Late Radiation-induced Toxicity Research Articles

Targeted Next-Generation Sequencing for the Identification of Genetic Predictors of Radiation-Induced Late Skin Toxicity in Breast Cancer Patients: A Preliminary Study.

Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

PD-0774 Impact of sarcopenia on acute radiotherapy-induced toxicity in head and neck cancer patients

Purpose or Objective: Sarcopenia, i.e. generalised and progressive loss of skeletal muscle mass and muscle function, is related to more late radiation-induced toxicities and worse survival in head and neck squamous cell carcinoma (HNSCC) patients. The objective of this study was to test the hypothesis that sarcopenia improves the performance of NTCP models to predict acute toxicity in HNSCC patients treated with definitive radiotherapy (RT). Materials and Methods: This was a retrospective analysis in a prospective cohort of HNSCC patients treated from January 2007 to December 2018 with RT with or without systemic therapy. Physician- and patient-rated toxicities, including dysphagia, xerostomia, sticky saliva, aspiration, oral mucositis, weight loss and fatigue, were collected prospectively during (week 1-7) and after treatment (week 12, month 6-24. Planning CT-scans were used for evaluating patients’ skeletal muscle mass at the third cervical vertebra for estimation of the skeletal muscle index (SMI). Chi-square and t-tests were used to compare the characteristics and baseline toxicities of sarcopenic and non-sarcopenic patients. The linear predictors for each endpoint from three to seven weeks during treatment were calculated based on the NTCP models developed at our department. The impact of sarcopenia was analysed using multivariable logistic regression analyses. If sarcopenia remained significant next to the linear predictor, likelihood-ratio tests were performed to test whether the model including sarcopenia performed significantly better. Results: A total of 977 HNSCC patients constituted the study population. The cut-off values of sarcopenia were established at SMI 0.99). Considering these results, late dysphagia was analysed as well and results for grade≥2 and grade≥3 dysphagia were similar (6-24 months after RT). In addition, sarcopenic HNSCC patients experienced more physician-rated dysphagia during and after treatment than non-sarcopenic HNSCC patients (Figure 1). Conclusion: This study showed that sarcopenia in HNSCC patients undergoing RT was an independent prognostic factor for the development of physician-rated acute dysphagia grade≥3 and late dysphagia grade≥2 and grade≥3, which might be explained by its impact on the swallowing muscles. However, sarcopenia did not improve the performance of NTCP-models RT-induced other evaluated acute toxicities.

Development and Implementation of Proton Therapy for Hodgkin Lymphoma: Challenges and Perspectives.

Simple SummaryHodgkin lymphoma (HL) is a highly curable disease; proton therapy for mediastinal HL irradiation might theoretically reduce late toxicities compared with classical radiotherapy techniques. However, optimal patient selection for this technique is subject to debate. While implementation at a larger scale of proton therapy for HL may face organizational, political, and societal challenges, new highly effective systematic drugs are being widely evaluated for this disease.Consolidative radiation therapy for early-stage Hodgkin lymphoma (HL) improves progression-free survival. Unfortunately, first-generation techniques, relying on large irradiation fields, were associated with an increased risk of secondary cancers, and of cardiac and lung toxicity. Fortunately, the use of smaller target volumes combined with technological advances in treatment techniques currently allows efficient organs-at-risk sparing without altering tumoral control. Recently, proton therapy has been evaluated for mediastinal HL treatment due to its potential to significantly reduce the dose to organs-at-risk, such as cardiac substructures. This is expected to limit late radiation-induced toxicity and possibly, second-neoplasm risk, compared with last-generation intensity-modulated radiation therapy. However, the democratization of this new technique faces multiple issues. Determination of which patient may benefit the most from proton therapy is subject to intense debate. The development of new effective systemic chemotherapy and organizational, societal, and political considerations might represent impediments to the larger-scale implementation of HL proton therapy. Based on the current literature, this critical review aims to discuss current challenges and controversies that may impede the larger-scale implementation of mediastinal HL proton therapy.

Mixed Photon and Carbon-Ion Beam Radiotherapy in the Management of Non-Metastatic Nasopharyngeal Carcinoma.

BackgroundCarbon-ion radiotherapy (CIRT) may further increase the therapeutic ratio for patients with newly diagnosed nasopharyngeal carcinoma (NPC). The purpose of the current study is to examine the effectiveness and toxicity profile of photon-based intensity-modulated radiotherapy (IMRT) plus CIRT boost in a relatively large cohort of NPC patients.MethodsIn the current study, non-metastatic NPC patients treated with IMRT plus CIRT boost at Shanghai Proton and Heavy Ion Center between June, 2015 and June, 2018 were included. Overall survival (OS), progression-free survival (PFS), local control, regional control, and distant control were calculated with Kaplan–Meier method. Acute and late toxicities were graded using CTCAE 4.03.ResultsA total of 69 patients were included in the analysis. Among those, 74% of the patients had locoregionally advanced (stage III/IV) disease, and 92.8% had cervical lymphadenopathy. With a median follow-up of 31.9 months, the 3-year OS, PFS, local control, regional control, and distant control rates were 94.9, 85.2, 96.9, 98.4, and 89.7%, respectively. Mixed treatment of IMRT with CIRT boost was well tolerated. Severe acute toxicities induced by radiation therapy were observed in only two patients (dermatitis). No severe radiation-induced late toxicity was observed at the time of analysis. Univariable analysis showed N2/3 disease was correlated with an inferior distant control (p = 0.040).ConclusionMixed treatment of IMRT plus CIRT boost provides an excellent disease control and a favorable toxicity profile for patients with non-metastatic NPC. Further follow-up is necessary to evaluate the long-term survivals and toxicities more accurately.

Acute and Late Toxicities of Patients Infected with SARS-CoV-2 and Treated for Cancer with Radiation Therapy During the COVID-19 Pandemic

Purpose This study aimed to assess the risk of acute and late radiation-induced toxicity in patients with COVID-19. Material and methods All the patients irradiated in Institut Curie from March to July 2020 were included if the first symptoms related to COVID-19 occurred no more than two months before the start of radiation therapy (RT) or 15 days after the end of RT. Results Twenty-nine patients were included in this analysis. Twenty-five patients had no co-morbidities (86.2%), including morbid obesity. The diagnosis of COVID-19 infection was based on a positive SARS-CoV-2 RNA test for 18 patients (62.1%), a positive serology test for three patients (10.3%), and/or radiologic findings for 12 patients (41.4%). Three patients with symptoms highly suggestive of COVID-19 were included, although they had negative biologic tests and did not have a chest CT scan. Median time from the diagnosis of COVID-19 to the onset of RT was 5.5 days. Modification of RT course due to COVID-19 status was observed in 15 patients, including four for whom RT was definitively stopped. Six patients needed hospitalization for hypoxemic lung disease requiring intensive care. The majority of patients did not experience severe (> grade 2) acute toxicity. After a median follow-up of 6 months (IQR, 1 – 9 months), none of the patients had unusual clinical or radiological late toxicities. Conclusion The observed acute and late toxicities were ultimately similar to those observed in a population not infected with COVID-19. These results do not prompt modification of standard RT protocols for irradiation of COVID-19 patients.

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

COMPARISON OF THE EFFECTIVENESS OF PROTON AND PHOTON THERAPY IN PATIENTS WITH BRAIN TUMORS

Owing to the development of molecular genetics, the role of radiation therapy and chemotherapy in treatment of patients with glioma (WHO Grade I–IV) has become more understandable. The overall survival among glioma patients has increased. As overall survival increases, oncologists are more likely to detect manifestations of late radiation toxicity that has a huge impact on Quality of Life in patients who have undergone radiation therapy in the past. In this regard, the question of finding more adequate radiation therapy techniques remains relevant. photon radiation therapy is the standard method; however, considering dosimetric advantages of proton therapy over photon therapy, its widespread use can potentially lead to the increased overall survival, decreased number of late radiation-induced complications and improved quality of life in the post-radiation period. This article presents some comparative characteristics of proton and photon radiation therapy in patients with gliomas (WHO Grade I–IV). dosimetry characteristics of protons in tissues were compared, data showing differences in survival of patients treated with photons versus patients treated with protons were presented, and general information on early and late radiation-induced toxicity arising from the treatment by these methods was disclosed.

Vocal-cord Only vs. Complete Laryngeal radiation (VOCAL): a randomized multicentric Bayesian phase II trial

BackgroundRadiotherapy, along with laser surgery, is considered a standard treatment option for patients with early glottic squamous cell cancer (SCC). Historically, patients have received complete larynx radiotherapy (CL-RT) due to fear of swallowing and respiratory laryngeal motion and this remains the standard approach in many academic institutions. Local control (LC) rates with CL-RT have been excellent, however this treatment can carry significant toxicities include adverse voice and swallowing outcomes, along with increased long-term risk of cerebrovascular morbidity. A recent retrospective study reported improved voice quality and similar local control outcomes with focused vocal cord radiotherapy (VC-RT) compared to CL-RT. There is currently no prospective evidence on the safety of VC-RT. The primary objective of this Bayesian Phase II trial is to compare the LC of VC-RT to that of CL-RT in patients with T1N0 glottic SCC.MethodsOne hundred and fifty-five patients with T1a-b N0 SCC of the true vocal cords that are n ot candidate or declined laser surgery, will be randomized in a 1:3 ratio the control arm (CL-RT) and the experimental arm (VC-RT). Randomisation will be stratified by tumor stage (T1a/T1b) and by site (each site will be allowed to select one preferred radiation dose regimen, to be used in both arms). CL-RT volumes will correspond to the conventional RT volumes, with the planning target volume extending from the top of thyroid cartilage lamina superiorly to the bottom of the cricoid inferiorly. VC-RT volumes will include the involved vocal cord(s) and a margin accounting for respiration and set-up uncertainty. The primary endpoint will be LC at 2-years, while secondary endpoints will include patient-reported outcomes (voice impairment, dysphagia and symptom burden), acute and late toxicity radiation-induced toxicity, overall survival, progression free survival, as well as an optional component of acoustic and objective measures of voice analysis using the Consensus Auditory-Perceptual Evaluation of Voice.DiscussionThis study would constitute the first prospective evidence on the efficacy and safety of VC-RT in early glottic cancer. If positive, this study would result in the adoption of VC-RT as standard approach in early glottic cancer.Trial registrationClinicalTrials.gov Identifier: NCT03759431Registration date: November 30, 2018

Long-term clinical outcomes of external beam radiation therapy for oligometastatic prostate cancer: A combination of prostate-targeted treatment and metastasis-directed therapy.

To assess the efficacy of combination of prostate-targeted treatment and metastasis-directed therapy for oligometastatic prostate cancer. We retrospectively evaluated the clinical outcomes of synchronously diagnosed oligometastatic prostate cancer patients treated with external beam radiation therapy for the prostate and all metastatic lesions (≤3 lesions) at Kyoto University Hospital between January 2004 and April 2019. The prescribed dose was basically ≥70Gy for the prostate with or without whole pelvic irradiation, and ≥45Gy for the metastatic lesions. Clinical outcomes were compared with a contemporary cohort of 55 synchronous oligometastatic prostate cancer patients treated with the standard of care. In total, 16 consecutive patients with synchronous oligometastatic prostate cancer were analyzed. The median follow-up period was 7.4years. The 8-year overall survival, prostate cancer-specific survival, biochemical failure-free, clinical failure-free and castration-resistant prostate cancer-free rates were 64.8%, 71.3%, 38.5%, 47.3% and 67.3%, respectively. No grade3 or higher radiation-induced late toxicities occurred. Patients with prostate-targeted treatment plus metastasis-directed therapy had a significantly higher castration-resistant prostate cancer-free rate than those without prostate-targeted treatment plus metastasis-directed therapy (P=0.00741). Prostate-targeted treatment plus metastasis-directed therapy through external beam radiation therapy can result in favorable long-term disease-free and survival outcomes with acceptable morbidities among synchronous oligometastatic prostate cancer patients. Therefore, this approach may represent a promising treatment strategy for this population. Further investigation is required.

Impact of range uncertainty on clinical distributions of linear energy transfer and biological effectiveness in proton therapy.

Increased radiation response after proton irradiation, such as late radiation-induced toxicity, is determined by high dose and elevated linear energy transfer (LET). Steep dose-averaged LET (LETd ) gradients and elevated LETd occur at the end of proton range and might be particularly sensitive to uncertainties in range prediction. Therefore, this study quantified LETd distributions and the impact of range uncertainty in robust dose-optimized proton treatment plans and assessed the biological effect in normal tissues and tumors of patients. For each of six cancer patients (two brain, head-and-neck, and prostate), two nominal treatment plans were robustly dose optimized using single- and multi-field optimization, respectively. For each plan, two additional scenarios with ±3.5% range deviation relative to the nominal plan were derived by global rescaling of stopping-power ratios. Dose and LETd distributions were calculated for each scenario using the beam parameters of the corresponding nominal plan. The variability in relative biological effectiveness (RBE) and probability of late radiation-induced brain toxicity (PIC ) was assessed. The optimization technique (single- vs multi-field) had a negligible impact on the LETd distributions in the clinical target volume (CTV) and in most organs at risk (OARs). LETd distributions in the CTV were rather homogeneous with arithmetic mean of LETd below3.2keV/µm and robust against range deviations. The RBE variability within the CTV induced by range uncertainty was small (≤0.05, 95% confidence interval). In OARs, LETd hotspots (>7keV/µm) occurred and LETd distributions were inhomogeneous and sensitive to range deviations. LETd hotspots and the impact of range deviations were most prominent in OARs of brain tumor patients which translated in RBE values exceeding 1.1 in all brain OARs. The near-maximum predicted PIC in healthy brain tissue of brain tumor patients was smaller than 5% and occurred adjacent to the CTV. Range deviations induced absolute differences in PIC up to 1.2%. Robust dose optimization generates LETd distributions in the target volume robust against range deviations. The current findings support using a constant RBE within the CTV. The impact of range deviations on the considered probability of late radiation-induced toxicity in brain tissue was limited for robust dose-optimized treatment plans. Incorporation of LETd in robust optimization frameworks may further reduce uncertainty related to the RBE-weighted dose estimation in normal tissues.

Radiotherapy Remains Underutilized in the Treatment of Soft-Tissue Sarcomas: Disparities in Practice Patterns in the United States

Practice patterns in the use of radiation therapy (RT) for soft tissue sarcoma (STS) remains quite variable, despite national guidelines recommending the addition of radiotherapy to surgery for patients with high grade STS. Furthermore, treatment with neoadjuvant RT can reduce many late RT toxicities. Likewise, the use of intensity modulated radiation therapy (IMRT) can reduce both early and late radiation-induced toxicities. Using the National Cancer Database (NCDB), we assessed patterns of care in regards to variations in overall radiotherapy use, preoperative versus postoperative treatment, and specific RT modalities in this population. Patients aged 18 years or older with stage II/III STS treated with limb-sparing surgery and radiation therapy from 2004 through 2015 were identified from the NCDB. Patterns of care were assessed using multivariable logistic regression analysis. Of 27,426 total patients, 11,654 (42%) were treated with surgery alone versus 15,772 (58%) with RT in addition to surgery, with no overall increase in RT use noted over the study period. Notable predictors of receipt of RT include larger tumor size (>5 cm), Grade III tumors, and tumors located in the extremity. Conversely, female gender, older age (≥ 70), African American race, insurance status, farther distance to treatment, and poor performance status were negative predictors of perioperative radiotherapy use. Of those receiving RT, 27% were treated neoadjuvantly and 73% were treated adjuvantly. The proportion of those receiving neoadjuvant vs. adjuvant RT increased over time. Relevant factors associated with neoadjuvant radiation include treatment at academic centers, larger tumors, and tumors located in the extremity. In addition, of those who received RT with modality specified as IMRT or 3D conformal RT (3DCRT), 61% were treated with IMRT and 39% were treated with 3DCRT. The proportion of those treated with IMRT increased with time. Relevant factors associated with IMRT use include treatment at academic centers, commercial insurance, larger tumors, and tumors arising in non-extremity locations (head and neck, thorax, and abdomen/pelvis). In this observational cohort study using the NCDB, we noted that a significant number of patients are not receiving guideline-concordant care. Our findings also note potential sociodemographic disparities that may be contributing to variations in practice patterns and highlight the concern that not all patients may be equally benefiting from available therapies for STS.

A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect

Background and purposeFLASH radiotherapy, a technique based on delivering large doses in a single fraction at the micro/millisecond timescale, spares normal tissues from late radiation-induced toxicity, in an oxygen-dependent process, whilst keeping full anti-tumor efficiency. We present a theoretical model taking into account the kinetics of formation and decay of reactive oxygen species, in particular of organic peroxyl radicals ROO. formed by addition of O2 to primary carbon-centred radicals R. and known to play a major role at the origin radio-induced complications. Materials and methodsThe model focuses on the time-dependent evolution of radiolytic products in living matter exposed to continuous irradiation at dose-rates in the range 10-3-107Gy·s-1. The 9 differential rate equations resulting from the radiolytic and enzymatic reactions network were solved using the published values of these reactions rate constants in a cellular environment. ResultsThe model suggests a correlation between the area-under-the-curve of time-evolving [ROO.] and the probability of normal tissue complications. The model does not lend weight to the hypothesis of transient oxygen depletion as a main determinant of FLASH but rather suggests a major role of radical–radical recombination. ConclusionThe model gives support to the reduction of ROO. lifetime as the main root of FLASH and compares favorably with published experimental results. We conclude that any process - in this case radical recombination - that shortens the lifetime or limits the radiolytic yield of ROO. is likely to protect normoxic tissues against the deleterious effects of radiation.

FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence.

One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity. Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc-/- mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro. In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc-/- mice harboring critically short telomeres and lack of telomerase activity. The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.

P1355 Short-term cardiac side-effects from radiotherapy in women with breast cancer

Abstract Introduction Breast cancer radiotherapy provides an apparent benefit for long-term survival and local recurrence rate. However, there is still much concern about the early and late radiation-induced cardiac toxicity. Therefore, various radiotherapy techniques have been developed to reduce the cardiopulmonary radiation doses in patients with left-sided breast cancer, who are at particular risk of developing post-radiation cardiac injury. Aim We sought to investigate the early effect of radiotherapy on left (LV) and right ventricular (RV) function in females subjected to this treatment. Methods Fifty left-sided breast cancer patients , who underwent adjuvant radiotherapy between May 2017 and May 2018 were included in the study. Forty-nine enrollees were initially treated with breast conserving surgery, and 1 - with mastectomy and axillary lymph node resection. Adjuvant radiotherapy was carefully planned to minimize the radiation side effects and 37 patient received radiotherapy with deep inspiration breath hold technique and 13 patients with free breathing technique. In most cases (n = 33), 3D conformal tangential field radiation therapy was applied, 13 patients received radiotherapy with dynamic-Rapid-Arc technique with additional 3D fields, and 4 patients underwent radiotherapy only with Rapid-Arc technique. Before surgery and 3 months after radiotherapy, echocardiography with measurement of conventional cardiac function parameters, as well as LV and RV longitudinal deformation analysis by speckle tracking technique was performed, and venous blood for biomarkers - galectin-3 reflecting myocardial fibrosis and NT-proBNP was sampled. Results At a mean follow-up of 97 ± 19 days , there were no significant changes in any of the studied cardiac systolic or diastolic function parameters (Table). There were no relationships between the change in LV longitudinal strain at follow-up and type of radiotherapy, as well as type of radiotherapy gating (both R = 0.02, p = 0.90). Similarly, no analogous associations were demonstrated for RV longitudinal strain (R = 0.02, p = 0.88, and R = 0.04, p = 0.77, respectively). No significant changes were found post radiotherapy in serum galectin-3 (7.2 ± 2.6 ng/ml vs. 6.8 ± 2.5 ng/ml; p = 0.58) and NT-proBNP (83 ± 68 pg/ml vs. 84 ± 54 pg/ml; p = 0.90). Conclusions Breast cancer radiotherapy with the use of contemporary planning techniques shows an excellent early cardiac safety. Abstract P1355 Figure.

Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy.

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.

Mapping of sentinel lymph node drainage using SPECT/CT to tailor elective nodal irradiation in head and neck cancer patients (SUSPECT-2): a single-center prospective trial

BackgroundThe majority of patients with head and neck squamous cell carcinoma (HNSCC) receive bilateral elective nodal irradiation (ENI), in order to reduce the risk of regional failure. Bilateral ENI, as compared to unilateral ENI, is associated with higher incidence of acute and late radiation-induced toxicity with subsequent deterioration of quality of life. Increasing evidence that the incidence of contralateral regional failure (cRF) in lateralized HNSCC is very low (< 10%) suggests that it can be justified to treat selected patients unilaterally. This trial aims to minimize the proportion of patients that undergo bilateral ENI, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.MethodsIn this one-armed, single-center prospective trial, patients with primary T1-4 N0-2b HNSCC of the oral cavity, oropharynx, larynx (except T1 glottic) or hypopharynx, not extending beyond the midline and planned for primary (chemo) radiotherapy, are eligible. After 99mTc-nanocolloid tracer injection in and around the tumor, lymphatic drainage is visualized using SPECT/CT. In case of contralateral lymph drainage, a contralateral sentinel node procedure is performed on the same day. Patients without contralateral lymph drainage, and patients with contralateral drainage but without pathologic involvement of any removed contralateral sentinel nodes, receive unilateral ENI. Only when tumor cells are found in a contralateral sentinel node the patient will be treated with bilateral ENI. The primary endpoint is cumulative incidence of cRF at 1 and 2 years after treatment. Secondary endpoints are radiation-related toxicity and quality of life. The removed lymph nodes will be studied to determine the prevalence of occult metastatic disease in contralateral sentinel nodes.DiscussionThis single-center prospective trial aims to reduce the incidence and duration of radiation-related toxicities and improve quality of life of HNSCC patients, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation.Trial registrationClinicalTrials.gov Identifier: NCT03968679, date of registration: May 30, 2019.

A phase II study of concurrent nab-paclitaxel/carboplatin combined with thoracic radiotherapy in locally advanced squamous cell lung cancer.

The development of chemoradiotherapy is urgently needed for locally advanced squamous cell lung cancer due to its poor prognosis and significant toxicity. Carboplatin combined with nab-paclitaxel is a useful choice as first-line therapy in advanced squamous cell lung cancer. This prospective phase II study aimed to explore the efficacy and toxicity of concurrent chemoradiotherapy with nab-paclitaxel, carboplatin, and thoracic radiotherapy in unresectable locally advanced squamous cell lung cancer. Patients with unresectable stage III squamous cell lung cancer were eligible. All patients received nab-paclitaxel weekly at a dose of 60 mg/m2, in combination with carboplatin [area under the plasma concentration time curve (AUC) 2] weekly during concurrent chemoradiotherapy. Thoracic radiation was administered at a dose of 66 Gy/33 fractions. The consolidation chemotherapy consisted of nab-paclitaxel (260 mg/m2 on day 1) and carboplatin (AUC 6 on day 1) every 21 days was administered in two cycles after the concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Initially, enrollment of 21 patients was planned; however, the trial was prematurely closed due to slow recruitment. Finally, a total of 8 patients were enrolled between January 2012 and July 2015 from one institute. All patients completed concurrent chemoradiotherapy, and 6 patients (75.0%) received consolidation chemoradiotherapy. The ORR was 75%, with complete response (CR) 1 (12.5%), partial remission 6 (62.5%), stable disease 1 (12.5%), progressive disease 1 (12.5%), respectively. After a median follow-up of 15.2 (range, 2.3-51.5) months, 7 patients were dead, and 1 was alive. The median PFS and OS were 12.1 and 15.2 months, respectively. According to Common Terminology Criteria for Adverse Events version 4.0, 6 patients (75.0%) experienced acute radiation esophagitis, 4 (50.0%) were grade 2 (G2), and 2 (25.0%) were G3; 4 patients (50%) experienced acute radiation pneumonitis, 3 (37.5%) were G2, and 1 (12.5%) was G3. No late radiation-induced esophageal and pulmonary toxicity was observed after 1-year follow-up. Concurrent nab-paclitaxel, carboplatin, and thoracic radiotherapy was shown to be an effective regimen for patients with unresectable locally advanced squamous cell lung cancer; however, further study should exercise caution due to the severe radiation esophagitis.

Quantitative proteomic analysis reveals AK2 as potential biomarker for late normal tissue radiotoxicity

BackgroundBiomarkers for predicting late normal tissue toxicity to radiotherapy are necessary to personalize treatments and to optimize clinical benefit. Many radiogenomic studies have been published on this topic. Conversely, proteomics approaches are not much developed, despite their advantages.MethodsWe used the isobaric tags for relative and absolute quantitation (iTRAQ) proteomic approach to analyze differences in protein expression levels in ex-vivo irradiated (8 Gy) T lymphocytes from patients with grade ≥ 2 radiation-induced breast fibrosis (grade ≥ 2 bf+) and patients with grade < 2 bf + after curative intent radiotherapy. Patients were selected from two prospective clinical trials (COHORT and PHRC 2005) and were used as discovery and confirmation cohorts.ResultsAmong the 1979 quantified proteins, 23 fulfilled our stringent biological criteria. Immunoblotting analysis of four of these candidate proteins (adenylate kinase 2, AK2; annexin A1; heat shock cognate 71 kDa protein; and isocitrate dehydrogenase 2) confirmed AK2 overexpression in 8 Gy-irradiated T lymphocytes from patients with grade ≥ 2 bf + compared with patients with grade < 2 bf+. As these candidate proteins are involved in oxidative stress regulation, we also evaluated radiation-induced reactive oxygen species (ROS) production in peripheral blood mononuclear cells from patients with grade ≥ 2 bf + and grade < 2 bf+. Total ROS level, and especially superoxide anion level, increased upon ex-vivo 8 Gy-irradiation in all patients. Analysis of NADPH oxidases (NOXs), a major source of superoxide ion in the cell, showed a significant increase of NOX4 mRNA and protein levels after irradiation in both patient groups. Conversely, only NOX4 mRNA level was significantly different between groups (grade ≥ 2 bf + and grade < 2 bf+).ConclusionThese findings identify AK2 as a potential radiosensitivity candidate biomarker. Overall, our proteomic approach highlights the important role of oxidative stress in late radiation-induced toxicity, and paves the way for additional studies on NOXs and superoxide ion metabolism.

Micro cone beam computed tomography for sensitive assessment of radiation-induced late lung toxicity in preclinical models

Background and purposePreclinical models are much needed to assess the effect of novel radio-sensitizers or mitigators on radiation dose limiting lung toxicity. Albeit showing radiation-induced lung pathologies, current mouse models lack the sensitivity to do so. Using micro image-guided radiotherapy (µIGRT) techniques, we aimed to establish murine models which enable the sensitive detection of lung damage aggravation and characterized functional, radiological and histological responses. Materials and methodsRight lungs of C57Bl/6J mice were irradiated using µIGRT with doses from 15 to 27 Gy and with 21 Gy and cisplatin as a radio-sensitizer in a second study. Mice were sacrificed for histological and pathological assessment at different time-points post-IR. Lung density was determined using the integrated micro cone-beam CT (µCBCT). Lung function was measured by double-chamber-plethysmography. ResultsµIGRT resulted in accurate deposition of the radiation dose in the right lung only as determined by ɣH2AX staining. Lung fibrosis was confirmed by pathological assessments and increased significantly at 21 Gy as determined by automated quantification of histochemical analyses. Lung function was affected in a dose-dependent manner. µCBCT-determined lung densities increased significantly over time in the irradiated lungs and showed a strong radiation dose-dependence. Importantly, the µCBCT analyses allowed the detection of additional lung damage caused by 3 Gy dose increments or by the combination with cisplatin. ConclusionµCBCT after right lung µIGRT enables the sensitive detection of effects inflicted by relative small dose increments or radio-sensitizers. Our preclinical model therefore facilitates the determination of lung damage exacerbation for the safety assessment of novel RT-drug combinations.

Hypofractionated radiotherapy in nine dogs with unresectable solitary lung adenocarcinoma.

Although lung lobectomy is the most common treatment option for dogs with solitary lung tumors, surgery often cannot be performed at the time of diagnosis. In this retrospective, case series study, we described the effects of hypofractionated radiotherapy for tumor mass reduction in nine dogs with solitary lung adenocarcinoma that were later considered for surgical resection, and we assessed the tolerability of the radiation protocol. Tumors were deemed unresectable by the attending veterinarian. The dose prescription was 7.0-12.0Gy/fraction in four to seven fractions, administered weekly for a total dose of 40-50Gy. Treatment planning prioritized normal tissue dose constraints. The median interval between the last radiotherapy session and maximum tumor size reduction was 56 (range: 26-196) days, with six and three dogs exhibiting a partial response and stable disease, respectively. Although acute and late radiation-induced toxicity to the skin and/or lungs developed in all nine dogs, it was self-limiting or improved with short-term anti-inflammatory treatment. Tumor progression after initial size reduction was confirmed in three dogs at 62, 126, and 175 days, respectively, after the last radiotherapy session. Seven of the nine dogs underwent lobectomy a median of 68 days after radiotherapy when tumors were in partial response or stable disease or at the time of progression, and five received systemic chemotherapy concurrent with or after radiotherapy. These findings suggest that hypofractionated radiotherapy for canine solitary lung adenocarcinoma is useful when the tumor is large or when surgery cannot be performed immediately after diagnosis.