Summary Background Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received ...radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. Methods We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov , number NCT01295827. Findings Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8–34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio HR 0·56 95% CI 0·34–0·91, p=0·019; median progression-free survival 4·4 months 95% CI 2·1–8·6 vs 2·1 months 1·6–2·3) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 0·30–0·84, p=0·0084; median progression-free survival 6·3 months 95% CI 2·1–10·4 vs 2·0 months 1·8–2·1). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 95% CI 0·36–0·94, p=0·026; median overall survival 10·7 months 95% CI 6·5–18·9 vs 5·3 months 2·7–7·7) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 95% CI 0·36–0·96, p=0·034; median overall survival 11·6 months 95% CI 6·5–20·5 vs 5·3 months 3·0–8·5). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group). Interpretation Our data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC. Funding US National Institutes of Health.
Background
Adaptive magnetic resonance imaging‐guided radiation therapy (MRgRT) can escalate dose to tumors while minimizing dose to normal tissue. We evaluated outcomes of inoperable pancreatic ...cancer patients treated using MRgRT with and without dose escalation.
Methods
We reviewed 44 patients with inoperable pancreatic cancer treated with MRgRT. Treatments included conventional fractionation, hypofractionation, and stereotactic body radiation therapy. Patients were stratified into high‐dose (biologically effective dose BED10 >70) and standard‐dose groups (BED10 ≤70). Overall survival (OS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were evaluated using Kaplan‐Meier method. Cox regression was performed to identify predictors of OS. Acute gastrointestinal (GI) toxicity was assessed for 6 weeks after completion of RT.
Results
Median follow‐up was 17 months. High‐dose patients (n = 24, 55%) had statistically significant improvement in 2‐year OS (49% vs 30%, P = 0.03) and trended towards significance for 2‐year FFLF (77% vs 57%, P = 0.15) compared to standard‐dose patients (n = 20, 45%). FFDF at 18 months in high‐dose vs standard‐dose groups was 24% vs 48%, respectively (P = 0.92). High‐dose radiation (HR: 0.44; 95% confidence interval CI: 0.21‐0.94; P = 0.03) and duration of induction chemotherapy (HR: 0.84; 95% CI: 0.72‐0.98; P = 0.03) were significantly correlated with OS on univariate analysis but neither factor was independently predictive on multivariate analysis. Grade 3+ GI toxicity occurred in three patients in the standard‐dose group and did not occur in the high‐dose group.
Conclusions
Patients treated with dose‐escalated MRgRT demonstrated improved OS. Prospective evaluation of high‐dose RT regimens with standardized treatment parameters in inoperable pancreatic cancer patients is warranted.
Adaptive magnetic resonance imaging (MRI)‐guided radiation therapy (RT) is a novel method to deliver dose‐escalated RT to inoperable pancreatic tumors. Dose‐escalated adaptive MRI‐guided RT improved survival without compromising safety.
The integration of adaptive radiation therapy (ART), or modifying the treatment plan during the treatment course, is becoming more widely available in clinical practice. ART offers strong potential ...for minimizing treatment-related toxicity while escalating or de-escalating target doses based on the dose to organs at risk. Yet, ART workflows add complexity into the radiation therapy planning and delivery process that may introduce additional uncertainties. This work sought to review presently available ART workflows and technological considerations such as image quality, deformable image registration, and dose accumulation. Quality assurance considerations for ART components and minimum recommendations are described. Personnel and workflow efficiency recommendations are provided, as is a summary of currently available clinical evidence supporting the implementation of ART. Finally, to guide future clinical trial protocols, an example ART physician directive and a physics template following standard NRG Oncology protocol is provided.
To investigate the dosimetric improvements in stereotactic body radiation therapy for patients with larger or central lung tumors using a highly noncoplanar 4π planning system.
This study involved 12 ...patients with centrally located or larger lung tumors previously treated with 7- to 9-field static beam intensity modulated radiation therapy to 50 Gy. They were replanned using volumetric modulated arc therapy and 4π plans, in which a column generation method was used to optimize the beam orientation and the fluence map. Maximum doses to the heart, esophagus, trachea/bronchus, and spinal cord, as well as the 50% isodose volume, the lung volumes receiving 20, 10, and 5 Gy were minimized and compared against the clinical plans. A dose escalation study was performed to determine whether a higher prescription dose to the tumor would be achievable using 4π without violating dose limits set by the clinical plans. The deliverability of 4π plans was preliminarily tested.
Using 4π plans, the maximum heart, esophagus, trachea, bronchus and spinal cord doses were reduced by 32%, 72%, 37%, 44%, and 53% (P≤.001), respectively, and R50 was reduced by more than 50%. Lung V20, V10, and V5 were reduced by 64%, 53%, and 32% (P≤.001), respectively. The improved sparing of organs at risk was achieved while also improving planning target volume (PTV) coverage. The minimal PTV doses were increased by the 4π plans by 12% (P=.002). Consequently, escalated PTV doses of 68 to 70 Gy were achieved in all patients.
We have shown that there is a large potential for plan quality improvement and dose escalation for patients with larger or centrally located lung tumors using noncoplanar beams with sufficient quality and quantity. Compared against the clinical volumetric modulated arc therapy and static intensity modulated radiation therapy plans, the 4π plans yielded significantly and consistently improved tumor coverage and critical organ sparing. Given the known challenges in central structure dose constraints in stereotactic body radiation therapy to the lung, 4π planning may increase efficacy and reduce toxicity.
The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this ...retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.
Glioblastoma is the most common brain tumor in adults. The mechanisms leading to glioblastoma are not well understood but animal studies support that inactivation of tumor suppressor genes in neural ...stem cells (NSC) is required and sufficient to induce glial cancers. This suggests that the NSC niches in the brain may harbor cancer stem cells (CSCs), Thus providing novel therapy targets. We hypothesize that higher radiation doses to these NSC niches improve patient survival by eradicating CSCs.
55 adult patients with Grade 3 or Grade 4 glial cancer treated with radiotherapy at UCLA between February of 2003 and May of 2009 were included in this retrospective study. Using radiation planning software and patient radiological records, the SVZ and SGL were reconstructed for each of these patients and dosimetry data for these structures was calculated.
Using Kaplan-Meier analysis we show that patients whose bilateral subventricular zone (SVZ) received greater than the median SVZ dose (= 43 Gy) had a significant improvement in progression-free survival if compared to patients who received less than the median dose (15.0 vs 7.2 months PFS; P = 0.028). Furthermore, a mean dose >43 Gy to the bilateral SVZ yielded a hazard ratio of 0.73 (P = 0.019). Importantly, similarly analyzing total prescription dose failed to illustrate a statistically significant impact.
Our study leads us to hypothesize that in glioma targeted radiotherapy of the stem cell niches in the adult brain could yield significant benefits over radiotherapy of the primary tumor mass alone and that damage caused by smaller fractions of radiation maybe less efficiently detected by the DNA repair mechanisms in CSCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Radiation therapy (RT) is an essential component of effective cancer care and is used across nearly all cancer types. The delivery of RT is becoming more precise through rapid advances in both ...computing and imaging. The direct integration of magnetic resonance imaging (MRI) with linear accelerators represents an exciting development with the potential to dramatically impact cancer research and treatment. These impacts extend beyond improved imaging and dose deposition. Real-time MRI-guided RT is actively transforming the work flows and capabilities of virtually every aspect of RT. It has the opportunity to change entirely the delivery methods and response assessments of numerous malignancies. This review intends to approach the topic of MRI-based RT guidance from a vendor neutral and international perspective. It also aims to provide an introduction to this topic targeted towards oncologists without a speciality focus in RT. Speciality implications, areas for physician education and research opportunities are identified as they are associated with MRI-guided RT. The uniquely disruptive implications of MRI-guided RT are discussed and placed in context. We further aim to describe and outline important future changes to the speciality of radiation oncology that will occur with MRI-guided RT. The impacts on RT caused by MRI guidance include target identification, RT planning, quality assurance, treatment delivery, training, clinical workflow, tumour response assessment and treatment scheduling. In addition, entirely novel research areas that may be enabled by MRI guidance are identified for future investigation.
•We present a review on the current state of MR-guided RT (RT).•Speciality implications, areas for physician education and research opportunities are identified.•Some impacts include target identification, quality assurance and tumour response assessment.
Late cardiotoxicity related to radiotherapy (RT) in breast cancer and Hodgkin’s lymphoma has been well-reported. However, the relatively higher cardiac dose exposure for esophageal cancer (EC) may ...result in the earlier onset of cardiac diseases. In this report, we examined the incidence, onset, and long-term survival outcomes of high-grade cardiac events after RT in a large cohort of patients with EC.
Between March 2005 and August 2017, a total of 479 patients with EC from a prospectively maintained institutional database at The University of Texas MD Anderson Cancer Center were analyzed. All patients were treated with either intensity-modulated RT or proton beam therapy, either preoperatively or definitively. We focused on any grade 3 or higher (G3+) cardiac events according to the Common Terminology Criteria for Adverse Events, version 5.0.
G3+ cardiac events occurred in 18% of patients at a median of 7 months with a median follow-up time of 76 months. Preexisting cardiac disease (p = 0.001) and radiation modality (intensity-modulated RT versus proton beam therapy) (p = 0.027) were significantly associated with G3+ cardiac events. Under multivariable analysis, the mean heart dose, particularly of less than 15 Gy, was associated with reduced G3+ events. Furthermore, G3+ cardiac events were associated with worse overall survival (p = 0.041).
Severe cardiac events were relatively common in patients with early onset EC after RT, especially those with preexisting cardiac disease and higher radiation doses to the heart. Optimal treatment approaches should be taken to reduce cumulative doses to the heart, especially for patients with preexisting cardiac disease.
To improve the quality of liver stereotactic body radiation therapy (SBRT) treatments, a novel 4π framework was developed with accompanying algorithms to optimize non-coplanar beam orientations and ...fluences. The dose optimization is performed on a patient-specific deliverable beam geometry solution space, parameterized with patient and linear accelerator gantry orientations.
Beams causing collision between the gantry and the couch or patient were eliminated by simulating all beam orientations using a precise computer assisted design model of the linear accelerator and a human subject. Integrated beam orientation and fluence map optimizations were performed on remaining beams using a greedy column generation method. Testing of the new method was performed on 10 liver SBRT cases previously treated with 50 to 60 Gy in 5 fractions using volumetric modulated arc therapy (VMAT). For each patient, both 14 and 22 non-coplanar fields were selected and optimized to meet the objective of ≥95% of the planning target volume (PTV) covered by 100% of the prescription dose. Doses to organs at risk, normal liver volumes receiving <15 Gy, integral dose, and 50% dose spillage volumes were compared against the delivered clinical VMAT plans.
Compared with the VMAT plans, the 4π plans yielded reduced 50% dose spillage volume and integral dose by 22% (range 10%-40%) and 19% (range 13%-26%), respectively. The mean normal liver volume receiving <15 Gy was increased by 51 cc (range 21-107 cc) with a 31% reduction of the mean normal liver dose. Mean doses to the left kidney and right kidney and maximum doses to the stomach and spinal cord were on average reduced by 70%, 51%, 67%, and 64% (P≤.05).
This novel 4π non-coplanar radiation delivery technique significantly improved dose gradient, reduced high dose spillage, and improved organ at risk sparing compared with state of the art VMAT plans.
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