Olfred Hansen

Influence of Late Side-Effects Upon Daily Life After Radiotherapy for Laryngeal and Pharyngeal Cancer

The influence on daily life from long-term side-effects was studied in patients treated more than 5 years ago with radiotherapy for laryngeal and pharyngeal cancer. Forty-six patients were asked to participate in telephone interviews and 44 participated. Only a minority (10%) stated serious problems related to the treatment. Problems related to the voice and severe xerostomia were especially mentioned. Half of the patients treated for pharyngeal cancer, complained of xerostomia and had occasionally a feeling of being handicapped. Social relations were impaired in 10% of the patients and 10% had retired due to their cancer or therapy related side-effects. It is concluded that radiotherapy seems to be a well tolerated treatment with relatively little impairment of the daily life in patients with laryngeal cancer. In patients with pharyngeal cancer, xerostomia is a major problem, which often persists more than 5 years after treatment.

Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. Results: Stromal CD8+ TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables. Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11); 2635–43. ©2015 AACR.

Phase III Trial Comparing Vinflunine With Docetaxel in Second-Line Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy

PURPOSE To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy. PATIENTS AND METHODS Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m(2) or docetaxel 75 mg/m(2) every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety. RESULTS Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed. CONCLUSION This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.

Locoregional Control of Non-Small Cell Lung Cancer in Relation to Automated Early Assessment of Tumor Regression on Cone Beam Computed Tomography

PURPOSE Large interindividual variations in volume regression of non-small cell lung cancer (NSCLC) are observable on standard cone beam computed tomography (CBCT) during fractionated radiation therapy. Here, a method for automated assessment of tumor volume regression is presented and its potential use in response adapted personalized radiation therapy is evaluated empirically. METHODS AND MATERIALS Automated deformable registration with calculation of the Jacobian determinant was applied to serial CBCT scans in a series of 99 patients with NSCLC. Tumor volume at the end of treatment was estimated on the basis of the first one third and two thirds of the scans. The concordance between estimated and actual relative volume at the end of radiation therapy was quantified by Pearsons correlation coefficient. On the basis of the estimated relative volume, the patients were stratified into 2 groups having volume regressions below or above the population median value. Kaplan-Meier plots of locoregional disease-free rate and overall survival in the 2 groups were used to evaluate the predictive value of tumor regression during treatment. Cox proportional hazards model was used to adjust for other clinical characteristics. RESULTS Automatic measurement of the tumor regression from standard CBCT images was feasible. Pearsons correlation coefficient between manual and automatic measurement was 0.86 in a sample of 9 patients. Most patients experienced tumor volume regression, and this could be quantified early into the treatment course. Interestingly, patients with pronounced volume regression had worse locoregional tumor control and overall survival. This was significant on patient with non-adenocarcinoma histology. CONCLUSIONS Evaluation of routinely acquired CBCT images during radiation therapy provides biological information on the specific tumor. This could potentially form the basis for personalized response adaptive therapy.

Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer: An updated retrospective study on local failure and survival rates

Abstract Introduction. Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is now an accepted and patient friendly treatment, but still controversy exists about its comparability to conventional radiation therapy (RT). The purpose of this single-institutional report is to describe survival outcome for medically inoperable patients with early stage NSCLC treated with SBRT compared with high dose conventional RT. Material and methods. From August 2005 to June 2012, 100 medically inoperable patients were treated with SBRT at Odense University Hospital. The thoracic RT consisted of 3 fractions (F) of 15–22 Gy delivered in nine days. For comparison a group of 32 medically inoperable patients treated with conventional RT with 80 Gy/35–40 F (5 F/week) in the period of July 1998 to August 2011 were analyzed. All tumors had histological or cytological proven NSCLC T1-2N0M0. Results. The median overall survival was 36.1 months versus 24.4 months for SBRT and conventional RT, respectively (p = 0.015). Local failure-free survival rates at one year were in SBRT group 93% versus 89% in the conventional RT group and at five years 69% versus 66%, SBRT and conventional RT respectively (p = 0.99). On multivariate analysis, female gender and performance status of 0–1 and SBRT predicted improved prognosis. Conclusion. In a cohort of patients with NSCLC there was a significant difference in overall survival favoring SBRT. Performance status of 0–1, female gender and SBRT predicted improved prognosis. However, staging procedure, confirmation procedure of recurrence and technical improvements of radiation treatment is likely to influence outcomes. However, SBRT seems to be as efficient as conventional RT and is a more convenient treatment for the patients.

Radiation dose response of normal lung assessed by Cone Beam CT – A potential tool for biologically adaptive radiation therapy

BACKGROUND Density changes of healthy lung tissue during radiotherapy as observed by Cone Beam CT (CBCT) might be an early indicator of patient specific lung toxicity. This study investigates the time course of CBCT density changes and tests for a possible correlation with locally delivered dose. METHODS A total of 665 CBCTs in 65 lung cancer patients treated with IMRT/VMAT to 60 or 66 Gy in 2 Gy fractions were analyzed. For each patient, CBCT lung density changes during the treatment course were related to the locally delivered dose. RESULTS A dose response is observed for the patient population at the end of the treatment course. However, the observed dose response is highly variable among patients. Density changes at 10th and 20th fraction are clearly correlated to those observed at the end of the treatment course. CONCLUSIONS CBCT density changes in healthy lung tissue during radiotherapy correlate with the locally delivered dose and can be detected relatively early during the treatment. If these density changes are correlated to subsequent clinical toxicity this assay could form the basis for biological adaptive radiotherapy.

Survival prediction of non-small cell lung cancer patients using radiomics analyses of cone-beam CT images

BACKGROUND AND PURPOSE In this study we investigated the interchangeability of planning CT and cone-beam CT (CBCT) extracted radiomic features. Furthermore, a previously described CT based prognostic radiomic signature for non-small cell lung cancer (NSCLC) patients using CBCT based features was validated. MATERIAL AND METHODS One training dataset of 132 and two validation datasets of 62 and 94stage I-IV NSCLC patients were included. Interchangeability was assessed by performing a linear regression on CT and CBCT extracted features. A two-step correction was applied prior to model validation of a previously published radiomic signature. Results 13.3% (149 out of 1119) of the radiomic features, including all features of the previously published radiomic signature, showed an R2 above 0.85 between intermodal imaging techniques. For the radiomic signature, Kaplan-Meier curves were significantly different between groups with high and low prognostic value for both modalities. Harrells concordance index was 0.69 for CT and 0.66 for CBCT models for dataset 1. Conclusions The results show that a subset of radiomic features extracted from CT and CBCT images are interchangeable using simple linear regression. Moreover, a previously developed radiomics signature has prognostic value for overall survival in three CBCT cohorts, showing the potential of CBCT radiomics to be used as prognostic imaging biomarker.

Pattern of loco-regional failure after definitive radiotherapy for non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) is associated with poor survival even though patients are treated with curatively intended radiotherapy. Survival is affected negatively by lack of loco-regional tumour control, but survival is also influenced by comorbidity caused by age and smoking, and occurrence of distant metastasis. It is challenging to evaluate loco-regional control after definitive radiotherapy for NSCLC since it is difficult to distinguish between radiation-induced damage to the lung tissue and tumour progression/recurrence. In addition it may be useful to distinguish between intrapulmonary failure and mediastinal failure to be able to optimize radiotherapy in order to improve loco-regional control even though it is not easy to discriminate between the two sites of failure. Material and methods. This study is a retrospective analysis of 331 NSCLC patients treated with definitive radiotherapy from 2002 to 2011. The patients were treated consecutively at the Department of Oncology, Odense University Hospital, Denmark with at least 60 Gy. All patients were followed in a planned follow-up schedule and no patients were lost for follow-up. Results. At the time of the analysis 93 patients had loco-regional failure only. Of these patients, 68 had intrapulmonary failure only, one patient had failure in mediastinum only, and 24 patients had intrapulmonary failure as well as mediastinal failure. Of the patients which had lung failure only, 78% had mediastinal involvement at treatment start. The only covariate with significant impact on developing intrapulmonary failure only was gross tumour volume. Median survival for the total group of 331 patients was 19 months. The median survival for patients with intrapulmonary failure only was 19 months, and it was 20 months for the patients with mediastinal relapse. Conclusion. We conclude that focus should be on increasing doses to intrapulmonary tumour volume, when dose escalation is applied to improve local tumour control in NSCLC patients treated with definitive radiotherapy, since most recurrences are located here.

Prediction of lung density changes after radiotherapy by cone beam computed tomography response markers and pre-treatment factors for non-small cell lung cancer patients.

BACKGROUND AND PURPOSE This study investigates the ability of pre-treatment factors and response markers extracted from standard cone-beam computed tomography (CBCT) images to predict the lung density changes induced by radiotherapy for non-small cell lung cancer (NSCLC) patients. METHODS AND MATERIALS Density changes in follow-up computed tomography scans were evaluated for 135 NSCLC patients treated with radiotherapy. Early response markers were obtained by analysing changes in lung density in CBCT images acquired during the treatment course. The ability of pre-treatment factors and CBCT markers to predict lung density changes induced by radiotherapy was investigated. RESULTS Age and CBCT markers extracted at 10th, 20th, and 30th treatment fraction significantly predicted lung density changes in a multivariable analysis, and a set of response models based on these parameters were established. The correlation coefficient for the models was 0.35, 0.35, and 0.39, when based on the markers obtained at the 10th, 20th, and 30th fraction, respectively. CONCLUSIONS The study indicates that younger patients without lung tissue reactions early into their treatment course may have minimal radiation induced lung density increase at follow-up. Further investigations are needed to examine the ability of the models to identify patients with low risk of symptomatic toxicity.

Time evolution of regional CT density changes in normal lung after IMRT for NSCLC

PURPOSE This study investigates the clinical radiobiology of radiation induced lung disease in terms of regional computed tomography (CT) density changes following intensity modulated radiotherapy (IMRT) for non-small-cell lung cancer (NSCLC). METHODS A total of 387 follow-up CT scans in 131 NSCLC patients receiving IMRT to a prescribed dose of 60 or 66 Gy in 2 Gy fractions were analyzed. The dose-dependent temporal evolution of the density change was analyzed using a two-component model, a superposition of an early, transient component and a late, persistent component. RESULTS The CT density of healthy lung tissue was observed to increase significantly (p<0.0001) for all dose levels after IMRT. The time evolution and the size of the density signal depend on the local delivered dose. The transient component of the density signal was found to peak in the range of 3-4 months, while the density tends to stabilize at times >12 months. CONCLUSIONS The radiobiology of lung injury may be analyzed in terms of CT density change. The initial transient change in density is consistent with radiation pneumonitis, while the subsequent stabilization of the density is consistent with pulmonary fibrosis.