Improved quality of life in head and neck cancer patients treated with modern arc radiotherapy techniques - A prospective longitudinal analysis.

Purpose: The present longitudinal study aimed to evaluate the potential impact of modern radiotherapy (RT) techniques on quality of life (QOL) in patients with head and neck (HNC) cancer. Materials and methods: In this single-center prospective study, participants were asked to complete QOL questionnaires that included the EORTC QLQ-C30, QLQ-H&N 35 and utility score by time trade-off (TTO) at three time points (2 weeks, 3 months and 6 months) after completion of RT. All patients were treated by modern RT techniques [volumetric modulated arc therapy (VMAT) or helical tomotherapy (HT)]. Patients who developed recurrence or died before the 6-month follow-up were excluded. Linear mixed models with random intercepts for participants and restricted maximum likelihood estimates were used to assess the effect of our study variables (age, sex, primary site, cancer stage, treatment, radiation dose and radiation method). Overall changes in QOL, utility scores and symptom burdens at different time points were tested using paired t tests. Results: A total of 45 patients were recruited from 2022 to 2023. Those who completed the surveys at 2 weeks with at least 1 follow-up (30 patients, 67%) were enrolled in the final analysis. The majority of these 30 patients were men (76.7%), had oral cancer (40%), had stage III or IV disease (60%), received surgical intervention (63%) and were treated with chemoradiation (80%). A curative total dose of 66 to 70 Gy was delivered to 23 (76.7%) patients, half of whom received HT. Patients who received chemotherapy had significantly lower global QoL scales (mean difference, 27.94; 95% CI, 9.33-46.55; p=0.005). Global QOL, physical function, symptoms of sticky saliva, cough, feelings of illness and weight loss improved significantly between 2 weeks and 3 months. There was no significant difference between 3 and 6 months. Interestingly, improvements in social function, social contact, pain and nutrition reached significance at 6 months. Subgroup analysis revealed greater pain relief over time for patients who underwent HT (p=0.030). Moreover, patients who participated in swallowing rehabilitation programs had a greater decrease in nausea and vomiting (p=0.036). Conclusion: HNC patients treated with modern RT techniques experience improved QOL and physical function over time. The most significant improvement occurs between 2 weeks and 3 months, after which the improvement plateaus. However, social function, social contact, pain and nutrition may require longer recovery intervals after treatment. HT with daily image guidance could provide a therapeutic opportunity for improving pain relief in patients with HNC.

The Role of Surgery in Metastatic Renal Cell Carcinoma in 2024.

Renal cell carcinoma (RCC) is the most common solid tumour of the kidney and accounts for 3% of all cancers. While immune checkpoint inhibitor (ICI)-based combination therapies have emerged as the first-line treatment for metastatic renal cell carcinoma (mRCC), the role of surgery has become more controversial. This review summarizes the evidence, current role and future directions for surgery in mRCC management. The survival benefits of cytoreductive nephrectomy (CN) shown in the interferon era have encountered increasing disputes in the tyrosine-kinase inhibitor (TKI) and ICI eras. Undoubtedly, several systematic reviews based on retrospective data have supported the survival benefits of CN. Nevertheless, 2 prospective trials, CARMENA and SURTIME, proved that sunitinib as the upfront therapy resulted in noninferior survival outcomes compared with immediate CN. The safety of CN does have solid ground in the current literature. Several studies suggested that preoperative systemic therapy did not seem to aggravate perioperative complications or mortality rates, in experienced centres. Meticulous patient selection is the rule of thumb in the modern management of mRCC patients. The limitations of the existing prognostication models, however, must be acknowledged. Clinicians should adopt a multidisciplinary and holistic approach and contemplate all patient, disease, surgeon and socio-economical factors, before deciding who should go for surgery. The advent of metastasis-directed therapy (MDT) and survival benefits of adjuvant pembrolizumab shown in the oligometastatic subgroup, where complete metastasectomy could be achieved (M1 NED), calls for more comparative studies against upfront ICI combinations. In summary, CN brings survival benefits to well-selected good-to-intermediate-risk mRCC patients. Individualized and multidisciplinary care is pivotal.

Impact of discrimination on training and career of radiation oncologists in France.

Purpose: In France, radiation oncologists are predominantly men with only 44 % of women. Many studies have highlighted gender disparities in medicine. The main objective of our study was to assess the impact of discriminations on radiation oncologists' career. Materials and methods: An anonymous online questionnaire, adapted from the one used by the ESMO W4O group, was sent to all radiation oncologists in France between March and June 2022. It included questions related to professional experience, gender, socio-ethnicity, sexual orientation, and personal life. Results: Among the 999 radiation oncologists and 168 residents in France, 225 questionnaires were collected (19.2 %). Among the respondents, 60 % were women and 25 % were residents. The mean age was 39.2 years (range: 25-78). The career satisfaction rate was 92 %, with no gender difference. Gender was considered to have a negative impact on the career development by 65 % of women. Social origin was an obstacle to career development for 37 % of all the respondents, and ethnic origin for 25 %. Sixty two percent of women reported having experienced inappropriate behavior or sexual harassment in their workplace, 38 % felt that having a child had "extremely" or "very" much impacted their career versus 8.5 % of men (p < 0.001). The most popular proposals for improvement were the creation of a network of women radiation oncologists with specific educational programs and the addition of quotas in institutions and key positions. Conclusions: This study is the first one assessing the various type of discrimination experienced by radiation oncologists in France. We make a few proposals for improvement of training and working conditions, regardless of the origin and gender.

Radiation and systemic immunotherapy for metastatic uveal melanoma: a clinical retrospective review.

Introduction: Metastatic uveal melanoma (mUM) is a difficult to treat disease. The liver is the primary site of metastasis in most patients, though uveal melanoma spreads widely in advanced disease. The only FDA approved immunotherapy medication for metastatic uveal melanoma is the HLA-A02:01 restricted bispecific T cell engager drug, Tebentafusp. Checkpoint inhibitor strategies and combination approaches have been tried with some limited success. We describe our experience treating patients at the University of Minnesota. Methods: Patients were included if they had biopsy-confirmed mUM. Twenty-five (25) patients meeting the criteria were identified. Medical records were reviewed and data extracted for patient baseline characteristics and response to treatments. Results: Median time to metastasis from the time of local therapy to the eye was 14.2 months (IQR; 9.3-22.0), and first site of metastasis was liver in 92% of patients. Two patients (8%) did not receive systemic therapy or radiation therapy for metastatic disease. Twenty-three (92%) patients received systemic therapy, 13 patients (52%) received ipilimumab-nivolumab as the first-line, while 4 patients (16%) received pembrolizumab. Landmark survival analysis by receipt of systemic therapy and radiation therapy treatments within 6 months of biopsy confirmed diagnosis is shown. Twenty patients (80%) received systemic therapy within 6 months of mUM diagnosis. Thirteen patients (52%) received liver directed radiation therapy within 6 months of mUM diagnosis. Discussion: Within our cohort, there was no overall survival benefit for patients receiving treatment of metastatic disease within 6 months of mUM diagnosis, versus those electing later or no treatment at all. There was remarkable clinical activity of ipilimumab and nivolumab in a subset of patients with mUM, in agreement with prior studies, and metastatic PD-L1 positive tumors were associated with a prolonged survival.

Immunogenic cell death after combined treatment with radiation and ATR inhibitors is dually regulated by apoptotic caspases.

Introduction: Inhibitors of the ATR kinase act as radiosensitizers through abrogating the G2 checkpoint and reducing DNA repair. Recent studies suggest that ATR inhibitors can also increase radiation-induced antitumor immunity, but the underlying immunomodulating mechanisms remain poorly understood. Moreover, it is poorly known how such immune effects relate to different death pathways such as caspase-dependent apoptosis. Here we address whether ATR inhibition in combination with irradiation may increase the presentation of hallmark factors of immunogenic cell death (ICD), and to what extent caspase activation regulates this response. Methods: Human lung cancer and osteosarcoma cell lines (SW900, H1975, H460, U2OS) were treated with X-rays and ATR inhibitors (VE822; AZD6738) in the absence and presence of a pan-caspase inhibitor. The ICD hallmarks HMGB1 release, ATP secretion and calreticulin surface-presentation were assessed by immunoblotting of growth medium, the CellTiter-Glo assay and an optimized live-cell flow cytometry assay, respectively. To obtain accurate measurement of small differences in the calreticulin signal by flow cytometry, we included normalization to a barcoded control sample. Results: Extracellular release of HMGB1 was increased in all the cell lines at 72 hours after the combined treatment with radiation and ATR inhibitors, relative to mock treatment or cells treated with radiation alone. The HMGB1 release correlated largely - but not strictly - with loss of plasma membrane integrity, and was suppressed by addition of the caspase inhibitor. However, one cell line showed HMGB1 release despite caspase inhibition, and in this cell line caspase inhibition induced pMLKL, a marker for necroptosis. ATP secretion occurred already at 48 hours after the co-treatment and did clearly not correlate with loss of plasma membrane integrity. Addition of pan-caspase inhibition further increased the ATP secretion. Surface-presentation of calreticulin was increased at 24-72 hours after irradiation, but not further increased by either ATR or caspase inhibition. Conclusion: These results show that ATR inhibition can increase the presentation of two out of three ICD hallmark factors from irradiated human cancer cells. Moreover, caspase activation distinctly affects each of the hallmark factors, and therefore likely plays a dual role in tumor immunogenicity by promoting both immunostimulatory and -suppressive effects.

Salivary gland cancers in elderly patients: challenges and therapeutic strategies.

Salivary gland carcinomas (SGCs) are the most heterogeneous subgroup of head and neck malignant tumors, accounting for more than 20 subtypes. The median age of SGC diagnosis is expected to rise in the following decades, leading to crucial clinical challenges in geriatric oncology. Elderly patients, in comparison with patients aged below 65 years, are generally considered less amenable to receiving state-of-the-art curative treatments for localized disease, such as surgery and radiation/particle therapy. In the advanced setting, chemotherapy regimens are often dampened by the consideration of cardiovascular and renal comorbidities. Nevertheless, the elderly population encompasses a broad spectrum of functionalities. In the last decades, some screening tools (e.g. the G8 questionnaire) have been developed to identify those subjects who should receive a multidimensional geriatric assessment, to answer the question about the feasibility of complex treatments. In the present article, we discuss the most frequent SGC histologies diagnosed in the elderly population and the relative 5-years survival outcomes based on the most recent data from the Surveillance, Epidemiology, and End Results (SEER) Program. Moreover, we review the therapeutic strategies currently available for locoregionally advanced and metastatic disease, taking into account the recent advances in precision oncology. The synergy between the Multidisciplinary Tumor Board and the Geriatrician aims to shape the most appropriate treatment pathway for each elderly patient, focusing on global functionality instead of the sole chronological age.

Impact of fiducial markers placement on the delineation of target volumes in radiation therapy for oesophageal cancer: FIDUCOR study.

Purpose: This prospective monocentric phase II study (FIDUCOR-study, NCT02526134) aimed to assess the impact of fiducial markers (FMs) implantation on conformal chemo-radiation therapy (CRT) planning in oesophageal carcinoma (EC) patients. Methods/materials: Fifteen EC patients were enrolled in the study. Each patient underwent two simulation CT-scans before (CT1) and after (CT2) FMs implantation, in the same position. FMs (3 mm length gold markers, preloaded in a 22G needle) were implanted after sedation, under endoscopic ultrasound (EUS) and X-Ray guidance, and were placed at the tumor's extremities, and in the visible lymph nodes. Target delineation and treatment plan were both performed first on CT1 with the assistance of diagnosis CT, gastroscopy and EUS details, and second on CT2 using FMs and CT-data. The value of FMs implantation was assessed by the difference of growth-tumor-volume (GTV) and clinical-target-volume (CTV) between CT1-based and CT2-based delineation. A significant difference was defined as a ≥5 mm-difference on axial(x) or coronal(y) slices, a ≥10mm-difference on sagittal slices, or a ≥20%-difference in GTV. The impact on dose distribution in organs at risk (OAR) (lung, heart, liver) was also studied. Results: Between 09/2014 and 12/2015, 15 patients could achieve fiducial procedures, without any complication. One FM migration occurred. We observed a significant modification of the GTV-dimension in 100% of the cases (15/15, 95%CI: [78.2;100.0]), mainly due to a difference in sagittal dimension with a mean variation of 11.2 mm and a difference> 10 mm for 8/15 patients (53.3%). One patient had a significant isocenter displacement as high as 20 mm. The oesophagus tumor was not seen on the CT-scan in one patient due to its small size. One patient had a distant lymph node metastasis not visible on CT-scan. We observed no significant impact on OAR distribution. Conclusion: In our study, FMs-implantation under EUS had a positive impact on accurate volume definition in EC-patients (modification of GTV in 15/15 patients). Close cooperation between gastroenterologist and radiation oncologist has the potential to improve local treatment of oesophageal carcinoma.

Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells.

Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling.

Radiation Oncology: Future Vision for Quality Assurance and Data Management in Clinical Trials and Translational Science.

The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.

Necessity of Pelvic Lymph Node Irradiation in Patients with Recurrent Prostate Cancer after Radical Prostatectomy in the PSMA PET/CT Era: A Narrative Review.

The main prostate cancer (PCa) treatments include surgery or radiotherapy (with or without ADT). However, none of the suggested treatments eliminates the risk of lymph node metastases. Conventional imaging methods, including MRI and CT scanning, are not sensitive enough for the diagnosis of lymph node metastases; however, the novel imaging method, PSMA PET/CT scanning, has provided valuable information about the pelvic LN involvement in patients with recurrent PCa (RPCa) after radical prostatectomy. The high sensitivity and negative predictive value enable accurate N staging in PCa patients. In this narrative review, we summarize the evidence on the treatment and extent of radiation in prostate-only or whole-pelvis radiation in patients with positive and negative LN involvement on PSMA PET/CT scans.

The Evolving Role of Radiotherapy for Pediatric Cancers With Advancements in Molecular Tumor Characterization and Targeted Therapies.

Ongoing rapid advances in molecular diagnostics, precision imaging, and development of targeted therapies have resulted in a constantly evolving landscape for treatment of pediatric cancers. Radiotherapy remains a critical element of the therapeutic toolbox, and its role in the era of precision medicine continues to adapt and undergo re-evaluation. Here, we review emerging strategies for combining radiotherapy with novel targeted systemic therapies (for example, for pediatric gliomas or soft tissue sarcomas), modifying use or intensity of radiotherapy when appropriate via molecular diagnostics that allow better characterization and individualization of each patient's treatments (for example, de-intensification of radiotherapy in WNT subgroup medulloblastoma), as well as exploring more effective targeted systemic therapies that may allow omission or delay of radiotherapy. Many of these strategies are still under investigation but highlight the importance of continued pre-clinical and clinical studies evaluating the role of radiotherapy in this era of precision oncology.

Cost-Effectiveness Analysis of Local Treatment in Oligometastatic Disease.

BACKGROUND: In certain malignancies, patients with oligometastatic disease benefit from radical ablative or surgical treatment. The SABR-COMET trial demonstrated a survival benefit for oligometastatic patients randomized to local stereotactic ablative radiation (SABR) compared to patients receiving standard care (SC) alone. Our aim was to determine the cost-effectiveness of SABR. MATERIALS AND METHODS: A decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY) associated with both strategies in a United States setting from a health care perspective. Analyses were performed over the trial duration of six years as well as a long-term horizon of 16 years. Model input parameters were based on the SABR-COMET trial data as well as best available and most recent data provided in the published literature. An annual discount of 3% for costs was implemented in the analysis. All costs were adjusted to 2019 US Dollars according to the United States Consumer Price Index. SABR costs were reported with an average of $11,700 per treatment. Deterministic and probabilistic sensitivity analyses were performed. Incremental costs, effectiveness, and cost-effectiveness ratios (ICER) were calculated. The willingness-to-pay (WTP) threshold was set to $100,000/QALY. RESULTS: Based on increased overall and progression-free survival, the SABR group showed 0.78 incremental QALYs over the trial duration and 1.34 incremental QALYs over the long-term analysis. Treatment with SABR led to a marginal increase in costs compared to SC alone (SABR: $304,656; SC: $303,523 for 6 years; ICER $1,446/QALY and SABR: $402,888; SC: $350,708 for long-term analysis; ICER $38,874/QALY). Therapy with SABR remained cost-effective until treatment costs of $88,969 over the trial duration (i.e. 7.6 times the average cost). Sensitivity analysis identified a strong model impact for ongoing annual costs of oligo- and polymetastatic disease states. CONCLUSION: Our analysis suggests that local treatment with SABR adds QALYs for patients with certain oligometastatic cancers and represents an intermediate- and long-term cost-effective treatment strategy.

The abscopal effect of radiation therapy.

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.

Health economic impact of a biopsy-based cell cycle gene expression assay in localized prostate cancer.

Background: Prior studies have established that broader incorporation of active surveillance, guided by additional prognostic tools, may mitigate the growing economic burden of localized prostate cancer in the USA. This study sought to further explore the potential of a particular gene expression-based prognostic tool to address this unmet need. Materials & methods: A deterministic, decision-analytic model was developed to estimate the economic impact of the Prolaris® test on a US commercial health plan. Results & conclusion: When adopted in patients classified by the American Urological Association as low or intermediate risk, the assay was projected to reduce costs by $1894 and $2129 per patient over 3 and 10 years, respectively, largely through the increased use of active surveillance.

Radiation Boost After Adjuvant Whole Breast Radiotherapy: Does Evidence Support Practice for Close Margin and Altered Fractionation?

Adding a boost to whole breast radiation (WBI) following breast-conserving surgery (BCS) may help improve local control, but it increases the total cost of treatment and may worsen cosmetic outcomes. Therefore, it is reserved for patients whose potential benefit outweighs the risks; however, current evidence is insufficient to support comprehensive and consistent guidance on how to identify these patients, leading to a potential for significant variations in practice. The use of a boost in the setting of close margins and hypofractionated radiotherapy represents two important areas where consensus guidelines, patterns of practice, and current evidence do not seem to converge. Close margins were previously routinely re-excised, but this is no longer felt to be necessary. Because of this recent practice change, good long-term data on the local recurrence risk of close margins with or without a boost is lacking. As for hypofractionation, although there is guidance recommending that the decision to add a boost be independent from the whole-breast fractionation schedule, it appears that patterns-of-practice data may show underutilization of a boost when hypofractionation is used. The use of a boost in these two common clinical scenarios represents important areas of future study for the optimization of adjuvant breast radiation.

National prevalence, trends and outcomes of takotsubo syndrome in hospitalizations with prior history of mediastinal/intrathoracic cancer and radiation therapy.

BACKGROUND: Radiation therapy (RT) for cancers in thoracic/mediastinal region has been linked with heart damage following years of radiation exposure. However, prevalence of takotsubo syndrome (TTS) in patients with prior intrathoracic/mediastinal malignancies treated with RT has never been analyzed on a large scale. METHODS: We identified adult hospitalizations with prior mediastinal/intrathoracic cancer and RT and TTS using ICD-9 CM codes and the National Inpatient Sample (2007-2014) after excluding current admissions for chemotherapy. We then assessed the prevalence, odds, trends and in-hospital outcomes of TTS-related admissions in patients with vs. without prior intrathoracic cancer and RT. RESULTS: We identified a total of 5,991,314 hospitalizations with prior intrathoracic/mediastinal malignancies and RT (~73 yrs., 85.2% female), of which 7663 (0.13%, 128 per 100,000) were diagnosed with TTS (~74 yrs., 95.8% females, 88.1% white). Higher odds and rising trends in TTS per 100,000 hospitalizations (from 31 to 241) were seen among patients with prior intrathoracic malignancies and RT as compared to those without (from 19 to 104) (ptrend < 0.001). All-cause in-hospital mortality (4.6% vs 2.8%; OR 1.45; 95%CI 1.29-1.63, p < 0.001), cardiogenic shock (4.3% vs 0.2%), cardiac arrest (3.1% vs 0.9%), arrhythmia (34.3% vs 24.6%), stroke (3.6% vs 2.8%), respiratory failure (14.5% vs 4.6%), and median length of stay and hospital charges were significantly higher in the TTS cohort. CONCLUSIONS: This study showed higher odds and increasing trends in TTS-related admissions with worse in-hospital outcomes among patients with prior intrathoracic/mediastinal cancer and RT, irrespective of the time interval from cancer diagnosis or RT to TTS occurrence.

Economic burden of illness associated with localized prostate cancer in the United States.

Aim: Prior studies have established the economic burden of prostate cancer on society. However, changes to screening, novel therapies and increased use of active surveillance (AS) create a need for an updated analysis. Methods: A deterministic, decision-analytic model was developed to estimate medical costs associated with localized prostate cancer over 10 years. Results: 10-year costs averaged $45,957, $99,445 and $188,928 for low-, intermediate- and high-risk patients, respectively. For low-risk patients, AS 10-year costs averaged $33,912/patient, whereas definitive treatment averaged $49,667/patient. Despite higher failure rates in intermediate-risk patients, AS remained less costly than definitive treatment, with 10-year costs averaging $90,614/patient and $99,394/patient, respectively. Conclusion: Broader incorporation of AS, guided by additional prognostic tools, may mitigate this growing economic burden.

Respiratory-Correlated (RC) vs. Time-Resolved (TR) Four-Dimensional Magnetic Resonance Imaging (4DMRI) for Radiotherapy of Thoracic and Abdominal Cancer.

Recent technological and clinical advancements of both respiratory-correlated (RC) and time-resolved (TR) four-dimensional magnetic resonance imaging (4DMRI) techniques are reviewed in light of tumor/organ motion simulation, monitoring, and assessment in radiotherapy. For radiotherapy of thoracic and abdominal cancer, respiratory-induced tumor motion, and motion variation due to breathing irregularities are the major uncertainties in treatment. RC-4DMRI is developed to assess tumor motion for treatment planning, whereas TR-4DMRI is developed to assess both motion and motion variation for treatment planning, delivery and assessment. RC-4DMRI is reconstructed to provide one-breathing-cycle motion, similar to 4D computed tomography (4DCT), the current clinical standard, but with higher soft-tissue contrast, no ionizing radiation, and less binning artifacts due to the use of an internal respiratory surrogate. Recent studies have shown that its spatial resolution has reached or exceeded that of 4DCT and scanning time becomes clinically acceptable. TR-4DMRI is recently developed with an adequate spatiotemporal resolution to assess tumor motion and motion variations for treatment simulation, delivery and assessment. The super-resolution approach is most promising since it can image any organ/body motion, whereas RC-4D MRI are limited to resolve only respiration-induced motion and some TR-4DMRI approaches may more or less depend on RC-4DMRI. TR-4DMRI provides multi-breath motion data that are useful not only in MR-guided radiotherapy but also for building a patient-specific motion model to guide radiotherapy treatment using an non-MR-equipped linear accelerator. Based on 4DMRI motion data, motion-corrected dynamic contrast imaging and diffusion-weighted imaging have also been reported, aiming to facilitate tumor delineation for more accurate radiotherapy targeting. Both RC- and TR-4DMRI have been evaluated for potential clinical applications, such as delineation of tumor volumes, where sufficiently high spatial resolution and large field-of-view are required. The 4DMRI techniques are promising to play a role in motion assessment in radiotherapy treatment planning, delivery, assessment, and adaptation.

An Open-Source Tool for Anisotropic Radiation Therapy Planning in Neuro-oncology Using DW-MRI Tractography.

There is evidence from histopathological studies that glioma tumor cells migrate preferentially along large white matter bundles. If the peritumoral white matter structures can be used to predict the likely trajectory of migrating tumor cells outside of the surgical margin, then this information could be used to inform the delineation of radiation therapy (RT) targets. In theory, an anisotropic expansion that takes large white matter bundle anatomy into account may maximize the chances of treating migrating cancer cells and minimize the amount of brain tissue exposed to high doses of ionizing radiation. Diffusion-weighted MRI (DW-MRI) can be used in combination with fiber tracking algorithms to model the trajectory of large white matter pathways using the direction and magnitude of water movement in tissue. The method presented here is a tool for translating a DW-MRI fiber tracking (tractography) dataset into a white matter path length (WMPL) map that assigns each voxel the shortest distance along a streamline back to a specified region of interest (ROI). We present an open-source WMPL tool, implemented in the package Diffusion Imaging in Python (DIPY), and code to convert the resulting WMPL map to anisotropic contours for RT in a commercial treatment planning system. This proof-of-concept lays the groundwork for future studies to evaluate the clinical value of incorporating tractography modeling into treatment planning.

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.