Early circulating tumor DNA changes predict outcomes in head and neck cancer patients under re-radiotherapy.

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re-irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re-radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow-up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV-based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA-positive samples were identified by tracking patient-specific CNVs found in earlier sequential plasma samples. ctDNA-positivity after 5 and 10 radiation fractions (both: log-rank, p = .050) as well as at the end of irradiation correlated with short progression-free survival (log-rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re-radiotherapy termination was associated with worse treatment outcome (log-rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re-radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re-radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow-up intervals, and dose prescription.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT-SNT Prospective Phase 2 Trial.

PURPOSE: Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. METHODS AND MATERIALS: Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. RESULTS: Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. CONCLUSIONS: To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

[Radiation therapy of malignant salivary gland tumors]. / Strahlentherapie von malignen Speicheldrüsentumoren.

Due to their rarity, histologic heterogeneity, and localization, treatment of malignant salivary gland tumors requires an interdisciplinary approach. First-line treatment includes complete tumor resection. Postoperative radiation therapy is advised in patients with risk factors, i.e., incomplete tumor resection, high-grade tumors, or perineural invasion. Definitive radiation therapy is only advised for inoperable tumors because of significantly lower local control and survival rates when compared to combined surgery and radiation therapy. In radiation oncology, modern techniques such as intensity-modulated radiation therapy (IMRT) or particle therapy with heavy ions (i.e., C12) have led to improved outcomes in the treatment of head and neck tumors, especially of adenoid cystic carcinomas. Given the biological and physical benefits of particles, particle therapy, particularly carbon ion radiation, is a promising therapeutic approach for salivary gland tumors that will be further investigated in prospective clinical studies.

Intensity modulated proton therapy for early-stage glottic cancer: high-precision approach to laryngeal function preservation with exceptional treatment tolerability.

BACKGROUND: Due to the increasing expertise in transoral laser surgery and image-guided radiation therapy, treatment outcomes have recently improved in patients with early-stage glottic cancer. The objective of the current study was to evaluate intensity-modulated proton therapy (IMPT) as novel treatment option. METHODS: A total of 15 patients with T1-2N0 glottic squamous cell carcinoma, treated between 2017 and 2020, were evaluated. Toxicity was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. RESULTS: The majority were T1a/b tumors (66.7%) and no patient had lymph node or distant metastases. The median total dose was 70 Gy relative biological effectiveness (RBE) (range 66-70 Gy RBE). The one- and two-year OS and metastases-free survival were 100%. One patient developed local failure and received salvage laryngectomy. No higher-grade acute or late toxicity was reported. The mean number of CTCAE grade I and II overall toxicity events per patient was 4.1 (95%-[confidence interval] CI 3.1-5.3) and 1.0 (95%-CI 0.5-1.5). CONCLUSION: High-precision proton therapy of T1-2N0 glottic cancer resulted in exceptional treatment tolerability with high rates of laryngeal function preservation and promising oncological outcome. IMPT has the potential to become a standard treatment option for patients with early-stage laryngeal cancer.

Ways to unravel the clinical potential of carbon ions for head and neck cancer reirradiation: dosimetric comparison and local failure pattern analysis as part of the prospective randomized CARE trial.

BACKGROUND: Carbon ion radiotherapy (CIRT) yields biophysical advantages compared to photons but randomized studies for the reirradiation setting are pending. The aim of the current project was to evaluate potential clinical benefits and drawbacks of CIRT compared to volumetric modulated arc therapy (VMAT) in recurrent head and neck cancer. METHODS: Dose-volume parameters and local failure patterns of CIRT compared to VMAT were evaluate in 16 patients from the randomized CARE trial on head and neck cancer reirradiation. RESULTS: Despite an increased target dose, CIRT resulted in significantly reduced organ at risk (OAR) dose across all patients (- 8.7% Dmean). The dose-volume benefits were most pronounced in the brainstem (- 20.7% Dmax) and the optic chiasma (- 13.0% Dmax). The most frequent local failure was type E (extraneous; 50%), followed type B (peripheral; 33%) and type A (central; 17%). In one patient with type A biological and/or dosimetric failure after CIRT, mMKM dose recalculation revealed reduced target coverage. CONCLUSIONS: CIRT resulted in highly improved critical OAR sparing compared to VMAT across all head and neck cancer reirradiation scenarios despite an increased prescription dose. Local failure pattern analysis revealed further potential CIRT specific clinical benefits and potential pitfalls with regard to image-guidance and biological dose-optimization.

Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation.

Advanced radiation techniques can reduce the severity of neurocognitive sequelae in young brain tumor patients. In the present analysis, we sought to compare neurocognitive outcomes after proton irradiation with patients who underwent photon radiotherapy (RT) and surgery. Neurocognitive outcomes were evaluated in 103 pediatric brain tumor patients (proton RT n = 26, photon RT n = 30, surgery n = 47) before and after treatment. Comparison of neurocognitive outcomes following different treatment modalities were analyzed over four years after treatment completion. Longitudinal analyses included 42 months of follow-up after proton RT and 55 months after photon RT and surgery. Neurocognitive assessment included standardized tests examining seven domains. A comparison of neurocognitive outcomes after RT (proton and photon with >90% additional surgery) and surgery showed no significant differences in any neurocognitive domain. Neurocognitive functioning tests after proton RT failed to identify alterations compared to baseline testing. Long-term follow up over four years after photon RT showed a decrease in non-verbal intelligence (-9.6%; p = 0.01) and visuospatial construction (-14.9%; p = 0.02). After surgery, there was a decline in non-verbal intelligence (-10.7%; p = 0.01) and processing speed (14.9%; p = 0.002). Differences in neurocognitive outcomes between RT and surgical cohorts in direct intermodal comparison at long-term follow-up were not identified in our study, suggesting that modern radiation therapy does not affect cognition as much as in the past. There were no alterations in long-term neurocognitive abilities after proton RT, whereas decline of processing speed, non-verbal intelligence, and visuospatial abilities were observed after both photon RT and surgery. Domains dependent on intact white matter structures appear particularly vulnerable to brain tumor treatment irrespective of treatment approach.

Safety and Efficacy of Stereotactic Body Radiotherapy in Ultracentral Lung Tumors Using a Risk-optimized Fractionation Scheme.

BACKGROUND: Delivery of stereotactic body radiotherapy (SBRT) to ultracentral lung tumors remains a major challenge, with potentially excessive SBRT-related toxicity. This study investigates a risk-optimized approach to ultracentral SBRT in an elderly and comorbid patient cohort. PATIENTS AND METHODS: Analysis encompassed 129 patients (mean age: 70 ± 11 years, median Charlson comorbidity index: 4 [range, 3-5]) following risk-adapted SBRT to central or ultracentral primary and secondary lung tumors between 2012 and 2019 (78 central, 51 ultracentral). Ultracentral tumors were defined by planning target volume overlap with the proximal bronchial tree. Whereas ultracentral tumors were treated with a risk-optimized fractionation scheme of 50 Gy in 10 fractions, central tumors received higher-fractionated 60 Gy in 8 fractions. Outcome parameters and toxicity for ultracentral and central tumors were assessed using Kaplan-Meier and competing risk analyses. RESULTS: Local failure rate was not significantly increased in ultracentral tumors compared with central tumors (2-year local failure rate ultracentral, 26.9%; 95% confidence interval [CI], 12.2%-44.2%; central, 14.6%; 95% CI, 6.6%-25.5%; P = .17). Overall survival was similar in both groups (2-year overall survival central, 55.4%; 95% CI, 44.5%-68.9%; ultracentral, 54.9%; 95% CI, 40.8%-73.9%; P = .6). Toxicity was moderate, with toxicity ≥ grade 3 rates of 15.3% (95% CI, 5.9%-28.9%) for ultracentral and 7.3% (95% CI, 2.7%-15.0%) for central tumors after 2 years (P = .27). No grade 4 toxicity and only 1 potential grade 5 toxicity were observed in the ultracentral cohort. CONCLUSION: Risk-optimized SBRT to ultracentral lung tumors is a reasonably effective and safe treatment alternative in frail patients.

Carbon ion reirradiation compared to intensity-modulated re-radiotherapy for recurrent head and neck cancer (CARE): a randomized controlled trial.

BACKGROUND: Intensity-modulated re-radiotherapy (reIMRT) has been established as a standard local treatment option in patients with non-resectable, recurrent head and neck cancer (rHNC). However, the clinical outcome is unfavorable and severe toxicities (≥grade III) occurred in 30-40% of patients. The primary aim of the current trial is to investigate carbon ion reirradiation (reCIRT) compared to reIMRT in patients with rHNC regarding safety/toxicity as well as local control, overall survival (OS), and quality of life (QoL). METHODS: The present trial will be performed as a single center, two-armed, prospective phase II study. A maximum of 72 patients will be treated with either reIMRT or reCIRT to evaluate severe (≥grade III) treatment-related toxicities (randomization ratio 1:1). The primary target value is to generate less than 35% acute/subacute severe toxicity (≥grade III), according to the Common Terminology Criteria for Adverse Events v5.0, within 6 months after study treatment. The total dose of reirradiation will range between 51 and 60 Gy or Gy (RBE), depending primarily on the radiotherapy interval and the cumulative dose to organs at risk. Individual dose prescription will be at the discretion of the treating radiation oncologist. The local and distant progression-free survival 12 months after reirradiation, the OS, and the QoL are the secondary endpoints of the trial. Explorative trial objectives are the longitudinal investigation of clinical patient-related parameters, tumor parameters on radiological imaging, and blood-based tumor analytics. DISCUSSION: Recent retrospective studies suggested that reCIRT could represent a feasible and effective treatment modality for rHNC. This current randomized prospective trial is the first to investigate the toxicity and clinical outcome of reCIRT compared to reIMRT in patients with rHNC. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04185974 ; December 4th 2019.