Dosimetric Parameters After VMAT Adaptive Radiotherapy in Patients With Locally Advanced NSCLC Undergoing 4DCT.

BACKGROUND/AIM: To investigate dosimetric differences in organs at risk (OARs) and cardiac substructures in patients with locally advanced non-small cell lung cancer (NSCLC) between the adaptive radiotherapy (ART) and non-ART groups. PATIENTS AND METHODS: Thirty patients were treated with definitive radiotherapy +/- chemotherapy. Cardiac substructures including the left anterior descending coronary artery (LAD) and large vessels, were contoured. Eight patients experienced tumor shrinkage and were replanned (ART). Cumulative plans after ART were compared to the original plans (not considering volume reduction) in terms of dosimetric parameters. The cumulative plans of the ART group (n=8) and non-ART group (n=22) were compared in terms of the same dosimetric parameters. RESULTS: Within the ART group, the following parameters were found to be significantly improved after re-planning: mean lung dose (MLD) (13.79 Gy vs. 15.6 Gy), V20Gy both lungs (17.88% vs. 27.38%), ipsilateral MLD (20.87 Gy vs. 24.44 Gy), and esophagus mean dose (20.79 Gy vs. 24.2 Gy). No dosimetric differences were observed in heart substructures. Dosimetric parameters, particularly LAD, were significantly worse in the ART group than in the non-ART group. This is probably because this OAR was not considered in the plan optimization after re-planning, because it was not routinely contoured as an OAR. CONCLUSION: Our analysis showed an improvement in dosimetric parameters in the lungs and esophagus in the ART group. This approach may lead to a possible reduction in toxicity. Contouring of cardiac substructures could lead to a plan optimization of their parameters and eventually reduce the risk of cardiac toxicities in these patients.

Identification of patient benefit from proton beam therapy in brain tumour patients based on dosimetric and NTCP analyses.

BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as the model-based approach. In this study, we assessed the dosimetric benefit of PBT compared to photon therapy (XRT), analysed the corresponding changes in normal tissue complication probability (NTCP) on a variety of available models, and illustrated model-based patient selection in an in-silico study for patients with brain tumours. METHODS: For 92 patients treated at two PBT centres, volumetric modulated arc therapy treatment plans were retrospectively created for comparison with the clinically applied PBT plans. Several dosimetric parameters for the brain excluding tumour and margins, cerebellum, brain stem, frontal and temporal lobes, hippocampi, cochleae, chiasm, optic nerves, lacrimal glands, lenses, pituitary gland, and skin were compared between both modalities using Wilcoxon signed-rank tests. NTCP differences (ΔNTCP) were calculated for 11 models predicting brain necrosis, delayed recall, temporal lobe injury, hearing loss, tinnitus, blindness, ocular toxicity, cataract, endocrine dysfunction, alopecia, and erythema. A patient was assumed to be selected for PBT if ΔNTCP exceeded a threshold of 10 percentage points for at least one of the side-effects. RESULTS: PBT substantially reduced the dose in almost all investigated OARs, especially in the low and intermediate dose ranges and for contralateral organs. In general, NTCP predictions were significantly lower for PBT compared to XRT, in particular in ipsilateral organs. Considering ΔNTCP of all models, 80 patients (87.0%) would have been selected for PBT in this in-silico study, mainly due to predictions of a model on delayed recall (51 patients). CONCLUSION: In this study, substantial dose reductions for PBT were observed, mainly in contralateral organs. However, due to the sigmoidal dose response, NTCP was particularly reduced in ipsilateral organs. This underlines that physical dose-volume parameters alone may not be sufficient to describe the clinical relevance between different treatment techniques and highlights potential benefits of NTCP models. Further NTCP models for different modern treatment techniques are mandatory and existing models have to be externally validated in order to implement the model-based approach in clinical practice for cranial radiotherapy.

Modelling of late side-effects following cranial proton beam therapy.

BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients' quality of life. METHODS: Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed. RESULTS: In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose-response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland. CONCLUSION: We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.

Combinatorial Effect of Magnetic Field and Radiotherapy in PDAC Organoids: A Pilot Study.

Pancreatic ductal adenocarcinoma (PDAC) is highly refractory to systemic treatment, including radiotherapy (RT) either as alone or in combination with chemotherapy. Magnetic resonance (MR)-guided RT is a novel treatment technique which conjugates the high MR imaging contrast resolution to the possibility of re-adapting treatment plan to daily anatomical variations. Magnetic field (MF) might exert a biological effect that could be exploited to enhance radiation effect. The aim of the present study was to lay the preclinical basis of the MF effect by exploring how it modifies the response to radiation in organoid cultures established from PDAC. The short-term effect of radiation, alone or in combination with MF, was evaluated in patient-derived organoids (PDOs) and monolayer cell cultures. Cell viability, apoptotic cell death, and organoid size following exposure to the treatment were evaluated. PDOs demonstrated limited sensitivity at clinically relevant doses of radiation. The combination of radiation and MF demonstrated superior efficacy than monotherapy in almost all the PDOs tested. PDOs treated with combination of radiation and MF were significantly smaller in size and some showed increased cell death as compared to the monotherapy with radiation. Long-time exposure to 1.5T MF can increase the therapeutic efficacy of radiation in PDAC organoids.

What is the role of reirradiation in the management of locoregionally relapsed non small-cell lung cancer?

The prognosis of lung cancer patients has improved in the last few years. Despite definitive therapy, local recurrence or a second primary tumour can occur in many patients within previously irradiated areas. Recent developement of more accurate techniques in radiation oncology allows delivery of high radiation dose to the tumor with the aim of improving local control, delaying disease progression and in some cases even curing. Nevertheless, the use of high dose in the reirradiation setting is not without risks, especially when treatment volumes overlap with previously irradiated tissues. The risk of adverse effects must be balanced with the choice of an effective treatment by selecting suitable candidates and the best radiation technique. In this systemic review efficacy and toxicity of reirradiation in locoregionally recurrent non-small-cell lung cancer is extensively discussed. Results indicate that reirradiation might be beneficial in well-selected patients. Prospective and high quality studies are necessary in this field.

Neurocognitive function and quality of life after proton beam therapy for brain tumour patients.

BACKGROUND: Neurocognitive function of adult patients with brain tumours may deteriorate after radiotherapy. Proton beam therapy (PBT) reduces the volume of irradiated healthy brain tissue and could potentially preserve neurocognition and quality of life (QoL). As present data are still limited, the impact of clinical factors and dosimetric parameters on neurocognitive function and QoL during recurrence-free follow-up after PBT is investigated. METHODS: The current study includes 62 brain tumour patients treated with PBT between 2015 and 2017. Neurocognition and QoL were assessed at baseline and every 3 months after PBT using the Montreal Cognitive Assessment (MoCA) test together with EORTC-QLQ-C30 and BN20 questionnaires, respectively. Objective and self-reported measures of neurocognitive functions were correlated. During two years of follow-up, the impact of clinical co-factors as well as dosimetric parameters of several brain structures were analysed using a mixed-model approach. RESULTS: At baseline, mean MoCA total score was 24.8/30 and self-reported cognitive function was 68.9/100. Both remained stable over time. Patients with impaired neurocognition on the MoCA test reported significantly lower global health status, cognitive, physical and role function as well as more fatigue, pain, headache and communication deficits compared to normal performing patients. For most follow-up time points, the majority of MoCA subitems correlated significantly to QoL items regarding neurocognition. Slight deterioration of the MoCA score was associated with tumours located in the left hemisphere and with an increase in relative volume of the anterior cerebellum that received doses of 30-40 Gy(RBE). CONCLUSION: Self-reported and objectively measured neurocognition and most other QoL domains remained largely stable over time during recurrence-free follow-up for brain tumour patients treated with PBT. The association between reduced cognitive function and irradiated volume of the anterior cerebellum requires validation in larger studies and comparison to patients treated with photon therapy.

Quantification of plan robustness against different uncertainty sources for classical and anatomical robust optimized treatment plans in head and neck cancer proton therapy.

OBJECTIVE: Classical robust optimization (cRO) in intensity-modulated proton therapy (IMPT) considers isocenter position and particle range uncertainties; anatomical robust optimization (aRO) aims to consider additional non-rigid positioning variations. This work compares the influence of different uncertainty sources on the robustness of cRO and aRO IMPT plans for head and neck squamous cell carcinoma (HNSCC). METHODS: Two IMPT plans were optimized for 20 HNSCC patients who received weekly control CTs (cCT): cRO, using solely the planning CT, and aRO, including 2 additional cCTs. The robustness of the plans in terms of clinical target volume (CTV) coverage and organ at risk (OAR) sparing was analyzed considering stepwise the influence of (1) non-rigid anatomical variations given by the weekly cCT, (2) with fraction-wise added rigid random setup errors and (3) additional systematic proton range uncertainties. RESULTS: cRO plans presented significantly higher nominal CTV coverage but are outperformed by aRO plans when considering non-rigid anatomical variations only, as cRO and aRO plans presented a median target coverage (D98%) decrease for the low-risk/high-risk CTV of 1.8/1.1 percentage points (pp) and -0.2 pp/-0.3 pp, respectively. Setup and range uncertainties had larger influence on cRO CTV coverage, but led to similar OAR dose changes in both plans. Considering all error sources, 10/2 cRO/aRO patients missed the CTV coverage and a limited number exceeded some OAR constraints in both plans. CONCLUSION: Non-rigid anatomical variations are mainly responsible for critical target coverage loss of cRO plans, whereas the aRO approach was robust against such variations. Both plans provide similar robustness of OAR parameters. ADVANCES IN KNOWLEDGE: The influence of different uncertainty sources was quantified for robust IMPT HNSCC plans.

Long term results of single high dose Stereotactic Body Radiotherapy in the treatment of primary lung tumors.

Stereotactic body radiotherapy (SBRT) is a standard treatment for inoperable early-stage NSCLC, with local control rates comparable to surgical series. Promising results have been achieved utilizing a high single-dose schedule. The aim of our study was to evaluate long-term local control and toxicity in a series of patients treated with SBRT delivered in a single dose of 30 Gy. 44 patients affected by early stage NSCLC were treated with SBRT delivered in a single dose of 30 Gy. Survival and prognostic factors were retrospectively evaluated. Median follow-up was 34 months (range 3-81). Three- and 5-year local progression-free survival (LPFS) were 87.8% and 87.8% respectively (median 30 months; range 6-81 months), 3- and 5-year OS and CSS were 64.9% and 36.9%, 80.9% and 65.5%, respectively. Two (4.6%) cases of grade 3 pneumonitis occurred. At the univariate analysis lesion diameter ≤ 25 mm was predictive of better 5-year LPFS (95.8% versus 56.3%; p = 0.003) and 5-year PFS (69.8% versus 27.8%; p = 0.002). The results of our study indicated a high local control, survival and tolerability after a long-term follow-up with the use of SBRT 30 Gy single dose. Further prospective studies could better define the role of this regimen.

Early and late side effects, dosimetric parameters and quality of life after proton beam therapy and IMRT for prostate cancer: a matched-pair analysis.

Purpose: To compare early and late toxicities, dosimetric parameters and quality of life (QoL) between conventionally fractionated proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) in prostate cancer (PCA) patients. Methods: Eighty-eight patients with localized PCA treated between 2013 and 2017 with either definitive PBT (31) or IMRT (57) were matched using propensity score matching on PCA risk group, transurethral resection of the prostate, prostate volume, diabetes mellitus and administration of anticoagulants resulting in 29 matched pairs. Early and late genitourinary (GU) and gastrointestinal (GI) toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) and QoL based on EORTC-QLQ-C30/PR25 questionnaires were collected prospectively until 12 months after radiotherapy (RT). Associations between toxicities and dose-volume parameters in corresponding organs at risk (OARs) were modeled by logistic regression. Results: There were no significant differences in GI and GU toxicities between both treatment groups except for late urinary urgency, which was significantly lower after PBT (IMRT: 25.0%, PBT: 0%, p = .047). Late GU toxicities and obstruction grade ≥2 were significantly associated with the relative volume of the anterior bladder wall receiving 70 Gy and the entire bladder receiving 60 Gy, respectively. The majority of patients in both groups reported high functioning and low symptom scores for the QoL questionnaires before and after RT. No or little changes were observed for most items between baseline and 3 or 12 months after RT, respectively. Global health status increased more at 12 months after IMRT (p = .040) compared to PBT, while the change of constipation was significantly better at 3 months after PBT compared to IMRT (p = .034). Conclusions: Overall, IMRT and PBT were well tolerated. Despite the superiority of PBT in early constipation and IMRT in late global health status compared to baseline, overall QoL and the risks of early and late GU and GI toxicities were similar for conventionally fractionated IMRT and PBT.

Orbital Radiotherapy Plus Concomitant Steroids in Moderate-to-Severe Graves' Ophthalmopathy: Good Results After Long-Term Follow-Up.

BACKGROUND: Orbital radiotherapy (RT) is an effective and consolidate treatment for steroid-refractory Graves' ophthalmopathy (GO); however, long term effects are not well known. OBJECTIVES: The aim of this study was to evaluate the long term efficacy and toxicity of orbital RT plus concomitant systemic steroids in a population of patients with moderate-to-severe GO or with eyesight threatening symptoms refractory to steroids. METHODS: Forty patients with moderate-to-severe GO or with eyesight threatening symptoms not responsive/resistant to steroids were treated with orbital RT at the dose of 20 Gy in 10 fractions plus concomitant steroids. Clinical activity score (CAS) and symptoms status were evaluated to determine response to the treatment. RESULTS: We reported overall improvement of symptoms, in particular, a regression at 1-year of diplopia in 32.5% eye movement impairment in 42.5%, eyesight in 27.5% and a 2 point reduction in CAS. After a median time of 56 months 21.9% of the patients underwent orbital decompression for relapse of GO, 4.8% received surgical correction of strabismus, and 2.4% received eyelid lipectomy. Acute toxicity was mild; grade 1 - 2 keratitis occurred in 19.5% of the patients and grade 3 keratitis was observed in 2.4% of the patients. Cataract occurred in 7.4% of the patients after a median time of 24-month-follow-up. No secondary malignancies were reported. CONCLUSIONS: Our results reported the long-term efficacy and the good tolerance of orbital RT. The combination of RT plus steroids in this setting may avoid or delay performing the surgery in some cases.

Including anatomical variations in robust optimization for head and neck proton therapy can reduce the need of adaptation.

BACKGROUND AND PURPOSE: Classical robust optimization considers uncertainties in patient setup and particle range. However, anatomical changes occurring during the treatment are neglected. Our aim was to compare classical robust optimization (cRO) with anatomical robust optimization (aRO), to quantify the influence of anatomical variations during the treatment course, and to assess the need of adaptation. MATERIALS AND METHODS: Planning CT and weekly control CTs (cCTs) from 20 head and neck patients were analysed. Three intensity-modulated proton therapy (IMPT) plans were compared: conventional PTV-based plan; cRO, using solely the planning CT, and aRO, including additionally the first 2 cCTs in the optimization. Weekly and total cumulative doses, considering anatomical variations during the treatment, were calculated and compared with the nominal plans. RESULTS: Nominal plans fulfilled clinical specifications for target coverage (D98% ≥95% of prescribed dose). The PTV-based and cRO approaches were not sufficient to account for anatomical changes during the treatment in 10 and 5 patients, respectively, resulting in the need of plan adaptation. With the aRO approach, in all except one patient the target coverage was conserved, and no adaptations were necessary. CONCLUSION: In 25% of the investigated cases, classical robust optimization is not sufficient to account for anatomical changes during the treatment. Adding additional information of random anatomical variations in the optimization improves plan robustness.

Assessing robustness of radiomic features by image perturbation.

Image features need to be robust against differences in positioning, acquisition and segmentation to ensure reproducibility. Radiomic models that only include robust features can be used to analyse new images, whereas models with non-robust features may fail to predict the outcome of interest accurately. Test-retest imaging is recommended to assess robustness, but may not be available for the phenotype of interest. We therefore investigated 18 combinations of image perturbations to determine feature robustness, based on noise addition (N), translation (T), rotation (R), volume growth/shrinkage (V) and supervoxel-based contour randomisation (C). Test-retest and perturbation robustness were compared for combined total of 4032 morphological, statistical and texture features that were computed from the gross tumour volume in two cohorts with computed tomography imaging: I) 31 non-small-cell lung cancer (NSCLC) patients; II): 19 head-and-neck squamous cell carcinoma (HNSCC) patients. Robustness was determined using the 95% confidence interval (CI) of the intraclass correlation coefficient (1, 1). Features with CI ≥ 0:90 were considered robust. The NTCV, TCV, RNCV and RCV perturbation chain produced similar results and identified the fewest false positive robust features (NSCLC: 0.2-0.9%; HNSCC: 1.7-1.9%). Thus, these perturbation chains may be used as an alternative to test-retest imaging to assess feature robustness.

Development and validation of NTCP models for acute side-effects resulting from proton beam therapy of brain tumours.

BACKGROUND: The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies, such as based on normal tissue complication probability (NTCP). We developed and externally validated NTCP models for common acute side-effects following PBT in brain tumour patients in effort to provide guidance on optimising patient quality of life. METHODS: An exploration cohort including 113 adult brain tumour patients who underwent PBT was investigated for the following endpoints: alopecia, scalp erythema, headache, fatigue and nausea. Dose-volume parameters of associated normal tissues were used for logistic regression modelling. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated on two cohorts of 71 and 96 patients, respectively. RESULTS: Statistically significant correlations of dose-volume parameters of the skin for erythema and alopecia were found. In internal cross-validation, the following prognostic parameters were selected: V35Gy (absolute volume receiving 35 Gy) for erythema grade ≥1, D2% (dose to 2% of the volume) for alopecia grade ≥1 and D5% for alopecia grade ≥2. Validation was successful for both cohorts with AUC >0.75. A bivariable model for fatigue grade ≥1 could not be validated externally. No correlations of dose-volume parameters of the brain were seen for headache or nausea. CONCLUSION: We developed and successfully validated NTCP models for scalp erythema and alopecia in primary brain tumour patients treated with PBT.

Technical Advances in Radiation Therapy for Brain Tumors.

Radiation therapy plays a critical role in the management of brain tumors. Recent advances in radiation techniques include the use of intensity-modulated radiotherapy (IMRT), volumetric-modulated arc therapy (VMAT) and stereotactic radiosurgery (SRS). All of these techniques allow the delivery of higher radiation doses to the target volume, at the same time reducing the risk of toxicity to normal tissues as compared with conventional 3D conformal radiotherapy (3D-CRT). Proton therapy may represent a treatment alternative to photon irradiation, due to the more favorable dose distribution to the target volume. This review summarizes current developments in radiation therapy and their clinical impact on the management of patients with brain tumors.

Between evidence and new perspectives on the current state of the multimodal approach to gastric cancer: Is there still a role for radiation therapy?

In patients affected by gastric cancer (GC), especially those in advanced stage, the multidisciplinary approach of treatment is fundamental to obtain a good disease control and quality of life. Although many chemotherapeutics in combination to radiotherapy are adopted in the peri- or postoperative setting, the most optimal timing, regimens and doses remains controversial. In the era of radical surgery performed with D2-lymphadenectomy, the role of radiation therapy remains to be better defined. Categories of patients, who could benefit more from an intensified local treatment rather than more toxic systemic therapy, are still under investigation. Evidence and recent updates of the randomized trials, meta-analysis and prospective trials show that the postoperative radiotherapy plays a fundamental role in reducing the loco-regional recurrence and in turn the disease-free survival in operable advanced GC patients, also after a well performed D2 surgery. Therapeutic decisions should be taken considering the individual patients, but the multimodal approach is necessary to guarantee a longer survival and a good quality of life. Ongoing randomized trials could better define the timing and the combination of radiotherapy and systemic therapy.

Mono- and Bi-weekly Hypofractionated Radiation Therapy for the Treatment of Epithelial Skin Cancer in Very Elderly Patients.

BACKGROUND/AIM: Epithelial skin cancer frequently occurs in the elderly population, sometimes in an advanced stage, when intensive treatments are needed. Radiotherapy can achieve high response rates. We evaluated efficacy and tolerability of hypofractionated radiotherapy in a population of very elderly patients with locally advanced epithelial skin cancer. PATIENTS AND METHODS: Two different hypofractionated schedules were administered (21 patients): 6 Gy in 10 bi-weekly fractions (13 lesions) and 5 Gy in 12 bi-weekly fractions (13 lesions). Median age at treatment was 88 years, life expectancy was ≤5 years in 90.5%. RESULTS: The overall response rate was 96.1%, with 92.4% complete responses. All patients experienced an improvement of their symptoms and a reduction of pain and medication. The median overall survival time was 28 months (95% confidence interval=4.7-51.2 months). At the time of analysis, 52.3% of patients had died. CONCLUSION: Hypofractionated radiotherapy is an effective option of treatment, with low toxicity and optimal results, and can also be safely administered to these frail patients.