Skip to main content
Download PDF

Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy

Radiation Oncology volume 19, Article number: 116 (2024) Cite this article

Abstract

Background

A predictive assay for late radiation toxicity would allow more personalized treatment planning, reducing the burden of toxicity for the more sensitive minority, and improving the therapeutic index for the majority. In a previous study in prostate cancer patients, the γ-H2AX foci decay ratio (γ-FDR) was the strongest predictor of late radiation toxicity. The current study aimed to validate this finding in a more varied group of patients with pelvic cancer. Additionally, the potential correlation between the γ-FDR and patient-reported outcomes was investigated.

Methods

Prostate and gynecological cancer patients with ≥ 24 months of follow-up were included in the current analysis. Toxicity was evaluated by physician (CTCAE version 4) and patient (EORTC questionnaires). γ-FDRs were determined in ex vivo irradiated lymphocytes. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses. The highest toxicity grade recorded during follow-up was used. The association between global quality of life and γ-FDR was tested by comparing the change in quality of life over time in patients with γ-FDR < or ≥ 3.41, a previously established threshold.

Results

Eighty-eight patients were included. Physician-assessed and patient-reported cumulative grade ≥ 2 toxicity was 25% and 29%, respectively; which is much lower than in the previous cohort (i.e., 51% CTCAE grade ≥ 2). Patients with toxicity exhibited less favorable dose-volume parameters. In men, these parameters showed significant improvement compared to the previous cohort. The proportion of patients with a low γ-FDR increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR < 3.41 was not correlated with the development of moderate to severe toxicity. Post-treatment decline in global quality of life was minimal, and similar for patients with γ-FDR < or ≥ 3.41.

Conclusions

In the present study, the γ-H2AX foci decay ratio could not be validated as a predictor of late radiation toxicity in patients with pelvic cancer. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in less toxicities. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency, next to severity, into consideration.

Introduction

Radiotherapy plays a pivotal role in the treatment of various pelvic tumors, including localized prostate cancer and locoregionally advanced cervical cancer. After radiotherapy, approximately 30% of prostate and cervical cancer patients develop moderate or severe late radiation toxicity, though toxicity rates vary widely [1,2,3,4,5,6,7,8,9]. Urinary frequency, fistulae, rectal bleeding, and diarrhea are among the most common and debilitating symptoms [9, 10]. Due to the chronic tendency of several symptoms, they may negatively impact quality of life (QoL) [11,12,13].

Personalized treatment strategies that account for individual risk factors could potentially mitigate the development of severe late radiation toxicity following pelvic radiotherapy. With a growing population of long-term cancer survivors, the implementation of such strategies could offer substantial benefits to numerous patients. However, despite decades of research, a reliable predictive method to assess the risk of late radiation toxicity remains elusive.

Many risk factors for late radiation toxicity have been described. Most studies focus on dosimetric and clinical factors, such as dose, irradiated volume, and comorbidities. In the past decades, there has been an increasing recognition of the role of genetic predisposition as a risk factor [14,15,16,17,18,19,20]. Recently, we investigated the contribution of genetic predisposition, particularly compared with dose-volume factors, to the risk of late radiation toxicity in prostate cancer patients treated with external beam radiotherapy (EBRT) [19]. In this study, a functional assay measuring DNA damage repair proficiency was used. Our findings indicated that an impaired repair of DNA double-strand breaks (DSBs), reflected by a lower γ-H2AX foci decay ratio (γ-FDR), is associated with moderate to severe late radiation toxicity. DNA DSBs are the most catastrophic lesions induced by ionizing radiation. When DNA DSBs are inflicted, the phosphorylation of histone H2AX is one of the earliest events in the DNA damage repair cascade. The induction and subsequent resolution of DSBs can therefore be observed over time by the immunofluorescent detection of phosphorylated H2AX (γ-H2AX). The γ-FDR quantifies DNA DSB repair proficiency by assessing the number of γ-H2AX foci in ex vivo irradiated lymphocytes at 30 min post-irradiation, divided by the number at 24 h.

Although expected to operate independently of cancer site and normal tissue type, the γ-H2AX assay’s ability to predict late radiation toxicity via the γ-FDR metric has not yet been examined in patient groups other than those with prostate cancer. To address this knowledge gap, we initiated a new prospective study to validate our previous findings in a more varied group of pelvic cancer patients. Furthermore, recognizing the growing interest in the use of patient-reported outcome measures for the evaluation of toxicity, we extended the physician-assessed toxicity grading with patient-reported outcomes (PROs). This research holds promise for refining patient-tailored treatment strategies and improving the overall QoL for cancer survivors after pelvic radiotherapy.

Materials and methods

Patients

Between September 2018 and July 2021, patients diagnosed with prostate or gynecologic cancer (i.e., cervix, uterus, vagina, vulva) were accrued at the Amsterdam UMC and the Leiden UMC. This study was approved by the medical ethics committee of the Amsterdam UMC. We included the subgroup of patients that had a follow-up duration of ≥ 24 months. Eligible patients had histologically confirmed cancer and underwent EBRT with curative intent. All patients were treated with volumetric modulated arc therapy (VMAT) using 10 MV photons. Patients with a history of pelvic irradiation were excluded. Prostate cancer patients who had salvage treatment after radical prostatectomy or EBRT combined with brachytherapy were also excluded. After written informed consent was obtained, blood was drawn from all patients before initiating treatment. Lymphocytes were isolated using Ficoll-Paque density gradient separation and stored in liquid nitrogen.

γ-H2AX foci assay

Lymphocytes were thawed and irradiated with 1 Gy γ-rays using a dedicated benchtop cell irradiator (Precision CellRad, North Branford, CT, USA) with a dose rate of approximately 1.1 Gy/min (150 kV, 5 mA). Induction and decay of radiation-induced γ-H2AX foci were determined in unstimulated G(0) cells. At 30 min and 24 h post-irradiation, lymphocytes were seeded on poly-D-lysine-coated slides and fixed in 4% paraformaldehyde. After fixation, slides were washed with PBS and were ready for immunostaining, this was performed using previously published methods [21].

γ-H2AX foci scoring

The number of γ-H2AX foci was determined in fluorescent stack images that were made using Leica Application Suite X software. Stack images of circa 60 slices with a 200-nm interval were obtained using a Leica-DM Upright Microscope (Leica, Wetzlar Germany). These stacks were deconvolved as 1 photomicrograph using Huygens Essential software. The number of foci per nucleus was scored using Cellular Imaging (CI) software version 6.2 (MATLAB version: 9.13.0), which was developed by R.A. Hoebe at the Department of Medical Biology [22]. This software used a deep learning (DL) model that was trained on our own data with CI Annotate DL version 1.5 and CI Train DL version 2.2, which use the StarDist Deep-Learning Algorithm [22, 23]. The γ-FDR was determined by dividing the number of γ-H2AX foci 30 min post-irradiation by the number of γ-H2AX foci 24 h post-irradiation. A minimum of 100 cells per patient per condition were assessed.

Delineations and dose-volume parameters

Delineation was carried out by a single experienced physician on CT planning images using RayStation software (version 8.99). The organs at risk (OARs) considered in this study were the bladder, anal canal, rectum, sigmoid, and bowel bag. The bladder, anal canal, and rectum were defined as previously described [19]. For the sigmoid, contouring was terminated when it was no longer visible as a traversing structure. The bowel bag was defined from the level of the most inferior bowel loop, or just above the sigmoid, whichever was more inferior. Rectum and sigmoid were excluded as part of the bag. Anteriorly, contouring was stopped at a level where no further exposure to dose was anticipated based on the treatment plan evaluation. Dose-volume histograms (DVHs) were generated for all OARs based on the clinically approved dose distribution used for treatment. The bowel bag variables were expressed as absolute volumes; for instance, the amount of milliliter receiving 30 Gy or more (bowel bag V30). Other variables were expressed as relative volumes; for example, the percentage of the bladder receiving 40 Gy or more (bladder V40). Depending on the specific analysis conducted, either the physical dose or the equieffective dose in 2 Gy per fraction (EQD2) was used. The EQD2 was calculated using an α/β ratio of 3 Gy (EQD23). When OAR doses were aggregated from cervical cancer EBRT and brachytherapy, the D2cc from brachytherapy was combined with the EBRT prescribed dose converted to EQD2.

Assessment of toxicity and QoL

Toxicity and QoL were assessed at the end of radiotherapy, and at 6, 12, 18, and 24 months after treatment. Toxicity grades were corrected for baseline conditions, QoL was also assessed at baseline. Toxicity was evaluated by both physician and patient.

PROs were assessed with the validated EORTC Core Quality of Life Questionnaire (QLQ-C30) and the prostate (-PR25), cervical (-CX24) or endometrial cancer-specific module (-EN24) [24,25,26,27,28]. Physician-assessed toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4; the first author reviewed all reported toxicities [29]. An overview of items analyzed for physician-assessed and patient-reported toxicity is presented in Table 1. Patients with residual disease after completion of treatment were not eligible for toxicity assessment. Outcomes were censored when patients were diagnosed with local, regional, or metastatic recurrence.

Table 1 Overview of items analyzed for physician-assessed and patient-reported toxicity
Full size table

Statistical analysis

Descriptive statistics were calculated for patient characteristics. Toxicity was reported as absolute number of moderate (CTCAE grade 2 or EORTC ‘quite a bit’) and severe (CTCAE grade 3 or EORTC ‘very much’) events, and as cumulative incidence rates. The maximal graded event was considered for analyses. Numeric values were analyzed using the Student’s t-test and categorical data were assessed using the Chi-square test. Correlation between γ-FDR and toxicity was assessed using both linear and logistic regression analyses.

Concerning QoL data, per sex, the mean score, standard deviation, and standard error of the mean of all scales were calculated. Changes in global QoL before and after treatment were estimated by means of simple analysis of derived summaries. For each patient a ‘change score’ was calculated, this resulted from subtracting the new baseline Qol-score from the long-term mean QoL-score. The new baseline QoL-score was defined as the maximum score of the original baseline and the early follow-up. Long-term mean QoL-score was calculated by taking the mean of scores at 12, 18, and 24 months. The association between global QoL and γ-FDR was tested by comparing the mean change scores of patients with a γ-FDR < or ≥ 3.41, our previously established threshold [14]. A 2-sided P-value of ≤ 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics for Windows, version 28.0 [30].

Results

Patients

One hundred and four patients had a follow-up of ≥ 24 months. All patients met the inclusion criteria. Eleven patients were excluded because of residual or early recurrent disease; five patients were excluded because they were lost to follow-up within 3 months after the end of treatment. Eighty-eight patients were available for analysis of morbidity outcome. Baseline patient and treatment characteristics are summarized in Table 2. Comparing patients with and without CTCAE grade ≥ 2 toxicity revealed older age (P = 0.043) and lower KPS (P = 0.031) as possible clinical risk factors in men (Table S1; correction for multiple comparisons was not applied).

Table 2 Clinical characteristics of 88 patients with pelvic cancer treated with curative EBRT
Full size table

Physician-assessed toxicity

CTCAE reports were available for 89% (n = 472) of the targeted 528 (88 patients x 6 visits) data points. No life-threatening toxicity was observed during follow-up. Grade 2 and grade 3 late radiation toxicities were recorded in 19 (22%) and 5 (6%) patients, respectively (Table 3). Women (i.e., patients irradiated for gynecologic cancer) experienced more toxicity than men (i.e., patients irradiated for prostate cancer). Specifically, 34% (12/35) of women had grade 2 toxicities versus 13% (7/53) of men, and all grade 3 events were recorded in women. This results in cumulative late grade ≥ 2 toxicities of 43% and 13% for women and men, respectively. Overall, in women more bowel than urinary grade ≥ 2 toxicity was recorded (23% vs. 14%, respectively), while in men more urinary than bowel grade ≥ 2 toxicity was recorded (9% vs. 6%, respectively). The sex difference was statistically significant for bowel toxicity (P = 0.017).

Table 3 Moderate and severe adverse events as determined according to the CTCAEv4 and EORTC
Full size table

Patient-reported QoL

EORTC QLQ-C30 and disease specific modules were available for 85% (n = 449) of the targeted 528 data points. At baseline and during follow-up, women registered a lower global QoL compared to men (Table S3). Global QoL-scores were relatively constant over time; overall mean scores for women and men were 70.1 and 81.4, respectively. In general, women also had worse scores on the functioning scales and symptom scales. Trends graphs for all QoL domains are presented in Figure S1.

Patient-reported toxicity

Questionnaire toxicity data was available for 86 of 88 patients; for one patient the baseline questionnaire was missing, the second patient did not complete any of the long-term questionnaires. During follow-up, moderate and severe toxicities were reported by 21 (24%) and 6 (7%) patients, respectively (Table 3). The cumulative rate of moderate to severee toxicity was 29% for both men (15/51) and women (10/35). Overall, women reported more moderate to severe bowel toxicity (17%) compared to urinary toxicity (9%). In contrast, men reported more moderate to severe urinary toxicity (27%) compared to bowel toxicity (10%). The sex difference was statistically significant for urinary toxicity (P = 0.031).

Dose-volume parameters

The average bladder values were almost identical between the group of patients without and those with grade ≥ 2 urinary toxicity (Table S4). For the anal canal, rectum, sigmoid, and bowel bag, mean volumes were almost always higher in both men and women with grade ≥ 2 bowel toxicity compared to those without, but it was never statistically significant (Tables S5-S8). With regard to the 31 women that had EBRT and brachytherapy, mean cumulative bladder D2cc (in EQD2) was significantly higher in those with grade ≥ 2 urinary toxicity compared to those without, i.e., 78.9 Gy and 68.4 Gy, respectively (P = 0.032; Table S9). We did not find a correlation between late bowel toxicity and mean cumulative rectum, sigmoid, and bowel D2cc (Table S10).

Triggered by lower than expected toxicity rates, we also compared the dose-volume parameters of men from the current with the past cohort. We found that mean V50 to V70 for both rectum and bladder were significantly higher in the past cohort (P < 0.001; Fig. 1). For example, the mean volume of the rectum receiving 50 Gy or more (rectum V50) was 51% in the past cohort, compared to 22% in the current cohort.

Fig. 1
figure 1

Distribution of bladder (A) and rectal (B) dose-volume parameters of prostate cancer patients from the past and current cohort. Box plots display the interquartile range, with the mean indicated, and error bars representing the full range of values. Each symbol corresponds to an individual patient. Mean V50 to V70 for the rectum and mean V50 to V75 for the bladder were significantly higher in the past cohort, with P < 0.001 for all parameters

Full size image

γ-H2AX foci decay ratios

In three patients, the γ-H2AX experiment failed and did therefore not result in a γ-FDR. A significant correlation between γ-FDR and severity of physician-assessed toxicity was not found (R2 = 0.021; P = 0.184; Fig. 2A); the mean γ-FDRs per grade increase of (CTCAE) toxicity were 3.51 (SEM 0.26; n = 21), 3.20 (SEM 0.18; n = 44), 2.97 (SEM 0.17; n = 15), and 3.12 (SEM 0.27; n = 5). In addition, a γ-FDR below the threshold of 3.41 was not correlated with the development of CTCAE grade ≥ 2 toxicity (odds ratio 1.76 and P-value 0.329). Between γ-FDR and severity of patient-reported toxicity a correlation was also not found (R2 = 0.003; P = 0.605; Fig. 2B); the mean γ-FDRs per grade increase of toxicity were 3.22 (SEM 0.28; n = 11), 3.28 (SEM 0.16; n = 49), 3.28 (SEM 0.31; n = 18), and 2.77 (SEM 0.30; n = 5). In addition, a γ-FDR below the threshold of 3.41 was not correlated with the development of patient-reported moderate to severe toxicity (odds ratio 1.21 and P-value 0.712).

A γ-FDR < or ≥ 3.41, our previously established threshold, was not associated with global QoL after treatment. In both men and women, the mean change score was not significantly different between patients with γ-FDR < 3.41 and patients with γ-FDR ≥ 3.41 (Table 4).

Fig. 2
figure 2

Foci decay ratios of all patients per toxicity group, patients are grouped based on their highest toxicity grade during follow-up. Foci decay ratio: number of foci at 30 min divided by number of foci at 24 h. A significant correlation between toxicity grade and foci decay ratios was not found. (A) Foci decay ratios versus physician-assessed toxicity score (R2 = 0.021; P = 0.184). (B) Foci decay ratios versus patient-reported toxicity score (R2 = 0.003; P = 0.605)

Full size image
Table 4 Mean global QoL change scores in men and women stratified by γ-FDR status
Full size table

Discussion

The key to prevention of burdensome late radiation toxicities, and thus ensuring QoL after radiotherapy treatment, is accurate prediction of the risk for individuals. In this prospective study of patients irradiated for prostate or gynecologic cancer, we aimed to validate the γ-FDR as a predictive marker for late radiation toxicity. In contradiction with earlier findings, the present analysis did not demonstrate a significant correlation between the γ-FDR and severity of physician-assessed toxicity. In addition, the γ-FDR was not correlated with either patient-reported toxicity or patient-reported global QoL.

Previously, we have observed that a less efficient repair of DNA DSBs in ex vivo irradiated lymphocytes, as quantified by the γ-FDR, was an independent risk factor for the development of CTCAE grade ≥ 2 late radiation toxicity [19]. This was a prospective study in 179 prostate cancer patients curatively treated with EBRT, specifically IMRT, between 2009 and 2013. Currently, the proportion of patients with a low γ-FDR also increased with severity of toxicity, but this trend was not statistically significant. In addition, a γ-FDR below a previously established threshold of 3.41 was not correlated with the development of moderate to severe late radiation toxicity. A plausible explanation for this result could be the unexpectedly low incidence of moderate or worse toxicity. The cumulative incidences of CTCAE grade ≥ 2 late radiation toxicities in men from the previous and present study were 51% and 13%, respectively. This significant decline likely reflects the adoption of increasingly conformal treatment techniques (i.e., VMAT), which effectively reduce radiation exposure to the OARs, thereby minimizing the risk of toxicity.

Another unexpected finding was that female patients, on average, reported lower toxicity rates than physicians did. The opposite happened in men. Recently, we compared patient- and physician-reported late radiation toxicity in long-term prostate cancer survivors in detail, and found a poor agreement, with survivors reporting higher rates than physicians [31]. These results were in line with other studies wherein PROs were compared with physician-reported outcomes after radiotherapy [32, 33]. The present finding in women may be partly explained by toxicity scores that do not necessarily result from complaints, but instead result from physical and/or additional examinations. For example, three women were diagnosed with hydronephrosis accompanied by renal dysfunction, thus requiring ureteral stents (CTCAE grade 3), without experiencing any complaints.

Older age and a lower KPS seemed to be associated with toxicity in men. While some studies support these findings, consistent evidence regarding these (and other) implicated clinical risk factors remains limited in independent studies [8, 34,35,36,37,38,39]. Upon examining dosimetric factors, we found that dose-volume parameters of all gastrointestinal OARs were less favorable in patients with CTCAE grade ≥ 2 bowel toxicity, in comparison to those without. Furthermore, in women who received EBRT followed by brachytherapy, we found that the mean cumulative bladder D2cc was significantly higher in those with grade ≥ 2 urinary toxicity compared to those without.

Currently, we also studied post-treatment QoL, and its potential association with γ-FDR status. A threshold of 3.41 was previously established from data of patients with either severe or no CTCAE toxicity [14]. A γ-FDR < 3.41 was not associated with worse global QoL after treatment. This observation aligns with the understanding that QoL is multifaceted, influenced not only by toxicity but also by personal factors such as comorbidity, coping strategies, social support, and emotional well-being [31, 40,41,42,43,44,45,46,47,48,49]. In the literature, long-term QoL after EBRT for prostate cancer has been reported to be high and comparable to normative cohorts [40, 44, 50]. Schaake et al. found a statistically significant decline in several dimensions of QoL following EBRT, when compared to both baseline levels and normative data from an age-matched reference population. However, these differences were all classified as small or trivial. In addition, post-treatment global QoL did not differ from baseline [44].

The main limitation of this study was the sample size, or rather, the sample size in combination with the lower than anticipated toxicity rates. This compromised the study’s statistical power. Considering the very low incidence of late toxicity in this patient cohort, the required sample size needs to be substantially enlarged to detect a possibly very small difference in late toxicity risk by molecular or genetic markers. A post-hoc analysis assuming similar toxicity incidence in both groups (i.e., patients with y-FDR < or ≥ the threshold), showed that almost 600 patients would have been required. An other limitation applies to the duration of the follow-up period of 24 months, as toxicities can take several years to fully manifest [51, 52]. Nonetheless, other studies have shown that the majority of symptoms tend to emerge within the initial two years after radiotherapy [53, 54].

The limitations hinder a comprehensive exploration of a potential correlation between γ-FDR and the severity of toxicity. However, given the decreasing incidence of moderate or worse late radiation toxicity, the clinical importance of any found correlation between γ-FDR and maximum experienced toxicity needs to be reevaluated. In the contemporary era of increasingly conformal radiotherapy, focusing on the maximum toxicity level might not provide the most useful insights for evaluating patients well-being. Furthermore, crude incidence rates reflect the worst symptom score without considering the length of follow-up, including duration of the symptom. By disregarding (severe but) transient events, a relation to the treatment is more plausible.

The impact of toxicity on QoL has been suggested to be closely related to whether treatment-related symptoms are transient or persist over time [46, 55, 56]. Therefore, it may be more appropriate to shift our focus from maximum experienced toxicity during follow-up to persistence of toxicities. This approach is consistent with the findings of Vittrup et al., who examined late, persistent, substantial, and treatment-related symptoms (LAPERS events) in patients from the EMBRACE study. The proportion of patients with LAPERS events was substantially lower than the proportion of patients identified by crude incidence rates, thereby highlighting that the occurrence of a symptom does not necessarily equate to its persistence [46]. The observation that late toxicity can exhibit a reversible or fluctuating pattern over time has also been described in other studies [53, 57]. In line with these findings, the present study highlights the need to address the persistence of toxicity in clinical radiotherapy research.

Conclusions

To the best of our knowledge, our study is the first to investigate the (potential) correlation between γ-FDR and the highest grade of both physician- and patient-reported toxicity. We were unable to validate the γ-FDR as a predictive marker in this relatively small sample with lower than expected toxicity rates. Improved radiotherapy techniques with smaller irradiated bladder and bowel volumes have probably resulted in these lower toxicity rates. Future studies on genetic markers of toxicity should be powered on these lower incidences. We further recommend taking persistency of toxicity, next to severity, into consideration. In conclusion, the findings underscore the need for more extensive research to fully elucidate the complexities of late radiation toxicity and its impact on patients’ well-being.

Data availability

The datasets generated and analyzed during the current study are not publicly available due the sensitive nature of most of the data. The datasets are available from the corresponding author on reasonable request.

Abbreviations

γ-H2AX:

Phosphorylated form of H2A histone family member X

γ-FDR:

γ-H2AX foci decay ratio

CI:

Cellular imaging

CTCAE:

Common Terminology Criteria for Adverse Events

D2cc:

Minimal dose to the most exposed 2 cc of the respective organ

DL:

Deep learning

DSBs:

Double-strand breaks

DVHs:

Dose-volume histograms

EBRT:

External beam radiotherapy

EORTC:

European Organization for Research and Treatment of Cancer

EQD2:

Equieffective dose in 2 Gy per fraction

OARs:

Organs at risk

PROs:

Patient-reported outcomes

QLQ-C30:

Core Quality of Life Questionnaire

QLQ-CX24:

Quality of Life Questionnaire - Cervical Cancer module

QLQ-EN24:

Quality of Life Questionnaire - Endometrial Cancer module

QLQ-PR25:

Quality of Life Questionnaire - Prostate Cancer module

QoL:

Quality of life

V50:

Volume (%) of the OAR receiving 50 Gy or more

V70:

Volume (%) of the OAR receiving 70 Gy or more

References

  1. Ohri N, Dicker AP, Showalter TN. Late toxicity rates following definitive radiotherapy for prostate cancer. Can J Urol. 2012;19:6373–80.

    PubMed  PubMed Central  Google Scholar 

  2. Zelefsky MJ, Levin EJ, Hunt M, Yamada Y, Shippy AM, Jackson A, Amols HI. Incidence of late rectal and urinary toxicities after three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2008;70:1124–9. https://doi.org/10.1016/j.ijrobp.2007.11.044.

    Article  PubMed  Google Scholar 

  3. Dearnaley D, Syndikus I, Mossop H, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047–60. https://doi.org/10.1016/s1470-2045(16)30102-4.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Monninkhof EM, van Loon JWL, van Vulpen M, Kerkmeijer LGW, Pos FJ, Haustermans K, et al. Standard whole prostate gland radiotherapy with and without lesion boost in prostate cancer: toxicity in the FLAME randomized controlled trial. Radiother Oncol. 2018;127:74–80. https://doi.org/10.1016/j.radonc.2017.12.022.

    Article  PubMed  Google Scholar 

  5. Widmark A, Gunnlaugsson A, Beckman L, Thellenberg-Karlsson C, Hoyer M, Lagerlund M, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394:385–95. https://doi.org/10.1016/s0140-6736(19)31131-6.

    Article  PubMed  Google Scholar 

  6. Kirwan JM, Symonds P, Green JA, Tierney J, Collingwood M, Williams CJ. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol. 2003;68:217–26. https://doi.org/10.1016/s0167-8140(03)00197-x.

    Article  PubMed  Google Scholar 

  7. Chen LA, Kim J, Boucher K, Terakedis B, Williams B, Nickman NA, Gaffney DK. Toxicity and cost-effectiveness analysis of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for postoperative treatment of gynecologic cancers. Gynecol Oncol. 2015;136:521–8. https://doi.org/10.1016/j.ygyno.2014.12.039.

    Article  PubMed  Google Scholar 

  8. Laan JJ, van Lonkhuijzen L, van Os RM, Tytgat KM, Dávila Fajardo R, Pieters BR, et al. Socioeconomic status as an independent risk factor for severe late bowel toxicity after primary radiotherapy for cervical cancer. Gynecol Oncol. 2017;147:684–9. https://doi.org/10.1016/j.ygyno.2017.10.013.

    Article  CAS  PubMed  Google Scholar 

  9. Pötter R, Tanderup K, Schmid MP, Jürgenliemk-Schulz I, Haie-Meder C, Fokdal LU, et al. MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study. Lancet Oncol. 2021;22:538–47. https://doi.org/10.1016/s1470-2045(20)30753-1.

    Article  PubMed  Google Scholar 

  10. Fernandes A, Bhuva NJ, Taylor A. Management of toxicities following pelvic irradiation for gynaecological cancers. Curr Opin Oncol. 2015;27:405–11. https://doi.org/10.1097/cco.0000000000000215.

    Article  CAS  PubMed  Google Scholar 

  11. Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250–61. https://doi.org/10.1056/NEJMoa074311.

    Article  CAS  PubMed  Google Scholar 

  12. Olopade FA, Norman A, Blake P, Dearnaley DP, Harrington KJ, Khoo V, et al. A modified inflammatory bowel disease questionnaire and the Vaizey Incontinence questionnaire are simple ways to identify patients with significant gastrointestinal symptoms after pelvic radiotherapy. Br J Cancer. 2005;92:1663–70. https://doi.org/10.1038/sj.bjc.6602552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schaake W, Wiegman EM, de Groot M, van der Laan HP, van der Schans CP, van den Bergh AC, Langendijk JA. The impact of gastrointestinal and genitourinary toxicity on health related quality of life among irradiated prostate cancer patients. Radiother Oncol. 2014;110:284–90. https://doi.org/10.1016/j.radonc.2013.11.011.

    Article  PubMed  Google Scholar 

  14. van Oorschot B, Uitterhoeve L, Oomen I, Ten Cate R, Medema JP, Vrieling H, et al. Prostate Cancer patients with late Radiation toxicity exhibit reduced expression of genes involved in DNA double-strand break repair and homologous recombination. Cancer Res. 2017;77:1485–91. https://doi.org/10.1158/0008-5472.Can-16-1966.

    Article  PubMed  Google Scholar 

  15. Lee TK, Allison RR, O’Brien KF, Johnke RM, Christie KI, Naves JL, et al. Lymphocyte radiosensitivity correlated with pelvic radiotherapy morbidity. Int J Radiat Oncol Biol Phys. 2003;57:222–9. https://doi.org/10.1016/s0360-3016(03)00411-5.

    Article  PubMed  Google Scholar 

  16. Svensson JP, Stalpers LJ, Esveldt-van Lange RE, Franken NA, Haveman J, Klein B, et al. Analysis of gene expression using gene sets discriminates cancer patients with and without late radiation toxicity. PLoS Med. 2006;3:e422. https://doi.org/10.1371/journal.pmed.0030422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. van Oorschot B, Hovingh SE, Moerland PD, Medema JP, Stalpers LJ, Vrieling H, Franken NA. Reduced activity of double-strand break repair genes in prostate cancer patients with late normal tissue radiation toxicity. Int J Radiat Oncol Biol Phys. 2014;88:664–70. https://doi.org/10.1016/j.ijrobp.2013.11.219.

    Article  PubMed  Google Scholar 

  18. West CM, Barnett GC. Genetics and genomics of radiotherapy toxicity: towards prediction. Genome Med. 2011;3:52. https://doi.org/10.1186/gm268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nuijens AC, Oei AL, van Oorschot B, Visser J, van Os RM, Moerland PD, et al. Gamma-H2AX Foci Decay ratio as a stronger predictive factor of late Radiation Toxicity Than dose-volume parameters in a prospective cohort of prostate Cancer patients. Int J Radiat Oncol Biol Phys. 2022;112:212–21. https://doi.org/10.1016/j.ijrobp.2021.08.020.

    Article  PubMed  Google Scholar 

  20. Kerns SL, Hall WA, Marples B, West CML. Normal tissue toxicity prediction: clinical translation on the Horizon. Semin Radiat Oncol. 2023;33:307–16. https://doi.org/10.1016/j.semradonc.2023.03.010.

    Article  PubMed  Google Scholar 

  21. van Oorschot B, Hovingh SE, Rodermond H, Güçlü A, Losekoot N, Geldof AA, et al. Decay of γ-H2AX foci correlates with potentially lethal damage repair in prostate cancer cells. Oncol Rep. 2013;29:2175–80. https://doi.org/10.3892/or.2013.2364.

    Article  CAS  PubMed  Google Scholar 

  22. MATLAB version. 9.13.0 (R2022b). Natick, Massachusetts: The MathWorks Inc.; 2022.

    Google Scholar 

  23. Schmidt U, Weigert M, Broaddus C, Myers G, st International Conference on Medical, Image C, Computer Assisted Intervention M. Cell detection with star-convex polygons. Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). 2018;11071 LNCS:265 – 73. https://doi.org/10.1007/978-3-030-00934-2_30

  24. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76. https://doi.org/10.1093/jnci/85.5.365.

    Article  CAS  PubMed  Google Scholar 

  25. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. The EORTC QLQ-C30 Scoring Manual (3rd Edition). European Organisation for Research and Treatment of Cancer, Brussels. 2001.

  26. van Andel G, Bottomley A, Fosså SD, Efficace F, Coens C, Guerif S, et al. An international field study of the EORTC QLQ-PR25: a questionnaire for assessing the health-related quality of life of patients with prostate cancer. Eur J Cancer. 2008;44:2418–24. https://doi.org/10.1016/j.ejca.2008.07.030.

    Article  PubMed  Google Scholar 

  27. Greimel ER, Kuljanic Vlasic K, Waldenstrom AC, Duric VM, Jensen PT, Singer S, et al. The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-life questionnaire cervical cancer module: EORTC QLQ-CX24. Cancer. 2006;107:1812–22. https://doi.org/10.1002/cncr.22217.

    Article  PubMed  Google Scholar 

  28. Greimel E, Nordin A, Lanceley A, Creutzberg CL, van de Poll-Franse LV, Radisic VB, et al. Psychometric validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24). Eur J Cancer. 2011;47:183–90. https://doi.org/10.1016/j.ejca.2010.08.014.

    Article  PubMed  Google Scholar 

  29. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). 2009. Version 4.0. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdf [accessed 13 October 2023].

  30. IBM Corp. Released 2021. IBM SPSS statistics for Windows, Version 28.0. Armonk, NY: IBM Corp.

  31. Nuijens AC, Oei AL, Bouhuijs A, Franken NAP, Rasch CRN, Stalpers LJA. A comparison between patient- and physician-reported late Radiation toxicity in long-term prostate Cancer survivors. Cancers (Basel). 2022;14. https://doi.org/10.3390/cancers14071670.

  32. Brouwers P, van Loon J, Houben RMA, Paulissen J, Engelen SME, Heuts M, et al. Are PROMs sufficient to record late outcome of breast cancer patients treated with radiotherapy? A comparison between patient and clinician reported outcome through an outpatient clinic after 10years of follow up. Radiother Oncol. 2018;126:163–9. https://doi.org/10.1016/j.radonc.2017.08.004.

    Article  CAS  PubMed  Google Scholar 

  33. Vistad I, Cvancarova M, Fosså SD, Kristensen GB. Postradiotherapy morbidity in long-term survivors after locally advanced cervical cancer: how well do physicians’ assessments agree with those of their patients? Int J Radiat Oncol Biol Phys. 2008;71:1335–42. https://doi.org/10.1016/j.ijrobp.2007.12.030.

    Article  PubMed  Google Scholar 

  34. Chen SW, Liang JA, Yang SN, Liu RT, Lin FJ. The prediction of late rectal complications following the treatment of uterine cervical cancer by high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2000;47:955–61. https://doi.org/10.1016/s0360-3016(00)00559-9.

    Article  CAS  PubMed  Google Scholar 

  35. Spampinato S, Jensen NBK, Pötter R, Fokdal LU, Chargari C, Lindegaard JC, et al. Severity and persistency of late gastrointestinal morbidity in locally Advanced Cervical Cancer: lessons learned from EMBRACE-I and implications for the future. Int J Radiat Oncol Biol Phys. 2022;112:681–93. https://doi.org/10.1016/j.ijrobp.2021.09.055.

    Article  PubMed  Google Scholar 

  36. Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 gy to 78 gy. Int J Radiat Oncol Biol Phys. 2005;61:1019–34. https://doi.org/10.1016/j.ijrobp.2004.07.715.

    Article  PubMed  Google Scholar 

  37. Defraene G, Van den Bergh L, Al-Mamgani A, Haustermans K, Heemsbergen W, Van den Heuvel F, Lebesque JV. The benefits of including clinical factors in rectal normal tissue complication probability modeling after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:1233–42. https://doi.org/10.1016/j.ijrobp.2011.03.056.

    Article  PubMed  Google Scholar 

  38. Hunter GK, Reddy CA, Klein EA, Kupelian P, Angermeier K, Ulchaker J, et al. Long-term (10-year) gastrointestinal and genitourinary toxicity after treatment with external beam radiotherapy, radical prostatectomy, or brachytherapy for prostate cancer. Prostate Cancer. 2012;2012:853487. https://doi.org/10.1155/2012/853487.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Jensen NBK, Pötter R, Spampinato S, Fokdal LU, Chargari C, Lindegaard JC, et al. Dose-volume effects and Risk factors for late Diarrhea in Cervix Cancer patients after Radiochemotherapy with image guided adaptive brachytherapy in the EMBRACE I study. Int J Radiat Oncol Biol Phys. 2021;109:688–700. https://doi.org/10.1016/j.ijrobp.2020.10.006.

    Article  Google Scholar 

  40. Lilleby W, Fosså SD, Waehre HR, Olsen DR. Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. Int J Radiat Oncol Biol Phys. 1999;43:735–43. https://doi.org/10.1016/s0360-3016(98)00475-1.

    Article  CAS  PubMed  Google Scholar 

  41. Gami B, Harrington K, Blake P, Dearnaley D, Tait D, Davies J, et al. How patients manage gastrointestinal symptoms after pelvic radiotherapy. Aliment Pharmacol Ther. 2003;18:987–94. https://doi.org/10.1046/j.1365-2036.2003.01760.x.

    Article  CAS  PubMed  Google Scholar 

  42. Al-Mamgani A, van Putten WL, van der Wielen GJ, Levendag PC, Incrocci L. Dose escalation and quality of life in patients with localized prostate cancer treated with radiotherapy: long-term results of the Dutch randomized dose-escalation trial (CKTO 96 – 10 trial). Int J Radiat Oncol Biol Phys. 2011;79:1004–12. https://doi.org/10.1016/j.ijrobp.2009.12.039.

    Article  PubMed  Google Scholar 

  43. Beckendorf V, Guerif S, Le Prisé E, Cosset JM, Bougnoux A, Chauvet B, et al. 70 gy versus 80 gy in localized prostate cancer: 5-year results of GETUG 06 randomized trial. Int J Radiat Oncol Biol Phys. 2011;80:1056–63. https://doi.org/10.1016/j.ijrobp.2010.03.049.

    Article  PubMed  Google Scholar 

  44. Schaake W, de Groot M, Krijnen WP, Langendijk JA, van den Bergh AC. Quality of life among prostate cancer patients: a prospective longitudinal population-based study. Radiother Oncol. 2013;108:299–305. https://doi.org/10.1016/j.radonc.2013.06.039.

    Article  PubMed  Google Scholar 

  45. Van den Bosch L, van der Laan HP, van der Schaaf A, Oosting SF, Halmos GB, Witjes MJH, et al. Patient-reported toxicity and quality-of-life profiles in patients with Head and Neck Cancer treated with definitive Radiation Therapy or Chemoradiation. Int J Radiat Oncol Biol Phys. 2021;111:456–67. https://doi.org/10.1016/j.ijrobp.2021.05.114.

    Article  PubMed  Google Scholar 

  46. Vittrup AS, Tanderup K, Bentzen SM, Jensen NBK, Spampinato S, Fokdal LU, et al. Persistence of late substantial patient-reported symptoms (LAPERS) after Radiochemotherapy including image guided adaptive brachytherapy for locally Advanced Cervical Cancer: a Report from the EMBRACE Study. Int J Radiat Oncol Biol Phys. 2021;109:161–73. https://doi.org/10.1016/j.ijrobp.2020.08.044.

    Article  PubMed  Google Scholar 

  47. Breetvelt IS, Van Dam FS. Underreporting by cancer patients: the case of response-shift. Soc Sci Med. 1991;32:981–7. https://doi.org/10.1016/0277-9536(91)90156-7.

    Article  CAS  PubMed  Google Scholar 

  48. Ream E, Richardson A. The role of information in patients’ adaptation to chemotherapy and radiotherapy: a review of the literature. Eur J Cancer Care (Engl). 1996;5:132–8. https://doi.org/10.1111/j.1365-2354.1996.tb00223.x.

    Article  CAS  PubMed  Google Scholar 

  49. Ilie G, Bradfield J, Moodie L, Lawen T, Ilie A, Lawen Z, et al. The role of response-shift in studies assessing quality of Life outcomes among Cancer patients: a systematic review. Front Oncol. 2019;9:783. https://doi.org/10.3389/fonc.2019.00783.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hjälm-Eriksson M, Ullén A, Nilsson S, Johansson H, Nilsson J, Castellanos E, Brandberg Y. High levels of health-related quality of life five years after curative treatment of prostate cancer with HDR-brachytherapy and external beam radiation. Acta Oncol. 2022;61:1179–85. https://doi.org/10.1080/0284186x.2022.2115314.

    Article  PubMed  Google Scholar 

  51. Jung H, Beck-Bornholdt HP, Svoboda V, Alberti W, Herrmann T. Quantification of late complications after radiation therapy. Radiother Oncol. 2001;61:233–46. https://doi.org/10.1016/s0167-8140(01)00457-1.

    Article  CAS  PubMed  Google Scholar 

  52. Kerns SL, Fachal L, Dorling L, Barnett GC, Baran A, Peterson DR, et al. Radiogenomics Consortium Genome-Wide Association Study Meta-Analysis of late toxicity after prostate Cancer Radiotherapy. J Natl Cancer Inst. 2020;112:179–90. https://doi.org/10.1093/jnci/djz075.

    Article  CAS  PubMed  Google Scholar 

  53. Georg P, Boni A, Ghabuous A, Goldner G, Schmid MP, Georg D, et al. Time course of late rectal- and urinary bladder side effects after MRI-guided adaptive brachytherapy for cervical cancer. Strahlenther Onkol. 2013;189:535–40. https://doi.org/10.1007/s00066-013-0365-7.

    Article  CAS  PubMed  Google Scholar 

  54. Mazeron R, Fokdal LU, Kirchheiner K, Georg P, Jastaniyah N, Šegedin B, et al. Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: results from the prospective multicenter EMBRACE study. Radiother Oncol. 2016;120:412–9. https://doi.org/10.1016/j.radonc.2016.06.006.

    Article  PubMed  Google Scholar 

  55. Thanarajasingam G, Atherton PJ, Novotny PJ, Loprinzi CL, Sloan JA, Grothey A. Longitudinal adverse event assessment in oncology clinical trials: the toxicity over Time (ToxT) analysis of Alliance trials NCCTG N9741 and 979254. Lancet Oncol. 2016;17:663–70. 10.1016/s1470-2045(16)00038 – 3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vittrup AS, Kirchheiner K, Fokdal LU, Bentzen SM, Nout RA, Pötter R, Tanderup K. Reporting of late morbidity after Radiation Therapy in large prospective studies: a descriptive review of the current status. Int J Radiat Oncol Biol Phys. 2019;105:957–67. https://doi.org/10.1016/j.ijrobp.2019.08.040.

    Article  PubMed  Google Scholar 

  57. Goldner G, Pötter R, Kranz A, Bluhm A, Dörr W. Healing of late endoscopic changes in the rectum between 12 and 65 months after external beam radiotherapy. Strahlenther Onkol. 2011;187:202–5. https://doi.org/10.1007/s00066-010-2211-5.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the nurses and the participating patients of the Amsterdam UMC (location AMC) and Leiden UMC Departments of Radiation Oncology.

Funding

This work was financially supported by the Dutch Cancer Society (KWF project number 11000). The funding sources were not involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands

    Anna C. Nuijens, Arlene L. Oei, Lisa Koster, Nicolaas A.P. Franken & Lukas J.A. Stalpers

  2. Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands

    Anna C. Nuijens, Arlene L. Oei & Nicolaas A.P. Franken

  3. Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands

    Anna C. Nuijens

  4. Department of Medical Biology and Core Facility Cellular Imaging, Van Leeuwenhoek Centre for Advanced Microscopy-Academic Medical Center (LCAM-AMC), University of Amsterdam, Amsterdam, The Netherlands

    Ron A. Hoebe

  5. Department of Radiation Oncology, Leiden University Medical Center, Leiden, the Netherlands

    Coen R.N. Rasch

Authors
  1. Anna C. Nuijens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arlene L. Oei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa Koster
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ron A. Hoebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nicolaas A.P. Franken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Coen R.N. Rasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lukas J.A. Stalpers
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: L.J.A.S. and A.C.N.; Methodology: L.J.A.S. and A.C.N.; Software: R.A.H.; Formal analysis: A.C.N.; Data curation: A.C.N. and L.K.; Writing- original draft: A.C.N.; Writing- review and editing: A.C.N., A.L.O., L.J.A.S., C.R.N.R. and N.A.P.F.; Visualization: A.C.N. and A.L.O.; Supervision: A.L.O., L.J.A.S., C.R.N.R. and N.A.P.F.; Funding acquisition: C.R.N.R., L.J.A.S. and N.A.P.F. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Arlene L. Oei.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the medical ethics committee of the Amsterdam UMC – location AMC (METC AMC protocol reference number 2018_114). Written informed consent was obtained from all patients involved in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nuijens, A.C., Oei, A.L., Koster, L. et al. Genetic markers of late radiation toxicity in the era of image-guided radiotherapy: lower toxicity rates reduce the predictive value of γ-H2AX foci decay ratio in patients undergoing pelvic radiotherapy. Radiat Oncol 19, 116 (2024). https://doi.org/10.1186/s13014-024-02501-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13014-024-02501-x

Keywords

Radiation Oncology

ISSN: 1748-717X

Contact us