Summary Background Evidence from retrospective studies suggests that disease progression after first-line chemotherapy for metastatic non-small-cell lung cancer (NSCLC) occurs most often at sites of ...disease known to exist at baseline. However, the potential effect of aggressive local consolidative therapy for patients with oligometastatic NSCLC is unknown. We aimed to assess the effect of local consolidative therapy on progression-free survival. Methods In this multicentre, randomised, controlled, phase 2 study, eligible patients from three hospitals had histological confirmation of stage IV NSCLC, three or fewer metastatic disease lesions after first-line systemic therapy, an Eastern Cooperative Oncology Group performance status score of 2 or less, had received standard first-line systemic therapy, and had no disease progression before randomisation. First-line therapy was four or more cycles of platinum doublet therapy or 3 or more months of EGFR or ALK inhibitors for patients with EGFR mutations or ALK rearrangements, respectively. Patients were randomly assigned (1:1) to either local consolidative therapy (chemoradiotherapy or resection of all lesions) with or without subsequent maintenance treatment or to maintenance treatment alone, which could be observation only. Maintenance treatment was recommended based on a list of approved regimens, and observation was defined as close surveillance without cytotoxic treatment. Randomisation was not masked and was balanced dynamically on five factors: number of metastases, response to initial therapy, CNS metastases, intrathoracic nodal status, and EGFR and ALK status. The primary endpoint was progression-free survival analysed in all patients who were treated and had at least one post-baseline imaging assessment. The study is ongoing but not recruiting participants. This study is registered with ClinicalTrials.gov , number NCT01725165. Findings Between Nov 28, 2012, and Jan 19, 2016, 74 patients were enrolled either during or at the completion of first-line systemic therapy. The study was terminated early after randomisation of 49 patients (25 in the local consolidative therapy group and 24 in the maintenance treatment group) as part of the annual analyses done by the Data Safety Monitoring Committee of all randomised trials at MD Anderson Cancer Center, and before a planned interim analysis of 44 events. At a median follow-up time for all randomised patients of 12·39 months (IQR 5·52–20·30), the median progression-free survival in the local consolidative therapy group was 11·9 months (90% CI 5·7–20·9) versus 3·9 months (2·3–6·6) in the maintenance treatment group (hazard ratio 0·35 90% CI 0·18–0·66, log-rank p=0·0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Grade 3 adverse events in the maintenance therapy group were fatigue (n=1) and anaemia (n=1) and in the local consolidative therapy group were oesophagitis (n=2), anaemia (n=1), pneumothorax (n=1), and abdominal pain (n=1, unlikely related). Interpretation Local consolidative therapy with or without maintenance therapy for patients with three or fewer metastases from NSCLC that did not progress after initial systemic therapy improved progression-free survival compared with maintenance therapy alone. These findings suggest that aggressive local therapy should be further explored in phase 3 trials as a standard treatment option in this clinical scenario. Funding MD Anderson Lung Cancer Priority Fund, MD Anderson Cancer Center Moon Shot Initiative, and Cancer Center Support (Core), National Cancer Institute, National Institutes of Health.
To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive ...non-small cell lung cancer (NSCLC) patients.
Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤ 4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT.
Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progression meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤ 25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤ 12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001).
Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose-response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.
Mepolizumab was the first licensed anti-IL5 monoclonal antibody for severe eosinophilic asthma (SEA). To date there are few data to confirm its efficacy in the real-world setting or assessment of ...baseline characteristics associated with response.
How do patients with severe eosinophilic asthma respond to mepolizumab in the real world setting and which characteristics are associated with a super-response to this therapy?
We conducted a retrospective review of all patients who received at least 16 weeks of treatment with mepolizumab (100 mg subcutaneously) for SEA at our regional asthma center in the United Kingdom. Clinical data were collected at each 4-week visit. At 16, 24, and 52 weeks, patients were classified as “responders” or “nonresponders.” A response was defined as ≥50% reduction in exacerbations; for patients whose condition requires maintenance oral corticosteroids (mOCS), a response was defined as ≥50% reduction in prednisolone dose. Super responders were defined as exacerbation-free and off mOCS at one year.
Ninety-nine patients were included in the analysis. Asthma exacerbations decreased from a baseline of 4.04 ± 2.57 to 1.86 ± 2.17 per year at one year (54% reduction; P < .001). Sixty-eight patients were receiving mOCS at the time of commencing mepolizumab. By one year, the daily median dose fell from 10 mg (interquartile range, 10 to 15) to 0 mg (interquartile range, 0 to 10; P < .001). Fifty-seven percent of them were able to discontinue mOCS; 72.7% (95% CI, 63.0 to 80.7) of the patients were classified as responders, and 28.3% (95% CI, 20.2 to 38.0) of the patients were classified as super responders. Baseline characteristics associated with responder and super responder status included the presence of nasal polyposis (P = .012), lower baseline Asthma Control Questionnaire 6 (P = .006), a lower BMI (P = .014), and, in those patients receiving mOCS, a significantly lower prednisolone dose at baseline (P = .005). At 16 weeks, the one-year responder status was correctly identified in 80.8% patients; by 24 weeks, this status rose to 92.9%.
In a real-world SEA cohort, treatment with mepolizumab reduced exacerbation frequency and mOCS requirements. Nasal polyposis, a lower BMI, and a lower maintenance prednisolone requirement at baseline were associated with better outcomes. Twelve-month response was identifiable in >90% of patients by week 24.
The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that ...influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. “Classic” RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a “critical volume” of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.
Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation ...rates and maintenance oral corticosteroids (mOCSs).
What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy?
We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma.
One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 56.9%), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients.
In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.
A Portrait of the Artist as a Younger Man Kavanagh, Brian D
International journal of radiation oncology, biology, physics,
2021-Dec-01, Letnik:
111, Številka:
5
Journal Article
To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to ...rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury.
Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer.
At the highest dose level, 6.6% of patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm(3) (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010).
Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.
The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer ...radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic.
For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk–benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC.
In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided.
This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.
•Recommendations for risk-mitigation pandemic scenario:•Do not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice.•Postponement or interruption of radiotherapy of COVID-19 positive patients is generally recommended Severe pandemic scenario characterized by reduced resources:•Factors for patient triage include potential for cure, relative benefit of radiation, life expectancy, and performance status.
Published data suggest that the risk of moderately severe (>or=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the ...volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely related to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.
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