Robotic Stereotactic Ablative Radiotherapy for Patients with Early-Stage Lung Cancer: Results of an Interim Analysis.

BACKGROUND/OBJECTIVES: Surgery is the primary treatment for early-stage lung cancer. Patients with medically inoperable lung carcinomas and patients who refuse to undergo surgery are treated with definite radiotherapy. Stereotactic ablative radiotherapy (SABR) is a compelling non-invasive therapeutic modality for this group of patients that confers promising results. METHODS: We report an interim analysis of an ongoing trial. Eighty-one patients with medically inoperable early-stage (T1,2N0) lung cancer underwent SABR in our institution. SABR was delivered via the CyberKnife M6 robotic radiosurgery system. The endpoints of the analysis were treatment efficacy and tolerance. RESULTS: There were no acute or late toxicities from the skin or the connective tissue of the thorax. A grade 2/3 lung injury of non-clinical significance was noted in 6% of patients, which was directly related to a higher biologically effective dose (BEDα/ß = 3) and larger irradiation lung volumes in both univariate and multivariate analyses. A local control (LC) was achieved in 100% of the patients at the first follow-up, and the projected 24-month local progression-free survival (LPFS) rate was 95%. The projected 24-month disease-specific overall survival (OS) was 94%. CONCLUSIONS: High LC and OS rates can be achieved with SABR for early-stage lung cancer, with minimal toxicity. This study continues to recruit patients.

Does adaptive radiotherapy for head and neck cancer favorably impact dosimetric, clinical, and toxicity outcomes?: A review.

PURPOSE: The current review aims to summarize the international experience of the impact of adaptive radiotherapy on dosimetry and clinical and toxicity outcomes. Additionally, it might trigger Radiation Oncologists to use ART and evaluate whether ART improves target volume coverage and/or normal tissue sparing and, consequently, therapeutic results. MATERIALS AND METHODS: We conducted an electronic literature search of PubMed/MEDLINE and ScienceDirect from January 2007 to January 2023. The search adhered to the PRISMA guidelines and employed keywords such as ART, HNC, parotid gland, and target volume. Furthermore, we examined the reference lists for studies pertinent to the present review. This study included both retrospective and prospective studies that were considered for inclusion. CONCLUSION: ART replanning appears to be a sustainable strategy to minimize toxicity by improving normal tissue sparing. Furthermore, it can enhance target volume coverage by correctly determining the specific dose to be delivered to the tumor. In conclusion, this review confirmed that ART benefits dosimetric, clinical/therapeutic, and toxicity outcomes.

Immunogenic Cell Death, DAMPs and Prothymosin α as a Putative Anticancer Immune Response Biomarker.

The new and increasingly studied concept of immunogenic cell death (ICD) revealed a previously unknown perspective of the various regulated cell death (RCD) modalities, elucidating their immunogenic properties and rendering obsolete the notion that immune stimulation is solely the outcome of necrosis. A distinct characteristic of ICD is the release of danger-associated molecular patterns (DAMPs) by dying and/or dead cells. Thus, several members of the DAMP family, such as the well-characterized heat shock proteins (HSPs) HSP70 and HSP90, the high-mobility group box 1 protein and calreticulin, and the thymic polypeptide prothymosin α (proTα) and its immunoreactive fragment proTα(100-109), are being studied as potential diagnostic tools and/or possible therapeutic agents. Here, we present the basic aspects and mechanisms of both ICD and other immunogenic RCD forms; denote the role of DAMPs in ICD; and further exploit the relevance of human proTα and proTα(100-109) in ICD, highlighting their possible clinical applications. Furthermore, we present the preliminary results of our in vitro studies, which show a direct correlation between the concentration of proTα/proTα(100-109) and the levels of cancer cell apoptosis, induced by anticancer agents and γ-radiation.

Two hypofractionated schedules for early stage breast cancer: Comparative retrospective analysis for acute and late radiation induced dermatitis.

PURPOSE: To compare two hypofractionated radiation schedules in early breast cancer concerning skin toxicity. METHODS: We retrospectively analyzed 80 patients (group A) versus 54 (group B) who underwent hypofractionated radiotherapy after breast conserving surgery. Group Α received 42.75Gy in 15 fractions over 5 weeks (3 fractions/ week) plus 8.55Gy boost to the tumor bed (3 fractions). Group Β received 45.05Gy (5 fractions/week) and 7.95Gy boost (3 fractions). Multivariate logistic regression analysis (MVLRA) was conducted for relevant parameters regarding RTOG/EORTC skin toxicity. RESULTS: Median follow up was 60 months. Median age was 75 years (group A) and 56 (group B). Mean values of radio-dermatitis were significantly higher in group A vs B until 3 months post RT (p<0.001 and p=0.002, respectively), while 6 months thereafter toxicity was regressed without any significant difference between groups. MVLRA showed a significant (p<0.001) odds ratio for age (2.36, 95%CI:1.11-3.75) and group A (1.31, 95%CI:1.12-1.49). CONCLUSION: Schedule B would be preferable in younger women in favor of toxicity. Schedule A could still be applied in elderly patients, unavailable attending daily schedules, with acceptable toxicity.

A five split-field three dimensional conformal technique versus an anterior-posterior on in postoperative radiotherapy for gastric carcinoma: a multicenter comparative study using quality of life measurements as well as clinical and dosimetric parameters.

PURPOSE: Several adjuvant approaches are regarded as available options in the management of localized, resectable gastric cancer .The objective of our study was to evaluate multiple field and anteroposterior conformal technique. METHODS: Ninety-seven patients received three dimensional conformal (3DCRT) postoperative adjuvant radiation therapy for gastric carcinoma. Thirty-five patients received anteroposterior (AP/PA) fields (Group B), while 62 patients were irradiated with multifield technique (Group A). Their ages ranged between 29-85 years. The objective of the study was to evaluate the quality of life (QoL) for all patients after the completion of radiotherapy using the QLQ-C30 of the EORTC questionnaire (European Organization for Research and Treatment of Cancer) and to investigate any measurable differences between those two radiation techniques according to QUANTEC criteria and the radiotoxicity. RESULTS: In terms of QUANTEC criteria, the multifield technique was superior concerning the left kidney (p=0.025), right kidney (p<0.001), spinal cord (p<0.001) and planning target volume (PTV) coverage (p<0.001). According to EORTC/ RTOG toxicity criteria, the rate of diarrhea was higher in AP/ PA technique (p=0.028). In terms of QLQ-C30, the multifield technique was superior concerning appetite loss (p=0.022), diarrhea (p=0.046) and global QoL (p<0.001). CONCLUSION: On the basis of QLQ-C30 questionnaire, EORTC/ RTOG toxicity and dosimetric parameters, the present report has shown that the three dimensional multifield conformal radiotherapy is superior compared to AP-PA techniques.

Documentation of a New Intracavitary Applicator for Transrectal Hyperthermia Designed for Prostate Cancer Cases: A Phantom Study.

Concerning clinical trials, intracavitary hyperthermia has already shown antitumor activity and has a potential role in the treatment of prostate cancer. The aim of this study was to document a new intracavitary applicator operating at 433 MHz, designed for transrectal hyperthermia, as well as to assess the specific absorption rate (SAR) distributions in terms of temperature measurements in a soft-tissue phantom. The microwave applicator consists of a dipole-type λ/2, a reflector, and the cooling system. The applicator was placed into a soft-tissue gel-phantom box that was mimicking the dielectric properties of the normal tissue. A calibrated thermometer was implanted inside the phantom at specific locations, to calculate temperature distributions. The maximum value of the SAR was 108 W/kg on the surface's central area at the footprint of the antenna, while the penetration depth was at around 3 cm. Our experimental measurements confirmed the role of the reflector concerning the directivity in a certain area and non icotropic, by means of protecting normal tissues around the prostate. The SAR experimental measurements showed that our applicator might be used effectively as a treatment device for prostate cancer, demonstrating a clear advantage over other similar transrectal devices.

Quality assurance protocol for superficial and deep hyperthermia systems established by the Hellenic Association of Medical Physicists (HAMP) in cooperation with the Hellenic Society of Oncologic Hyperthemia (HSOH): A study based on European Society for Hyperthermic Oncology (ESHO) quality assurance guidelines.

PURPOSE: During the last years hyperthermia is a developing therapeutic modality in Greece. Quality assurance (QA) procedures are essential for ensuring the correct operation of the hyperthermia system and therefore the selective heating of the tumor with minimum toxicity to the surrounding healthy tissues. The European Society for Hyperthermic Oncology (ESHO) has proposed QA guidelines for superficial as well as deep hyperthermia systems. The purpose of this study was to describe the adapted QA protocol for superficial and deep hyperthermia systems established in Greece. METHODS: A working group was created by the Hellenic Association of Medical Physicists (HAMP) for the proposal of QA guidelines for superficial and deep hyperthermia systems. A review of the protocol proposed by ESHO, together with the existing protocols in other European and International centers, as well as protocols suggested by European or International organizations, was performed. Then, a protocol was suggested, describing procedures for QA according to the current technology and the existing equipment used in Greece. RESULTS: A protocol describing the procedures for QA of superficial and deep hyperthermia systems was proposed. These procedures aim to evaluate the correct operation of the device, the thermometric system, the generator, the incorporated power meter and the applicators. It will also ensure the electrical safety of the devices. CONCLUSIONS: The proposed protocol, applied by medical physicists in Greece, will ensure an efficient treatment with safety and minimum adverse effects. This protocol has been approved by the Hellenic Society of Oncologic Hyperthermia and the Hellenic Association of Medical Physicists.

Toxicity and efficacy of a hypofractionated (3 weekly fractions of 850c Gy) irradiation schedule for stage IIIb / IV non-small cell lung cancer elderly patients with low performance status and unfit for chemotherapy.

PURPOSE: To evaluate in an observational way the clinical impact of a hypofractionated irradiation schedule in patients with unresectable non-small cell lung cancer (NSCLC). METHODS: Forty elderly patients (24 men/16 women) diagnosed with unresectable stage IIIb/IV NSCLC unfit for chemotherapy, were treated with once-a-week hypofractionation schedule. All patients had a poor performance status. A dose of 255 Gy in 3 weekly fractions was prescribed while a 3D conformal technique (3D-CRT) was used for irradiation. The primary study endpoints were to assess the therapeutic impact of this schedule in terms of relapse free survival (RFS), overall survival (OS) survival and palliation of symptoms. The secondary endpoints were the evaluation of acute toxicity of the lung, esophagus and the skin. The intended followup was 3 years. The median age was 73.5 years (range 71-85). RESULTS: The median RFS was 12 months, while the median OS was 17 months. Symptoms relief was up to 20% for cough, 52.5% for haemoptysis, 40% for thoracic pain and 17.5% for dyspnoea. Acute lung toxicity in terms of radiation pneumonitis was recorded as 6/40 (15%) grade 1, 26/40 (65%) grade 2 and 8/40 (25%) grade 3. Additionally, grade 1 and 2 acute esophageal toxicity was recorded in 10/40 (25%) and 30/40 (75%) patients, respectively. Acute skin toxicity with grade 2 erythema was recorded in only 2/40 (5%) patients while most patients developed grade 1 skin erythema. Grade 3 late lung toxicity was recorded in 10/40 (25%) patients. CONCLUSIONS: This study showed that the proposed scheme has a moderate radiation-induced lung toxicity rate and an acceptable therapeutic ratio. Taking into consideration its cost effectiveness, the proposed hypofractionated scheme is a good alternative to conventional fractionation.

Clinical implications of in silico mathematical modeling for glioblastoma: a critical review.

Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.

Evaluation of Intensity Modulated Radiation Therapy Delivery System using a Volumetric Phantom on the Basis of the Task Group 119 Report of American Association of Physicists in Medicine.

The current work describes the implementation of the American Association of Physicists in Medicine (AAPM)'s Task Group 119 report on a volumetric phantom (Delta4, Scandidos, Uppsala, Sweden) following the stated dose goals, to evaluate the step-and-shoot intensity modulated radiation therapy (IMRT) system. Delta4 consists of diode detectors, lying on two crossed planes, measuring the delivered dose, and providing two-dimensional dosimetric information. Seven plans of different goals and complexity were performed, with individual structure sets. TG199 structure sets and plans were transferred and implemented on the Delta4 phantom taking into account its cylindrical geometry. All plans were delivered with a 6 MV linear accelerator equipped with multileaf collimator of 1 cm thickness. Plan results for each test met the recommended dose goals. The evaluation was performed in terms of dose deviation, distance to agreement, and gamma index passing rate. In all test cases, the gamma index passing rate was measured >90%. Delta4 phantom has proven to be fast, applicable, and reliable for the step-and-shoot IMRT commissioning following TG119's recommended tests. Although AAPM's TG119 report is referring to the implementation of test plans that do not correspond to patient plans, it could be used as an evaluation tool of various IMRT systems, considering the local treatment planning system and the delivery system.

A Retrospective Analysis of Toxicity and Efficacy for 2 Hypofractionated Irradiation Schedules Versus a Conventional One for Post-Mastectomy Adjuvant Radiotherapy in Breast Cancer.

INTRODUCTION: The aim of this analysis was a retrospective evaluation of the efficacy and toxicity of 2 hypofractionated irradiation schedules compared to conventional therapy in post-mastectomy patients. METHODS: 3 irradiation schedules were analyzed: 48.30 Gy in 21 fractions (group A, n = 60), 42.56 Gy in 16 fractions (group B, n = 27) and 50 Gy in 25 fractions (group C, n = 30) of the front chest wall. All groups were also treated with a supraclavicular field, with 39.10 Gy in 17 fractions (group A), 37.24 Gy in 14 fractions (group B) or 45 Gy in 25 fractions (group C). RESULTS: No local recurrences were noted in any group during 36 months of follow-up. Acute skin toxicity presented in all groups, with 58.3%, 70.4% and 60% of grade I; 35%, 25.9% and 40% of grade II; 6.7%, 3.7% and 0% of grade III being seen in groups A, B and C, respectively. Late skin toxicity was noted only as grade I in 16.7%, 25.9% and 26.7% of groups A, B and C, respectively. No significant difference was noted among all groups for either acute or late skin toxicity, or for radio-pneumonitis (chi2 test, p > 0.05). CONCLUSION: All schedules were equally effective with equivalent toxicity. A prospective randomized study is needed to confirm our results.

MLC positional accuracy evaluation through the Picket Fence test on EBT2 films and a 3D volumetric phantom.

The accuracy of MLC positions during radiotherapy is important as even small positional deviations can translate into considerable dose delivery errors. This becomes crucial when radiosensitive organs are located near the treated volume and especially during IMRT, where dose gradients are steep. A test commonly conducted to measure the positional accuracy of the MLCs is the Picket Fence test. In this study two alterations of the Picket Fence test were performed and evaluated, the first one using radiochromic EBT2 films and the second one the Delta4PT diode array phantom and its software. Our results showed that EBT2 films provide a relatively fast, qualitative visual inspection of the significant leaf dispositions. When slight inaccuracies need to be revealed or precise numerical results for each leaf position are needed, Delta4PT provides the desired accuracy of 1 mm. In treatment modalities where a higher accuracy is required in the delivered dose distribution, such as in IMRT, precise numerical values of the measurements for the MLC positional inspection are required.

The first implementation of IMRT technique for head & neck and prostate cancer patients in public sector in Greece: feasibility, treatment planning and dose delivery verification using the delta(4PT) Pre-Treatment volumetric quality assurance system.

PURPOSE: Intensity Modulated Radiation Therapy (IMRT) is nowadays the treatment of choice, in terms of technique, for either head & neck or prostate cancer. With this paper, we are sharing our experience for the first inplementation of IMRT planning in the public sector in Greece, and especially in the Aretaieion University Hospital of Athens. METHODS: From May 2013 until January 2014 four prostate and four head & neck cancer patients were evaluated in the present study. We used the ONCENTRA IMRT treatment planning with a step and shoot technique in a SIEMENS ONCORE Linac. The dose verification method used was based on the delta4(PT) Pre-Treatment volumetric quality assurance system, by Scadidos. RESULTS: In all cases, the Relative Standard Deviation between the prescribed and the calculated average dose received by the target volume was less than 5%, while the γ-index was more than 90%. The acute toxicity was low and equivalent to published data with IMRT technique. CONCLUSION: In conclusion, the first implementation of IMRT technique in the Medical School of Athens was feasible and safe as well as in terms of dose verification. The IMRT technique is already in clinical use and further results with long term radiation induced toxicity will be reported.

The impact of intermediate time between chemotherapy and hypofractionated radiotherapy to the radiation induced skin toxicity for breast adjuvant treatment.

To evaluate the impact of intermediate time between chemotherapy and radiotherapy (ITCR) to skin toxicity for a hypofractionated irradiation schedule. Forty-four patients with stage I-II invasive breast cancer receiving postoperative radiotherapy (RT) after lumpectomy and axillary dissection were studied. All patients received RT with 6 MV linear accelerator (LINAC) with a total tumor dose of 53 Gy (Equivalent dose-EQD2- 60 Gy), 2.65 Gy per fraction, in 20 fractions. All patients received six cycles of cyclophosphamide methotrexate fluorouracil chemotherapy i.v. every 21 days. Acute and late effects and cosmetic results were assessed using the European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group (EORTC/RTOG) Rating System. The mean follow-up was 7 years. The spearman rho test showed that there was a significant correlation between short ITCR and acute skin toxicity 3 months post RT, by means of acute radiation induced morbidity. None of the related late-toxicity parameters was correlated with the ITCR. However, there was significantly higher acute toxicity when the ITCR was less than 20 days (p < 0.05). We may suggest that when a hypofractionated irradiation schedule is used for breast cancer patients, then the ITCR should be more than 20 days from chemotherapy.

Comparison of two radiotherapeutic hypofractionated schedules in the application of tumor bed boost.

AIM: Evaluation of related radiation toxicity and efficacy in terms of local control of 2 radiotherapeutic hypofractionated schedules in the application of tumor bed boost by using 2 different planning techniques. METHOD: Eighty-one patients with stage I-II disease were retrospectively selected with either concomitant (group A) or sequential (group B) boost for the tumor bed. In group A, 27 patients were treated with a total dose of 46 Gy to the whole breast and 54 Gy to the tumor bed in 20 concomitant fractions. In group B, 54 patients were treated with a total dose of 42.4 Gy in 16 fractions to the whole breast and 53 Gy to the tumor bed by 4 sequential fractions. The boost was administered with multiple photon-beam fields. The median follow-up time was 24 months. RESULTS: The statistical analysis for the 2 groups of the study showed that skin toxicity was significantly worse in group A (P < .05, Kruskal-Wallis H test). For groups A and B at the completion of radiation therapy, grade 1 skin toxicity was observed in 18/27 patients (66.6%) and 13/54 patients (24.1%), respectively, whereas grade 2/3 was observed in 9/27 patients (33.3%) vs. 5/54 patients (9.3%), respectively (P < .001). One year after irradiation, in group A and in group B, the skin toxicity was of grade 1 in 6/27 patients (22.2%) vs. 2/54 patients (3.7%), respectively (P = .008). Within 2 years, the breast returned to its original form in all patients. No patient showed local disease recurrence. CONCLUSIONS: The accelerated hypofractionated schedules in the application of the tumor bed boost by using the 2 different planning techniques appears to be effective and well tolerated.

The determination of radiobiologically optimized half-lives for radionuclides used in permanent brachytherapy implants.

PURPOSE: To use tumor growth kinetics and other biologic parameters in an extended version of the linear-quadratic (LQ) formulation to determine radiobiologically optimized half-lives of radionuclides which might be used in permanent brachytherapy implants. METHODS AND MATERIALS: A version of the LQ model suitable for the analysis of permanent brachytherapy implants has been modified to investigate the radionuclide half-lives that will maximize the biologically effective dose (BED) delivered to tumors with repopulation rates (K values) in the range 0.01-1.1 Gyday(-1). The method assumes that part of the physical dose delivered to the tumor may be radiobiologically wasted because of the repopulation phenomenon, whereas adjacent normal tissues will exhibit little or no wastage. To perform the analysis, it is necessary to stipulate alpha/beta ratios and sublethal damage recovery rates together with the normal tissue tolerance BED. The analysis also takes into account a range of likely relative biological effectiveness (RBE) values. RESULTS: Rapidly growing tumors require the shortest radionuclide half-lives, but even slow-growing tumors such as prostate adenocarcinomas can be satisfactorily treated with radionuclides possessing half-lives substantially less than that associated with I(125). The likelihood that prostate tumors possess an alpha/beta value which is comparable with, or lower than, that associated with late-responding normal tissues would also mitigate against the use of long-lived radionuclides. Although a number of parameter assumptions are involved, the results suggest that, for a wide range of tumor types, shorter-lived radionuclides are more versatile for achieving reasonable clinical results. The theoretically derived optimum half-lives typically range from around 0-5 days for fast-repopulating tumors (K 1.1 Gyday(-1)) to approximately 14-50 days for slow-growing tumors (K approximately 0.1 Gyday(-1) or less). For prostate implantation, 103Pd is overall a better choice than 125I. CONCLUSION: With so many variables and parameter uncertainties, it is not appropriate to attempt to define optimum radionuclide half-lives too closely. However, this study suggests that half-lives in the approximate range 4-17 days are likely to be significantly better for a wide range of tumor types for which the radiobiologic characteristics may not be precisely known in advance.