David Palma

Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review.

OBJECTIVESnPatients with severe chronic obstructive pulmonary disease (COPD) have a high risk of lung cancer and of postsurgical complications. We studied outcomes after stereotactic body radiotherapy (SBRT) in patients with severe COPD, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and performed a systematic review of the literature on outcomes after SBRT or surgery in these patients.nnnMETHODSnA single-institution cohort of 176 patients with COPD GOLD III-IV and Stage I non-small-cell lung cancer (NSCLC) treated with SBRT was evaluated. A systematic review identified studies reporting outcomes after SBRT or surgery for Stage I NSCLC in patients with GOLD III-IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of ≤40%.nnnRESULTSnIn the single-institution cohort, median follow-up was 21 months and median overall survival (OS) was 32 months. Actuarial 3-year local control was 89%, and 1- and 3-year OS were 79% and 47%, respectively. COPD severity correlated with OS (p = 0.01). The systematic review identified four other studies (two surgical, two SBRT, n = 196 patients). SBRT studies were published more recently and included older patients than surgical studies. Mean 30-day mortality was 0% post-SBRT and 10% after surgery. Local or locoregional control was high (≥89%) after both treatments. Post-SBRT, actuarial OS was 79-95% at 1 year and 43-70% at 3 years. Postsurgical actuarial OS was 45-86% at 1 year and 31-66% at 3 years.nnnCONCLUSIONSnSBRT and surgery differ in risk of 30-day mortality in patients with severe COPD. Despite the negative selection of SBRT patients, survival at 1 and 3 years is comparable between the two treatments.

Treatment of stage I NSCLC in elderly patients: A population-based matched-pair comparison of stereotactic radiotherapy versus surgery

BACKGROUNDnElderly patients with stage I NSCLC who undergo surgical resection are at high risk of treatment-related toxicity. Stereotactic body radiation therapy (SBRT) may provide an alternative treatment with a favorable toxicity profile.nnnMETHODSnA population-based registry in North-Holland was used to conduct a matched-pair analysis of overall survival (OS) after surgery versus SBRT for elderly patients (age ⩾75) who were diagnosed between 2005 and 2007. Patients were matched by age, stage, gender, and treatment year; co-morbidity data was not available. SBRT was delivered at two centers; 17 centers provided surgery.nnnRESULTSnA total of 120 patients could be matched (60 surgery, 60 SBRT). Median age was 79years, 67% were male, and 64% had T1 disease. Median follow-up was 43months. Thirty-day mortality was 8.3% after surgery and 1.7% after SBRT. OS at one- and three-years was 75% and 60% after surgery, and 87% and 42% after SBRT, respectively (log-rank p=0.22). Limiting the analysis to SBRT patients with pathological confirmation of disease and their matches revealed no significant difference between groups.nnnCONCLUSIONnSimilar OS outcomes are achieved with surgery or SBRT for stage I NSCLC in elderly patients. Comorbidity data and outcomes from centralized surgical programs are needed for more robust conclusions.

Treatment of large stage I-II lung tumors using stereotactic body radiotherapy (SBRT): Planning considerations and early toxicity

PURPOSEnTo study the dosimetric predictors of early clinical toxicity following SBRT in patients with lung tumors and planning target volumes (PTV) exceeding 80 cm(3).nnnMETHODSnEighteen consecutive patients who were treated using volumetric modulated arc therapy (RapidArc™) were assessed. All were either unfit or refused to undergo surgery or chemoradiotherapy. PTV planning objectives were as used in the ROSEL study protocol. Clinical toxicity was scored using Common Toxicity Criteria AE4.0. Lung volumes receiving 5, 10, 15, and 20 Gy (V(5), V(10), V(15) and V(20)) and mean lung dose were assessed and correlated to symptomatic radiation pneumonitis (RP).nnnRESULTSnMedian age, age-adjusted Charlson-comorbidity score and PTV size were 74, 7.5 and 137 cm(3), respectively. At a median follow-up of 12.8 months, 8 deaths were recorded: 5 arising from comorbidity, 2 were potentially treatment-related and 1 had local recurrence. RP was reported in 5 patients (grade 2 in 3 and grade 3 in 2). All RP occurred in plans without a high priority optimization objective on contralateral lung. Acute RP was best predicted by contralateral lung V(5) (p<0.0001).nnnCONCLUSIONnAfter SBRT using RapidArc in lung tumors >80 cm(3), the contralateral lung V(5) best predicts RP. Limiting contralateral lung V(5) to <26% may reduce acute toxicity.

New developments in arc radiation therapy: A review

Arc therapies have gained widespread clinical interest in radiation oncology over the past decade. Arc therapies have several potential advantages over standard techniques such as intensity-modulated radiation therapy, with implications for patients, administrators, and oncologists. This review focuses on the rationale for arc therapy, descriptions of the modern arc techniques that are currently clinically available, and highlights some distinguishing features of arc therapies, such as dose distributions, treatment times, and imaging capabilities. Arc therapies are exciting examples of progress in radiotherapy through technological innovation, aimed at ultimately improving the therapeutic ratio for patients receiving radiation.

Radiological Changes After Stereotactic Radiotherapy for Stage I Lung Cancer

Introduction: Stereotactic body radiation therapy (SBRT) is entering routine clinical use for selected patients with early-stage non-small cell lung cancer. Post-SBRT radiological changes are commonly seen on follow-up computed tomography (CT) imaging and can cause diagnostic dilemmas. The aim of this study is to describe the incidence, radiological severity, and long-term morphology of these changes. Methods: CT scans from patients treated between 2003 and June 2008 were eligible for evaluation if radiological follow-up had been performed at our center for at least 2 years, and there was no definite evidence of local recurrence. Timing, incidence, morphology, and severity of lung changes were determined. Results: CT scans from 61 patients (68 lesions) with a median follow-up of 2.5 years were evaluated. Within 6 months, 54% of lesions were associated with additional radiological abnormalities, and this figure reached 99% after 36 months. Most changes were scored as mild to moderate, and although the median time to first observation was 17 weeks, 25% appeared ≥1 year post-SBRT. In 47% of lesions, the morphology or severity of changes continued to evolve more than 2 years posttreatment. Conclusions: Mild-moderate radiological changes are common after lung SBRT. Some degree of late change is nearly universal, and it often continues to evolve more than 2 years post-SBRT. Clinicians should be aware of these radiological findings, which need to be distinguished from the uncommon cases of local failure post-SBRT.

Lung Density Changes After Stereotactic Radiotherapy: A Quantitative Analysis in 50 Patients

PURPOSEnRadiologic lung density changes are observed in more than 50% of patients after stereotactic body radiotherapy (SBRT) for lung cancer. We studied the relationship between SBRT dose and posttreatment computed tomography (CT) density changes, a surrogate for lung injury.nnnMETHODS AND MATERIALSnThe SBRT fractionation schemes used to treat Stage I lung cancer with RapidArc were three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, prescribed at the 80% isodose. Follow-up CT scans performed at less than 6 months (n = 50) and between 6 and 9 months (n = 30) after SBRT were reviewed. Posttreatment scans were coregistered with baseline scans using a B-spline deformable registration algorithm. Voxel-Hounsfield unit histograms were created for doses between 0.5 and 50 Gy. Linear mixed effects models were used to assess the effects of SBRT dose on CT density, and the influence of possible confounders was tested.nnnRESULTSnIncreased CT density was associated with higher dose, increasing planning target volume size, and increasing time after SBRT (all p < 0.0001). Density increases were apparent in areas receiving >6 Gy, were most prominent in areas receiving >20 Gy, and seemed to plateau above 40 Gy. In regions receiving >36 Gy, the reduction in air-filled fraction of lung after treatment was up to 18%. No increase in CT density was observed in the contralateral lung receiving ≥3 Gy.nnnCONCLUSIONSnA dose-response relationship exists for quantitative CT density changes after SBRT. A threshold of effect is seen at low doses, and a plateau at highest doses.

Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: Outcomes of a markov model analysis

BACKGROUND AND PURPOSEnTo model outcomes of SBRT versus best supportive care (BSC) in elderly COPD patients with stage I NSCLC.nnnMATERIAL AND METHODSnA Markov model was constructed to simulate the quality-adjusted and overall survival (OS) in patients ⩾75years undergoing either SBRT or BSC for a five-year timeframe. SBRT rates of local, regional and distant recurrences were obtained from 247 patients treated at the VUMC, Amsterdam. Recurrence rates were converted into transition probabilities and stratified into four groups according to T stage (1, 2) and COPD GOLD score (I-II, III-IV). Data for untreated patients were obtained from the California Cancer Registry. Tumor stage and GOLD score utilities were adapted from the literature.nnnRESULTSnOur model correlated closely with the source OS data for SBRT treated and untreated patients. After SBRT, our model predicted for 6.8-47.2% five-year OS and 14.9-27.4 quality adjusted life months (QALMs). The model predicted for 9.0% and 2.8% five-year OS, and 10.1 and 6.1 QALMs for untreated T1 and T2 patients, respectively. The benefit of SBRT was the least for T2, GOLD III-IV patients.nnnCONCLUSIONnOur model indicates that SBRT should be considered in elderly stage I NSCLC patients with COPD.

Time and dose-related changes in radiological lung density after concurrent chemoradiotherapy for lung cancer

Radiation pneumonitis is an important cause of morbidity after concurrent thoracic chemoradiotherapy (CCRT). However, asymptomatic changes in lung density on computed tomography (CT)-scans occur more commonly, and correspond to regions of inflammatory changes. Characterization of dose- and time-related changes in radiological lung density (RLD) may facilitate improved radiation planning, and allow for a more objective measure for assessing damage. We studied changes in RLD following CCRT with cisplatin-etoposide, using deformable registration to co-register follow-up scans. All CT-scans performed for up to 24 months post-treatment were evaluated in 25 patients treated with CCRT for stage III non-small-cell lung cancer. A total of 104 scans (median of 3 per patient) were co-registered with planning scans using a deformable registration tool (VelocityAI, Atlanta, USA). Last follow-up scan was at median 9.4 months (range 3.4-22.6 months). Seven patients developed clinical radiation pneumonitis. RLD changes (in Hounsfield units) were measured in regions receiving 3-66Gy. Linear mixed models were used to study dose-density changes over time. No significant changes in RLD were observed in the first 3 months post-treatment. Increases in RLD were observed at 3-6 months (p<0.0001) and 6-12 months (p=0.006), but stabilized at 1 year. Increases were most evident in regions receiving >30Gy, with only minor density changes at lower dose levels. Planning target volume size was significantly associated with RLD changes (p=0.03). Limiting lung doses to ≤30Gy during CCRT may limit sub-clinical damage, and the time-course of RLD changes may allow for early quantification of pulmonary damage when evaluating novel treatment strategies.

3D human lung histology reconstruction and registration to in vivo imaging.

Stereotactic ablative radiotherapy (SABR) delivers high-dose-per-fraction radiotherapy to tumours and spares surrounding tissue. It is effective for early-stage non-small cell lung cancer. However, SABR causes radiationinduced lung injuries that mimic recurring cancer, confounding detection of recurrences and early salvage therapy. We have previously developed radiomics-based recurrence detection. However, our radiomics system needs to be validated against histologic markers of viable tumour post-SABR. In this paper, our goals were to develop semiautomatic (1) 2D reconstruction of pseudo whole-mount (PWM) tissue sections from scanned slides, (2) 3D reconstruction and registration of PWM sections to pre-surgery computed tomography (CT), and (3) quantitative registration error measurement. Lobectomy tissue sections on standard 1” × 3” slides were obtained from patients who underwent SABR. Our graphical user interface allows interactive stitching of the sections into PWMs. Using our developed 3D Slicer-based thin-plate spline warping tool, we performed 3D PWM reconstruction and registered them to CT via correspondence of homologous intrinsic landmarks. The target registration error for 229 fiducial pairs defining vessels and airways was calculated for 56 PWMs reconstructed from 9 patients. We measured a mean of 7.33 mm, standard deviation of 4.59 mm and root mean square of 8.65 mm. This proof-of-principle study demonstrates for the first time that it is feasible to register in vivo human lung CT images with histology, with no modifications to the clinical pathology workflow other than videography to document gross dissection. Ongoing work to automate this process will yield a tool for histologic lung imaging and radiomics validation.

Early detection of lung cancer recurrence after stereotactic ablative radiation therapy: radiomics system design.

Stereotactic ablative radiotherapy (SABR) is the standard treatment recommendation for Stage I non-small cell lung cancer (NSCLC) patients who are inoperable or who refuse surgery. This option is well tolerated by even unfit patients and has a low recurrence risk post-treatment. However, SABR induces changes in the lung parenchyma that can appear similar to those of recurrence, and the difference between the two at an early follow-up time point is not easily distinguishable for an expert physician. We hypothesized that a radiomics signature derived from standard-of-care computed tomography (CT) imaging can detect cancer recurrence within six months of SABR treatment. This study reports on the design phase of our work, with external validation planned in future work. In this study, we performed cross-validation experiments with four feature selection approaches and seven classifiers on an 81-patient data set. We extracted 104 radiomics features from the consolidative and the peri-consolidative regions on the follow-up CT scans. The best results were achieved using the sum of estimated Mahalanobis distances (Maha) for supervised forward feature selection and a trainable automatic radial basis support vector classifier (RBSVC). This system produced an area under the receiver operating characteristic curve (AUC) of 0.84, an error rate of 16.4%, a false negative rate of 12.7%, and a false positive rate of 20.0% for leaveone patient out cross-validation. This suggests that once validated on an external data set, radiomics could reliably detect post-SABR recurrence and form the basis of a tool assisting physicians in making salvage treatment decisions.