 CrossRef MEDLINE
e8.Boda-Heggemann J, Knopf A-C, Simeonova-Chergou A, et al.: Deep inspiration breath hold-based radiation therapy: a clinical review. Int J Radiat Oncol Biol Phys 2016; 94: 478–92 CrossRef MEDLINE
e9.Vogelius IR, Bentzen SM: A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis. Acta Oncol 2012; 51: 975–83 CrossRef MEDLINE PubMed Central
e10.Jin H, Tucker SL, Liu HH, et al.: Dose-volume thresholds and smoking status for the risk of treatment-related pneumonitis in inoperable non-small cell lung cancer treated with definitive radiotherapy. Radiother Oncol 2009; 91: 427–32 CrossRef MEDLINE PubMed Central
e11.Douw L, Klein M, Fagel SS, et al.: Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 2009; 8: 810–8 CrossRef
e12.Bosma I, Vos MJ, Heimans JJ, et al.: The course of neurocognitive functioning in high-grade glioma patients. Neuro Oncol 2007; 9: 53–62 CrossRef MEDLINE PubMed Central
e13.Lawrie TA, Gillespie D, Dowswell T, et al.: Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma. Cochrane Database Syst Rev 2019; 8: CD013047 CrossRef MEDLINE PubMed Central
e14.Khan L, Soliman H, Sahgal A, Perry J, Xu W, Tsao MN: External beam radiation dose escalation for high grade glioma. Cochrane Database Syst Rev 2020; 5: CD011475 CrossRef MEDLINE
e15.Tallet AV, Azria D, Barlesi F, et al.: Neurocognitive function impairment after whole brain radiotherapy for brain metastases: actual assessment. Radiat Oncol 2012; 7: 77 CrossRef MEDLINE PubMed Central
e16.Li J, Bentzen SM, Renschler M, Mehta MP: Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007; 25: 1260–6 CrossRef MEDLINE
e17.Nieder C, Leicht A, Motaref B, Nestle U, Niewald M, Schnabel K: Late radiation toxicity after whole brain radiotherapy: the influence of antiepileptic drugs. Am J Clin Oncol 1999; 22: 573–9 CrossRef MEDLINE
e18.Kroeze SGC, Fritz C, Hoyer M, et al.: Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev 2017; 53: 25–37 CrossRef MEDLINE
e19.Zeng H, Hendriks LEL, van Geffen WH, Witlox WJA, Eekers DBP, De Ruysscher DKM: Risk factors for neurocognitive decline in lung cancer patients treated with prophylactic cranial irradiation: a systematic review. Cancer Treat Rev 2020; 88: 102025 CrossRef MEDLINE
e20.Wiggenraad R, Verbeek-de Kanter A, Kal HB, Taphoorn M, Vissers T, Struikmans H: Dose-effect relation in stereotactic radiotherapy for brain metastases. A systematic review. Radiother Oncol 2011; 98: 292–7 CrossRef MEDLINE
e21.Akanda ZZ, Hong W, Nahavandi S, Haghighi N, Phillips C, Kok DL: Post-operative stereotactic radiosurgery following excision of brain metastases: a systematic review and meta-analysis. Radiother Oncol 2020; 142: 27–35 CrossRef MEDLINE
e22.Treglia G, Muoio B, Trevisi G, et al.: Diagnostic performance and prognostic value of PET/CT with different tracers for brain tumors: a systematic review of published meta-analyses. Int J Mol Sci 2019; 20: 4669 CrossRef MEDLINE PubMed Central
e23.Trott KR: Special radiobiological features of second cancer risk after particle radiotherapy. Phys Med 2017; 42: 221–7 CrossRef MEDLINE
e24.Brenner DJ, Curtis RE, Hall EJ, Ron E: Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 2000; 88: 398–406 CrossRef
e25.Vallard A, Magné N, Guy JB, et al.: Is breast-conserving therapy adequate in BRCA 1/2 mutation carriers? The radiation oncologist‘s point of view. Br J Radiol 2019; 92: 20170657 CrossRef MEDLINE PubMed Central
e26.Bhatti P, Veiga LH, Ronckers CM, et al.: Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 2010; 174: 741–52 CrossRef MEDLINE PubMed Central
e27.Taylor AJ, Little MP, Winter DL, et al.: Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J Clin Oncol 2010; 28: 5287–93 CrossRef MEDLINE PubMed Central
e28.Henderson TO, Amsterdam A, Bhatia S, et al.: Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Inter Med 2010; 152: 444–54 CrossRef MEDLINE
e29.Bowers DC, Nathan PC, Constine L, et al.: Subsequent neoplasms of the CNS among survivors of childhood cancer: a systematic review. Lancet Oncol 2013; 14: e321–8 CrossRef
e30.Gebauer J, Baust K, Bardi E, et al.: Guidelines for long-term follow-up after childhood cancer: practical implications for the daily work. Oncol Res Treat 2020; 43: 61–9 CrossRef MEDLINE
e31.Rombouts AJM, Hugen N, van Beek JJP, Poortmans PMP, de Wilt JHW, Nagtegaal ID: Does pelvic radiation increase rectal cancer incidence?—a systematic review and meta-analysis. Cancer Treat Rev 2018; 68: 136–44 CrossRef MEDLINE
e32.Wallis CJD, Mahar AL, Choo R, et al.: Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ 2016; 352: i851 CrossRef MEDLINE PubMed Central
e33.Liu L, Zhao T, Zhong Q, Cui J, Xiu X, Li G: The role of prophylactic cranial irradiation in patients with non-small cell lung cancer: an updated systematic review and meta-analysis. Front Oncol 2020; 10: 11 CrossRef MEDLINE PubMed Central
e34.Dhawan S, Patil CG, Chen C, Venteicher AS: Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. Cochrane Database Syst Rev 2020; 1: CD009229 CrossRef MEDLINE PubMed Central
e35.Gehrke AK, Baisley MC, Sonck AL, Wronski SL, Feuerstein M: Neurocognitive deficits following primary brain tumor treatment: systematic review of a decade of comparative studies. J Neurooncol 2013; 115: 135–42 CrossRef MEDLINE
e36.Zhu Z, Zhao S, Liu Y, et al.: Risk of secondary rectal cancer and colon cancer after radiotherapy for prostate cancer: a meta-analysis. Int J Colorectl Dis 2018; 33: 1149–58 CrossRef MEDLINE
e37.Franklin JG, Paus MD, Pluetschow A, Specht L: Chemotherapy, radiotherapy and combined modality for Hodgkin‘s disease, with emphasis on second cancer risk. Cochrane Database Syst Rev 2005; 2005: CD003187 CrossRef MEDLINE PubMed Central
e38.Taylor AJ, Winter DL, Pritchard-Jones K, et al.: Second primary neoplasms in survivors of Wilms‘ tumour—a population-based cohort study from the British Childhood Cancer Survivor Study. Int J Cancer 2008; 122: 2085–93 CrossRef MEDLINE
e39.Bavle A, Tewari S, Sisson A, Chintagumpala M, Anderson M, Paulino AC: Meta-analysis of the incidence and patterns of second neoplasms after photon craniospinal irradiation in children with medulloblastoma. Pediat Blood Cancer 2018; 65: e27095 CrossRef MEDLINE