Thomas J. Dilling

Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

OBJECTIVES Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients. METHODS Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews. RESULTS For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival. CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.

Clinical and Dosimetric Predictors of Radiation Pneumonitis in a Large Series of Patients Treated With Stereotactic Body Radiation Therapy to the Lung

PURPOSE To report clinical and dosimetric factors predictive of radiation pneumonitis (RP) in patients receiving lung stereotactic body radiation therapy (SBRT) from a series of 240 patients. METHODS AND MATERIALS Of the 297 isocenters treating 263 patients, 240 patients (n=263 isocenters) had evaluable information regarding RP. Age, gender, current smoking status and pack-years, O2 use, Charlson Comorbidity Index, prior lung radiation therapy (yes/no), dose/fractionation, V5, V13, V20, Vprescription, mean lung dose, planning target volume (PTV), total lung volume, and PTV/lung volume ratio were recorded. RESULTS Twenty-nine patients (11.0%) developed symptomatic pneumonitis (26 grade 2, 3 grade 3). The mean V20 was 6.5% (range, 0.4%-20.2%), and the average mean lung dose was 5.03 Gy (0.547-12.2 Gy). In univariable analysis female gender (P=.0257) and Charlson Comorbidity index (P=.0366) were significantly predictive of RP. Among dosimetric parameters, V5 (P=.0186), V13 (P=.0438), and Vprescription (where dose=60 Gy) (P=.0128) were significant. There was only a trend toward significance for V20 (P=.0610). Planning target volume/normal lung volume ratio was highly significant (P=.0024). In multivariable analysis the clinical factors of female gender, pack-years smoking, and larger gross internal tumor volume and PTV were predictive (P=.0094, .0312, .0364, and .052, respectively), but no dosimetric factors were significant. CONCLUSIONS Rate of symptomatic RP was 11%. Our mean lung dose was <600 cGy in most cases and V20<10%. In univariable analysis, dosimetric factors were predictive, while tumor size (or tumor/lung volume ratio) played a role in multivariable and univariable and analysis, respectively.

Volumetric modulated arc planning for lung stereotactic body radiotherapy using conventional and unflattened photon beams: a dosimetric comparison with 3D technique

PurposeFrequently, three-dimensional (3D) conformal beams are used in lung cancer stereotactic body radiotherapy (SBRT). Recently, volumetric modulated arc therapy (VMAT) was introduced as a new treatment modality. VMAT techniques shorten delivery time, reducing the possibility of intrafraction target motion. However dose distributions can be quite different from standard 3D therapy. This study quantifies those differences, with focus on VMAT plans using unflattened photon beams.MethodsA total of 15 lung cancer patients previously treated with 3D or VMAT SBRT were randomly selected. For each patient, non-coplanar 3D, coplanar and non-coplanar VMAT and flattening filter free VMAT (FFF-VMAT) plans were generated to meet the same objectives with 50 Gy covering 95% of the PTV. Two dynamic arcs were used in each VMAT plan. The couch was set at ± 5° to the 0° straight position for the two non-coplanar arcs. Pinnacle version 9.0 (Philips Radiation Oncology, Fitchburg WI) treatment planning system with VMAT capabilities was used. We analyzed the conformity index (CI), which is the ratio of the total volume receiving at least the prescription dose to the target volume receiving at least the prescription dose; the conformity number (CN) which is the ratio of the target coverage to CI; and the gradient index (GI) which is the ratio of the volume of 50% of the prescription isodose to the volume of the prescription isodose; as well as the V20, V5, and mean lung dose (MLD). Paired non-parametric analysis of variance tests with post-tests were performed to examine the statistical significance of the differences of the dosimetric indices.ResultsDosimetric indices CI, CN and MLD all show statistically significant improvement for all studied VMAT techniques compared with 3D plans (p < 0.05). V5 and V20 show statistically significant improvement for the FFF-VMAT plans compared with 3D (p < 0.001). GI is improved for the FFF-VMAT and the non-coplanar VMAT plans (p < 0.01 and p < 0.05 respectively) while the coplanar VMAT plans do not show significant difference compared to 3D plans. Dose to the target is typically more homogeneous in FFF-VMAT plans. FFF-VMAT plans require more monitor units than 3D or non-coplanar VMAT ones.ConclusionBesides the advantage of faster delivery times, VMAT plans demonstrated better conformity to target, sharper dose fall-off in normal tissues and lower dose to normal lung than the 3D plans for lung SBRT. More monitor units are often required for FFF-VMAT plans.

Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments

PURPOSE The effects of respiratory motion on the tumor dose can be divided into the gradient and interplay effects. While the interplay effect is likely to average out over a large number of fractions, it may play a role in hypofractionated [stereotactic body radiation therapy (SBRT)] treatments. This subject has been extensively studied for intensity modulated radiation therapy but less so for volumetric modulated arc therapy (VMAT), particularly in application to hypofractionated regimens. Also, no experimental study has provided full four-dimensional (4D) dose reconstruction in this scenario. The authors demonstrate how a recently described motion perturbation method, with full 4D dose reconstruction, is applied to describe the gradient and interplay effects during VMAT lung SBRT treatments. METHODS VMAT dose delivered to a moving target in a patient can be reconstructed by applying perturbations to the treatment planning system-calculated static 3D dose. Ten SBRT patients treated with 6 MV VMAT beams in five fractions were selected. The target motion (motion kernel) was approximated by 3D rigid body translation, with the tumor centroids defined on the ten phases of the 4DCT. The motion was assumed to be periodic, with the period T being an average from the empirical 4DCT respiratory trace. The real observed tumor motion (total displacement ≤ 8 mm) was evaluated first. Then, the motion range was artificially increased to 2 or 3 cm. Finally, T was increased to 60 s. While not realistic, making T comparable to the delivery time elucidates if the interplay effect can be observed. For a single fraction, the authors quantified the interplay effect as the maximum difference in the target dosimetric indices, most importantly the near-minimum dose (D99%), between all possible starting phases. For the three- and five-fractions, statistical simulations were performed when substantial interplay was found. RESULTS For the motion amplitudes and periods obtained from the 4DCT, the interplay effect is negligible (<0.2%). It is also small (0.9% average, 2.2% maximum) when the target excursion increased to 2-3 cm. Only with large motion and increased period (60 s) was a significant interplay effect observed, with D99% ranging from 16% low to 17% high. The interplay effect was statistically significantly lower for the three- and five-fraction statistical simulations. Overall, the gradient effect dominates the clinical situation. CONCLUSIONS A novel method was used to reconstruct the volumetric dose to a moving tumor during lung SBRT VMAT deliveries. With the studied planning and treatment technique for realistic motion periods, regardless of the amplitude, the interplay has nearly no impact on the near-minimum dose. The interplay effect was observed, for study purposes only, with the period comparable to the VMAT delivery time.

Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection

PURPOSE We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. METHODS AND MATERIALS Patients were identified from our institutional review board-approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. RESULTS The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). CONCLUSIONS Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.

Study of 201 non-small cell lung cancer patients given stereotactic ablative radiation therapy shows local control dependence on dose calculation algorithm.

PURPOSE Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). METHODS AND MATERIALS Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Grays competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. RESULTS Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Grays test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume. CONCLUSIONS Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.

Variability of Image Features Computed from Conventional and Respiratory-Gated PET/CT Images of Lung Cancer.

Radiomics is being explored for potential applications in radiation therapy. How various imaging protocols affect quantitative image features is currently a highly active area of research. To assess the variability of image features derived from conventional [three-dimensional (3D)] and respiratory-gated (RG) positron emission tomography (PET)/computed tomography (CT) images of lung cancer patients, image features were computed from 23 lung cancer patients. Both protocols for each patient were acquired during the same imaging session. PET tumor volumes were segmented using an adaptive technique which accounted for background. CT tumor volumes were delineated with a commercial segmentation tool. Using RG PET images, the tumor center of mass motion, length, and rotation were calculated. Fifty-six image features were extracted from all images consisting of shape descriptors, first-order features, and second-order texture features. Overall, 26.6% and 26.2% of total features demonstrated less than 5% difference between 3D and RG protocols for CT and PET, respectively. Between 10 RG phases in PET, 53.4% of features demonstrated percent differences less than 5%. The features with least variability for PET were sphericity, spherical disproportion, entropy (first and second order), sum entropy, information measure of correlation 2, Short Run Emphasis (SRE), Long Run Emphasis (LRE), and Run Percentage (RPC); and those for CT were minimum intensity, mean intensity, Root Mean Square (RMS), Short Run Emphasis (SRE), and RPC. Quantitative analysis using a 3D acquisition versus RG acquisition (to reduce the effects of motion) provided notably different image feature values. This study suggests that the variability between 3D and RG features is mainly due to the impact of respiratory motion.

Stereotactic body radiotherapy for early-stage non-small-cell lung cancer: report of the ASTRO Emerging Technology Committee.

*Fox Chase Cancer Center, Philadelphia, PA; yUniversity of Texas, MD Anderson Cancer Center, Houston, TX; zCancer Institute of New Jersey, New Brunswick, NJ; {Saint Barnabas Health Care System, Toms River, NJ; xH. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; **Mayo Clinic and Mayo Foundation, Rochester, MN; yyUniversity of Colorado Health Services, Boulder, CO; {{University of Wisconsin, Madison, WI; xxWayne State University School of Medicine, Detroit, MI; and ***21st Century Oncology, Inc, Moorestown, NJ.

Four-dimensional dosimetry validation and study in lung radiotherapy using deformable image registration and Monte Carlo techniques

Thoracic cancer treatment presents dosimetric difficulties due to respiratory motion and lung inhomogeneity. Monte Carlo and deformable image registration techniques have been proposed to be used in four-dimensional (4D) dose calculations to overcome the difficulties. This study validates the 4D Monte Carlo dosimetry with measurement, compares 4D dosimetry of different tumor sizes and tumor motion ranges, and demonstrates differences of dose-volume histograms (DVH) with the number of respiratory phases that are included in 4D dosimetry. BEAMnrc was used in dose calculations while an optical flow algorithm was used in deformable image registration and dose mapping. Calculated and measured doses of a moving phantom agreed within 3% at the center of the moving gross tumor volumes (GTV). 4D CT image sets of lung cancer cases were used in the analysis of 4D dosimetry. For a small tumor (12.5 cm3) with motion range of 1.5 cm, reduced tumor volume coverage was observed in the 4D dose with a beam margin of 1 cm. For large tumors and tumors with small motion range (around 1 cm), the 4D dosimetry did not differ appreciably from the static plans. The dose-volume histogram (DVH) analysis shows that the inclusion of only extreme respiratory phases in 4D dosimetry is a reasonable approximation of all-phase inclusion for lung cancer cases similar to the ones studied, which reduces the calculation in 4D dosimetry.

Impact of Gender, Partner Status, and Race on Locoregional Failure and Overall Survival in Head and Neck Cancer Patients in Three Radiation Therapy Oncology Group Trials

PURPOSE We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). METHODS AND MATERIALS Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. RESULTS A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09-1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09-1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09-1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09-1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05-1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. CONCLUSIONS Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination.