Small Lung Tumors Research Articles

Monte Carlo evaluation of the dose calculation algorithm of TomoTherapy for clinical cases in dynamic jaws mode

PurposeFor the TomoTherapy® system, longitudinal conformation can be improved by selecting a smaller field width but at the expense of longer treatment time. Recently, the TomoEdge® feature has been released with the possibility to move dynamically the jaws at the edges of the target volume, improving longitudinal penumbra and enabling faster treatments. Such delivery scheme requires additional modeling of treatment delivery. Using a previously validated Monte Carlo model (TomoPen), we evaluated the accuracy of the implementation of TomoEdge in the new dose engine of TomoTherapy for 15 clinical cases. MethodsTomoPen is based on PENELOPE. Particle tracking in the treatment head is performed almost instantaneously by 1) reading a particle from a phase-space file corresponding to the largest field and 2) correcting the weight of the particle depending on the actual jaw and MLC configurations using Monte Carlo pre-generated data. 15 clinical plans (5 head-and-neck, 5 lung and 5 prostate tumors) planned with TomoEdge and with the last release of the treatment planning system (VoLO®) were re-computed with TomoPen. The resulting dose-volume histograms were compared. ResultsGood agreement was achieved overall, with deviations for the target volumes typically within 2% (D95), excepted for small lung tumors (17 cm3) where a maximum deviation of 4.4% was observed for D95. The results were consistent with previously reported values for static field widths. ConclusionsFor the clinical cases considered in the present study, the introduction of TomoEdge did not impact significantly the accuracy of the computed dose distributions.

Abstract 20: POT1 mutations predispose to familial melanoma

Abstract Mutations in CDKN2A account for approximately 40% of familial melanoma cases, and rare mutations in CDK4, BRCA2, BAP1 and in the promoter of TERT also contribute to the disease. However, about half of familial melanoma cases remain unaccounted for. Here we set out to identify high-penetrance susceptibility genes in these unexplained cases. To achieve this, we sequenced 184 melanoma cases from 105 pedigrees (168 exomes and 16 whole genomes) recruited in the United Kingdom, the Netherlands, and Australia that had been screened and found negative for pathogenetic variants in CDKN2A and CDK4. These patients came from pedigrees with between two and eleven cases of melanoma or were single cases that presented with either multiple primary melanomas, multiple primary cancers, one of which was melanoma, and/or an early age of onset (<4th decade). Analysis of these data showed that these pedigrees carried no mutations in BAP1 or BRCA2. We found three missense and one splice acceptor mutation, each co-segregating in a different pedigree, in the protection of telomeres 1 (POT1) gene. Importantly, the missense mutations were all located in the highly conserved N-terminal oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, which function to mediate protein – DNA binding. We show that these mutations completely abolish the POT1-DNA complex. Furthermore, we use two methods (one bioinformatic, the other experimental) to assess telomere length in POT1 missense mutation carriers and non-carriers, conclusively showing that individuals with POT1 mutations have substantially longer telomeres than controls. We also amplified and sequenced the POT1 gene product in two of the splice acceptor mutation carriers, showing that the mutation does lead to aberrant splicing. The families that carry POT1 mutations in this study present not only with melanoma but also with other cancers, namely breast, small cell lung, endometrial and brain tumours, suggesting a possible role for germline POT1 mutations in susceptibility to a range of cancers in addition to melanoma. Furthermore, genotyping across the four identified positions in a melanoma case-control series (1,739 cases and 2,402 controls) revealed that each of two cases carried one of these mutations, whereas no mutations were found in controls, suggesting that POT1 mutations could also account for sporadic melanoma cases. In this study we describe germline mutations in the gene encoding the telomere-associated protein POT1 in almost 4% of CDKN2A/CDK4-negative familial melanoma pedigrees and in almost 6% of pedigrees with five or more melanoma cases, making POT1 the second most frequently mutated high-penetrance familial melanoma gene reported to date. In combination with the recently described TERT promoter mutation, these findings significantly extend our understanding of a novel mechanism predisposing to the development of familial melanoma. Since the dysregulation of telomere protection by POT1 has recently been identified as a target for potential therapeutic intervention, in the future, it may be possible that early identification of families with POT1 mutations may facilitate better management of their disease. Citation Format: Carla Daniela Robles-Espinoza, Mark Harland, Andrew J. Ramsay, Lauren G. Aoude, Victor Quesada, Zhihao Ding, Karen A. Pooley, Antonia L. Pritchard, Jessamy C. Tiffen, Mia Petljak, Jane M. Palmer, Judith Symmons, Peter Johansson, Mitchell S. Stark, Michael G. Gartside, Helen Snowden, Grant W. Montgomery, Nicholas G. Martin, Jimmy Z. Liu, Jiyeon Choi, Matthew Makowski, Kevin M. Brown, Alison M. Dunning, Thomas M. Keane, Carlos Lopez-Otin, Nelleke A. Gruis, Nicholas K. Hayward, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams. POT1 mutations predispose to familial melanoma. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 20. doi:10.1158/1538-7445.CANSUSC14-20

Abstract 5250: The effect of introducing a C118S mutation into the endogenous Kras gene on early tumorigenesis

Abstract The Ras family of small GTPase, comprised of HRAS, NRAS, and KRAS, have been found mutated to remain in an active oncogenic state in many different human cancers, which is well established to promote tumorigenesis. All three RAS isoforms contain a conserved C118, of which the thiol group can be post-translationally modified by processes such as S-nitrosylation, which have been reported to promote RAS activation. To investigate the effect of blocking such modifications on RAS function in vivo, a C118S mutation, which lacks the reactive thiol group, was knocked into the endogenous Kras gene in mice. We now report that KrasC118S/C118S mice were born at the expected ratio with no overt phenotypes. To explore the effect of this mutation on early tumorigenesis, Kras+/+, KrasC118S/+, and KrasC118S/C118S mice were treated with the carcinogen urethane to induce oncogenic mutations in Kras and lung lesions. Interestingly, both KrasC118S/+ and KrasC118S/C118S mice developed fewer and smaller lung tumors than control Kras+/+ mice, suggesting that KrasC118S impairs lung tumorigenesis. Such a reduction in tumorigenesis could be the consequence of the C118S mutation on either the unaffected Kras allele or the Kras allele with the oncogenic mutation. To evaluate the first possibility, we tested and found that mice harboring a Cre-activated LSL-KrasG12D allele formed a similar number and size of lung tumors after activation of this allele when the remaining Kras allele was wild-type or C118S mutant. These data indicate that the reduction in tumor lesions observed in KrasC118S/+ and KrasC118S/C118S mice treated with urethane was unlikely to be the consequence of the C118S mutation on the non-oncogenic Kras allele. To evaluate the second possibility, we tested and found that oncogenic mutations occurred preferentially in the native compared to the C118S mutant Kras allele in KrasC118S/+ mice treated with urethane, suggesting a selection against oncogenic mutations on the KrasC118S allele. These results are consistent with the hypothesis that post-translational modifications such as S-nitrosylation on C118 enhance the oncogenic activity of Kras in vivo, and demonstrate for the first time that blocking the ability of a protein to be modified by processes like S-nitrosylation has a biological consequence in vivo. Citation Format: Lu Huang, Christopher M. Counter. The effect of introducing a C118S mutation into the endogenous Kras gene on early tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5250. doi:10.1158/1538-7445.AM2014-5250

289 * PREDICTORS OF NON-CANCEROUS LESION IN LUNG TUMOUR SHOWING GROUND-GLASS OPACITY ON THIN-SECTION COMPUTED TOMOGRAPHY BASED ON A MULTI-INSTITUTIONAL PROSPECTIVE STUDY

Objectives: Peripheral small lung tumours (LTs) showing ground-glass opacity (GGO) tend to be treated without preoperative histological diagnosis due to difficulty in obtaining tissue samples. Exclusion of non-cancerous lesions (NCLs) is essential when considering non-surgical treatment such as stereotactic radiotherapy. Here, we sought for preoperative predictors of NCLs in peripheral LTs. Methods: Between May 2009 and April 2011, 333 patients were prospectively enrolled from 51 institutions to the JCOG0804/WJOG4507L trial which investigated the efficacy of lesser pulmonary resection. The key eligibility criteria were: 1) peripherally located definitive or suspected LC with maximum diameter ≤2 cm, and 2) radiological non-invasive tumour with consolidation/tumour ratio (CTR) of <0.25 based on thin-section CT (Suzuki J Thorac Oncol 2011;6:751–6). Among all resected LTs, the incidences of NCL and pre-cancerous lesions were examined. Also, the logistic regression analysis was conducted to investigate a predictor of NCL using the maximum tumour dimension (≤1cm/>1 cm) and CTR (0/>0) as an explanatory variable. Results: Among 333 patients, 345 LTs were included in the analysis. There were 314 (91.0%) LC, 17 (4.9%) pre-cancerous lesions, and 14 (4.1%) NCL. The maximum tumour dimension ≤1 cm was detected to be a significant predictor of NCL with multivariate analysis. There were 10 (8.6%) NCLs in 116 LT ≤1 cm, while 4 (1.7%) NCLs in 229 LTs >1 cm. Conclusion: NCLs were found only in 4.1% of peripheral LTs with GGO. However, when tumour diameter was 1 cm or smaller, approximately 10% were NCLs, necessitating histological diagnosis when non-surgical treatment is considered.

Feasibility of X-Ray Acoustic Computed Tomography as a Tool for Noninvasive Volumetric In Vivo Dosimetry

motion XZ 6.3 (range: 5.9-7.1) mm, YZ 10.4 (9.6-11.2) mm, and ZZ 7.1 (6.6-7.7) mm. Root Mean Square (RMS) error between TT-tracked tumor motion and RPM was <0.9mm in all directions. Tumor B (4cm): TT could not track the position of the tumor at all angles as half-fan CBCT captured the tumor in only half of the images and high density and central airway structures obscured the target. Therefore, analysis was only performed for 100 (300-40 ) kV-source rotation. 4DCTmotion was XZ 1.8, YZ 7.5 and ZZ 8.6 mm. 100 TTon clinical kV projection series showed mean motion XZ 3.7 (2.5-5.8) mm, YZ 7.3 (5.3-9.2) mm, and ZZ 7.8 (5.5-10.6) mm. RMS error between TT and RPM was <1.1mm. Benchmarking tumor A: 360 TT showed mean motion X Z 3.5, Y Z 11.6 and Z Z 5.2 mm with standard deviation (SD) <0.7mm. Correlation coefficients of TT-tracked tumormotionwith center ofmass displacement on 4DCTwere 0.64, 0.95 and 0.84 (X, Y, Z). For tumor B: 2 sets of TT over 100 (300-40 /120-220 ) showed mean motion XZ 1.9, YZ 7.7 and ZZ 8.4mm (SD<0.8mm) and correlation coefficients of 0.63, 0.94 and 0.91 (X, Y, Z). Conclusions: TT software can track small lung tumors when they are visible in kV projections. Tumor motion during CBCT can vary from the planning 4DCT. TT and RPM motion were closely associated. Benchmarking TT against known tumor displacements showed good agreement. Author Disclosure: J.R. van Sornsen de Koste: I. Travel Expenses; has received travel support of Varian Medical Systems. M. Dahele: I. Travel Expenses; has received travel support/honoraria from Varian Medical Systems and travel support from Brainlab. S. Senan: I. Travel Expenses; has received travel support and honoraria from Varian Medical Systems. B. Slotman: I. Travel Expenses; has received travel support/honoraria from Varian Medical Systems. W. Verbakel: I. Travel Expenses; has received travel/honoraria support from Varian Medical Systems.

Challenges in the treatment of early non-small cell lung cancer: what is the standard, what are the challenges and what is the future for radiotherapy?

In the last 15 years, the use of Stereotactic Ablative Radiation Therapy (SABRT) in the management of small peripheral lung tumours has developed considerably, so that it currently represents a standard of care for inoperable stage I non-small cell lung cancer (NSCLC), offering a survival advantage over traditional radiotherapy, local control rates at 3 years around 90%, with a low risk of toxicity. Indications have extended to larger tumours up to 5 cm and centrally located tumours. In this review we will explore the role of SABRT in early stage NSCLC, the state of the art, the challenges and the future for this technique. There are ongoing studies to optimize such approaches within a multicentric setting. Trials comparing surgery to SABRT in operable or marginally operable have failed because of poor accrual. Several questions remain that need to be addressed in prospective studies.

Video-assisted thoracoscopic surgery using mobile computed tomography: new method for locating of small lung nodules.

BackgroundThe O-arm is an intraoperative imaging device that can provide computed tomography images. Surgery for small lung tumors was performed based on intraoperative computed tomography images obtained using the O-arm. This study evaluated the usefulness of the O-arm in thoracic surgery.MethodsFrom July 2013 to November 2013, 10 patients with small lung nodules or ground glass nodules underwent video-assisted thoracoscopic surgery using the O-arm. A needle was placed on the visceral pleura near the nodules. After the lung was re-expanded, intraoperative computed tomography was performed using the O-arm. Then, the positional relationship between the needle marking and the tumor was recognized based on the intraoperative computed tomography images, and lung resection was performed.ResultsIn 9 patients, the tumor could be seen on intraoperative computed tomography images using the O-arm. In 1 patient with a ground glass nodule, the lesion could not be seen, but its location could be inferred by comparison between preoperative and intraoperative computed tomography images. In only 1 patient with a ground glass nodule, a pathological complete resection was not performed. There were no complications related to the use of the O-arm.ConclusionsThe O-arm may be an additional tool to facilitate intraoperative localization and surgical resection of non-palpable lung lesions.

SU‐E‐J‐176: Results of Images Acquired with Backscattered MV Radiation Using a Pinhole Collimator

Purpose:To ascertain the feasibility of acquiring real time images of small lung tumors from scattered photons while undergoing radiation treatment. There are several methodologies currently used to track tumor location such as MV‐cine acquisition and kV fluoroscopy. However, MVcine offers no information parallel to the beam axis while kV fluoroscopy offers little potential for soft tissue discernability while also increasing the patient dose. This study investigates the feasibility of observing an actual simulated tumor while exploring techniques that may improve image quality.Methods:A prototype imager consisting of a gamma camera pinhole collimator and a computed radiography (CR) plate were used in conjunction with a Varian TrueBeam linac. One study consisted of a 2.5 cm diameter solid water cylinder representing a solid tumor imbedded within a lung equivalent material slab. The cylinder with the lung slab was sandwiched between 1 cm lung equivalent slabs and these were sandwiched between 2 slabs of solid water. The top water slab was 1 cm thick. The other imaging study consisted of three different density plugs, 0.46, 1.09, and 1.82 g/cm3 placed on the accelerator couch. The gantry was orientated 70° relative to the CR plate. The slabs and plugs were irradiated with 2000 MU and 500 MU respectively using the 6FFF mode.Results:The solid water plug was visually discernible in the slab phantom. The ratio of the signal coming from the higher density plugs (placed on the treatment couch) to that between the plugs increased from 1.02 to about 3.0 after subtracting the background image acquired with no plugs present.Conclusion:Preliminary results indicate that a lung tumor could be visualized with scattered radiation during treatment. Improvements in discerning an object can be enhanced by filtering out the head leakage and background scattered radiation not emanating from the imaged object.

High-Frequency Jet Ventilation under General Anesthesia Facilitates CT-Guided Lung Tumor Thermal Ablation Compared with Normal Respiration under Conscious Analgesic Sedation

PurposeTo determine whether technical difficulty of computed tomography (CT)–guided percutaneous lung tumor thermal ablations is altered with the use of high-frequency jet ventilation (HFJV) under general anesthesia (GA) compared with procedures performed with normal respiration (NR) under conscious sedation (CS). Materials and MethodsThermal ablation treatment sessions performed with NR under CS or HFJV under GA with available anesthesia records and CT fluoroscopic images were retrospectively reviewed; 13 and 33 treatment sessions, respectively, were identified. One anesthesiologist determined the choice of anesthesiologic technique independently. Surrogate measures of procedure technical difficulty—time duration, number of CT fluoroscopic acquisitions, and radiation dose required for applicator placement for each tumor—were compared between anesthesiologic techniques. The anesthesiologist time and complications were also compared. Parametric and nonparametric data were compared by Student independent-samples t test and χ2 test, respectively. ResultsPatients treated with HFJV under GA had higher American Society of Anesthesiologists classifications (mean, 2.66 vs 2.23; P = .009) and smaller lung tumors (16.09 mm vs 27.38 mm; P = .001). The time duration (220.30 s vs 393.94 s; P = .008), number of CT fluoroscopic acquisitions (10.31 vs 19.13; P = .023), and radiation dose (60.22 mGy·cm vs 127.68 mGy·cm; P = .012) required for applicator placement were significantly lower in treatment sessions performed with HFJV under GA. There was no significant differences in anesthesiologist time (P = .20), rate of pneumothorax (P = .62), or number of pneumothoraces requiring active treatment (P = .19). ConclusionsHFJV under GA appears to reduce technical difficulty of CT-guided percutaneous applicator placement for lung tumor thermal ablations, with similar complication rates compared with treatment sessions performed with NR under CS. The technique is safe and may facilitate treatment of technically challenging tumors.

Single incision video-assisted thoracoscopic anatomic segmentectomy.

Anatomic segmentectomy was first described in 1939 by Churchill and Belsey (1). Although segmentectomy is usually indicated for benign lesions or for metastasis when the goal is resecting the lesion while sparing parenchyma, anatomic segmentectomy has also been demonstrated to be effective in the resection of small lung cancers (2). Recently, due to the increasing incidence of small lung tumors, there has been renewed interest in the use of anatomic segmentectomy, especially for patients unable to tolerate lobectomy. Several recently published studies have shown that segmentectomy can be performed safely without compromising oncologic results (3,4). Video-assisted thoracoscopic surgery (VATS) is currently a better choice than thoracotomy for segmentectomy. Although most surgeons use three to four incisions, the surgery can also be performed using only one (5).

Nonintubated thoracoscopic segmentectomy-left upper lobe trisegmentectomy.

Enhanced computed tomography screening protocols have recently identified increasing numbers of small lung tumors in patients with high surgical risks (1). Consequently there has been increasing interest in minimally invasive surgical approaches, including thoracoscopic approaches, parenchyma-sparing resection, and less invasive anesthesia for management of lung tumors (2). The role of thoracoscopic segmentectomy is therefore increasingly reevaluated, not only as a traditional parenchyma-sparing procedure in high-risk patients with compromised medical conditions but also in patients with non-small cell lung cancer less than 2.0 cm (1). From 2009, we started a nonintubated thoracoscopic surgery program for patients who were reluctant or unsuitable to have a conventional intubated single lung ventilation during thoracic surgery (3). With a combination of target-controlled sedation and regional anesthesia—either by thoracic epidural anesthesia or intercostal nerve blocks with intrathoracic vagal blockade—the results of nonintubated thoracoscopic surgery are encouraging (2-5). In the current video, we demonstrate how a nonintubated technique was applied in thoracoscopic segmentectomy and mediastinal lymphadenectomy to treat a patient with early stage lung cancer (Video 1). Video 1 Nonintubated thoracoscopic segmentectomy—left upper lobe trisegmentectomy. Clinical vignette A 74-year-old man, who had undergone a total gastrectomy for gastric cancer in a different institution in 2003, was transferred to our hospital for management of an incidentally discovered left upper lobe lung nodule. Computed tomography-guided biopsy of the tumor revealed a primary pulmonary adenocarcinoma. Preoperative pulmonary function tests showed that he had a mild obstructive defect with forced expiratory volume in one second being 84.9% of predicted. Considering his age and reduced lung function, lingual-preserving left upper lobectomy (left upper lobe tri-segmentectomy) was planned instead of left upper lobectomy to preserve more lung parenchyma after surgery.

Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer

Abnormal alternative splicing has been associated with cancer. Genome-wide microarrays can be used to detect differential splicing events. In this study, we have developed ExonPointer, an algorithm that uses data from exon and junction probes to identify annotated cassette exons. We used the algorithm to profile differential splicing events in lung adenocarcinoma A549 cells after downregulation of the oncogenic serine/arginine-rich splicing factor 1 (SRSF1). Data were generated using two different microarray platforms. The PCR-based validation rate of the top 20 ranked genes was 60% and 100%. Functional enrichment analyses found a substantial number of splicing events in genes related to RNA metabolism. These analyses also identified genes associated with cancer and developmental and hereditary disorders, as well as biologic processes such as cell division, apoptosis, and proliferation. Most of the top 20 ranked genes were validated in other adenocarcinoma and squamous cell lung cancer cells, with validation rates of 80% to 95% and 70% to 75%, respectively. Moreover, the analysis allowed us to identify four genes, ATP11C, IQCB1, TUBD1, and proline-rich coiled-coil 2C (PRRC2C), with a significantly different pattern of alternative splicing in primary non-small cell lung tumors compared with normal lung tissue. In the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon overexpressed in primary lung tumors. Specific siRNA downregulation of the exon-containing variant significantly reduced cell growth. In conclusion, using a novel analytical tool, we have identified new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer.

Abstract B32: The impact of PET-CT on staging, management, and prognostication of small cell lung cancer.

Abstract Introduction: Although frequently used, there is no randomized data assessing the role of PET CT in the staging process of SCLC patients, or its impact on patients' management. We aimed to review retrospectively the utility of PET-CT in patients diagnosed with SCLC in a single tertiary medical center and to address these issues. Methods: We included all patients diagnosed with SCLC between January 2007 and December 2011 at Rabin Medical Center (Petach-Tikva, Israel), either staged by PET-CT or not. Data retrieved included: age, gender, Veteran's staging (LD or ED, as determined by the institute multidisciplinary team during thoracic tumor-board meeting), ECOG performance status, staging procedures done and their results (FDG-PET scan, CT scans, MRIs, Bone Scans, BMBs), pathology immunohistochemistry characteristics (Ki67, chromogranin, synaptophysin), serum markers levels (NSE, LDH, chromogranin, CEA), treatment modality (chemotherapy versus chemoradiation), Disease Free Survival (DFS), Progression Free Survival (PFS) and Overall Survival (OS). In the group of patients who underwent PET CT during the initial evaluation, we re-assessed staging, both according to the Veteran's Administration Lung Group's 2-stage classification (LD and ED) and according to the American Joint Committee on Cancer Staging manual, 7th edition (TNM). Staging was performed by two independent radiologists: one (HB), a nuclear medicine specialist, to decide on the stage according to PET-CT findings, and the other (YR), thoracic radiologist, to decide on the stage according to chest, abdomen and pelvic contrast-enhanced CT scan findings (with bone scan results if available) and blinded to the PET results. PET scans were also evaluated for SUVmax (maximal standardized uptake value) and TLG (total lesion glycolysis). Results: 108 patients were diagnosed and treated for SCLC in the above mentioned period. 2 patients were excluded from the analysis for lack pathology or staging procedure data and 10 patients were excluded since their PET imaging was done elsewhere, not accessible for our assessment. Finally, out of 96 patients, 54 had a PET-CT done as part of their staging procedure. PET-staged patients had significantly less staging procedures done than non-PET-staged patients (24% underwent 3-4 staging procedures versus 62%, p=0.04). PET altered management in 19 patients (35%), with 13 patients with suspected metastatic disease, who benefited from down-staging by PET. It appears that treatment was significantly delayed in PET-staged patients with a mean of 30 days from diagnostic procedure to treatment versus 26 days (p=0.04). TLG was found to correlate with OS and PFS, with high TLG level predicting poorer survival (HR=3.38, CI 1.385-8.259, p=0.007). Conclusions: Although PET-CT adds to SCLC patients' management by reducing the amount of staging procedures and possibly down staging patients who otherwise would have been treated with palliative intent, in the setup of a public tertiary medical center, waiting for the PET to be done and reported could result in treatment delay. Randomized data is necessary to properly evaluate the sensitivity, specificity and influence on management of this modality. TLG appears to be a new promising prognostic biomarker in small cell lung tumors. Citation Format: Alona Zer, Yael Rapson, Meital Nadam, Dov Flex, Aaron M. Allen, Salomon M. Stemmer, David Groshar, Hanna Bernstine. The impact of PET-CT on staging, management, and prognostication of small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B32.

Stereotactic body radiotherapy for small lung tumors in the University of Tokyo Hospital.

Our work on stereotactic body radiation therapy (SBRT) for primary and metastatic lung tumors will be described. The eligibility criteria for SBRT, our previous SBRT method, the definition of target volume, heterogeneity correction, the position adjustment using four-dimensional cone-beam computed tomography (4D CBCT) immediately before SBRT, volumetric modulated arc therapy (VMAT) method for SBRT, verifying of tumor position within internal target volume (ITV) using in-treatment 4D-CBCT during VMAT-SBRT, shortening of treatment time using flattening-filter-free (FFF) techniques, delivery of 4D dose calculation for lung-VMAT patients using in-treatment CBCT and LINAC log data with agility multileaf collimator, and SBRT method for centrally located lung tumors in our institution will be shown. In our institution, these efforts have been made with the goal of raising the local control rate and decreasing adverse effects after SBRT.

Density Features of Screened Lung Tumors in Low-Dose Computed Tomography

Using low-dose computed tomography (LDCT), small and heterogeneous lung tumors are detected in screening. The criteria for assessing detected tumors are crucial for determining follow-up or resection strategies. The purpose of this study was to investigate the capacity of density features in differentiating lung tumors. From July 2008 to December 2011, 48 surgically confirmed tumors (29 malignancies, comprising 17 cases of adenocarcinoma and 12 cases of adenocarcinoma in situ [AdIs], and 19 benignancies, comprising 11 cases of atypical adenomatous hyperplasia [AAH] and eight cases of benign non-AAH) in 38 patients were retrospectively evaluated, indicating that the positive predictive value (PPV) of physicians is 60.4% (29/48). Three types of density features, tumor disappearance rate (TDR), mean, and entropy, were obtained from the CT values of detected tumors. Entropy is capable of differentiating malignancy from benignancy but is limited in differentiating AdIs from benign non-AAH. The combination of entropy and TDR is effective for predicting malignancy with an accuracy of 87.5% (42/48) and a PPV of 89.7% (26/29), improving the PPV of physicians by 29.3%. The combination of entropy and mean adequately clarifies the four pathology groups with an accuracy of 72.9% (35/48). For tumors with a mean below -400 Hounsfield units, the criterion of an entropy larger than 5.4 might be appropriate for diagnosing malignancy. For others, the pathology is either benign non-AAH or adenocarcinoma; adenocarcinoma has a higher entropy than benign non-AAH, with the exception of tuberculoma. Combining density features enables differentiating heterogeneous lung tumors in LDCT.

Japanese Multi-institutional Study of Stereotactic Body Radiation Therapy for More Than 2000 Patients With Stage I Non-Small Cell Lung Cancer

In Japan, small lung tumors are frequently detected under popularized CT screening and stereotactic body radiation therapy (SBRT) has been generally used as a curative treatment option for patients with early stage primary lung cancer. We organized a multi-institutional SBRT study group in Japanese Radiological Society (JRS-SBRTSG) and conducted various studies of SBRT for primary or oligometastatic cancer. The purpose of this study was to evaluate the treatment outcomes of SBRT for stage I non-small cell lung cancer (NSCLC) in the practice level with the Japanese large database. This is a retrospective analysis to review 2226 patients (median age, 77 years; male 1560, female 666) with stage I (IA 1601, IB 625) NSCLC treated at 20 institutions of JRS-SBRTSG. Histology was proven in 1658 patients (adenocarcinoma 961, squamous cell carcinoma 541, others 156). A total dose of 32 -70 Gy mainly at the isocenter was prescribed in 3-12 fractions. The median calculated biological effective dose (BED) was 107 Gy (range, 58-150 Gy) based on alpha/beta = 10 Gy). The median follow-up period for all patients was 32 months. Overall survival rate at three year (OS-3y) and disease-specific survival rate at three year of total patients was 72% and 85%, respectively. Locally progression free rate at three year of T1 and T2 tumors were 87% and 72%, respectively. Nodal and distant metastases were observed in 11.3% and 22.3% of patients, respectively. Pulmonary complications of NCI-CTC criteria grade ≥ 3 were noted in 2.9% of total patients. OS-3y of female patients was better (83%) than for male patients (68%) (p < 0.01). OS-3y was better (75%) for BED ≥100 Gy subgroup (n = 2042) compared to 63% for BED < 100 Gy (n = 184) (p < 0.01). OS-3y of medically operable patients (n = 726) was better (78%) than for inoperable patients (n = 1500, 68%) (p < 0.01). OS-3y of histology-unknown patients (n = 568) was a little better (77%) than for histology-proven patients (n = 1658, 63%) (p < 0.05). OS-3y of patients accompanying chronic pulmonary interstitial change was much worse (41%) than others. OS-3y of patients accompanying pulmonary emphysema was worse (64%) than others. The outcomes of SBRT for stage I NSCLC in Japanese multi-institutional large patient database were retrospectively analyzed. The local progression-free and overall survival rate in the practice level showed a similar results to that of JCOG (Japan Clinical Oncology Group) 0403; a prospective phase II study of SBRT (48 Gy in 4 fractions) for stage IA NSCLC. The patient's subgroup of medically operable, BED ≥ 100 Gy and no pulmonary interstitial change nor emphysema had better prognosis.

Pulmonary Changes in FDG-PET/CT After Cure of Small Lung Tumors With Stereotactic Ablative Radiation Therapy (SBRT): Which Imaging Features Can Be Expected?

anteroposterior direction. Fluoroscopic movies were recorded simultaneously with the respiratory waveforms for 30 seconds with and without audio coaching. One measurement session consisted of simultaneously recorded 5 cycles of the tumor motion and respiratory waveform. The tumor position corresponding to the phase of respiratory waveform was identified using image processing and template matching techniques. Data of 20 sessions consisting of 100 respiratory cycles each with and without audio coaching were acquired from 6 patients who underwent respiratorygated SBRT between August 2011 and September 2012. Results: The amplitude of the tumor motion varied widely. The difference between the amplitude on fluoroscopy under audio instructions and that on planning 4D-CT was over 5 mm in 51 cycles and was up to 21 mm. The fluctuations of the most cranial position of the tumor were comparatively small. They were within 5 mm under free-breathing conditions and within 4 mm with audio coaching. The phase shift of the most cranial position of the tumor on fluoroscopy with audio coaching from that on 4D-CT was 20% or more in 43 cycles. The phases at which the tumor position was within 5 mm from the most cranial position on fluoroscopy with audio coaching were compared to the actually irradiated gating phases based on 4D-CT. The phase shifts were not observed in 3 patients, while the phase shifts up to 75% were observed in the other 3. The phase shifts between the most cranial position of the tumor and the lowest point of the respiratory waveform decreased significantly in 1 patient with audio coaching. Conclusions: Tumor motion could vary among individual patients and during planning and treatment for the same patient. Audio coaching was not sufficient to improve respiratory patterns. An individual approach to respiratory management is necessary in respiratory-gated SBRT. Author Disclosure: F. Baba: None. Y. Nonogaki: None. S. Tanaka: None. S. Hasegawa: None. M. NIshihashi: None. S. Ayakawa: None. M. Iwana: None. Y. Shibamoto: None.

Forcing lateral electron disequilibrium to spare lung tissue: a novel technique for stereotactic body radiation therapy of lung cancer

Stereotactic body radiation therapy (SBRT) has quickly become a preferred treatment option for early-stage lung cancer patients who are ineligible for surgery. This technique uses tightly conformed megavoltage (MV) x-ray beams to irradiate a tumour with ablative doses in only a few treatment fractions. Small high energy x-ray fields can cause lateral electron disequilibrium (LED) to occur within low density media, which can reduce tumour dose. These dose effects may be challenging to predict using analytic dose calculation algorithms, especially at higher beam energies. As a result, previous authors have suggested using low energy photons (<10 MV) and larger fields (>5 × 5 cm2) for lung cancer patients to avoid the negative dosimetric effects of LED. In this work, we propose a new form of SBRT, described as LED-optimized SBRT (LED-SBRT), which utilizes radiotherapy (RT) parameters designed to cause LED to advantage. It will be shown that LED-SBRT creates enhanced dose gradients at the tumour/lung interface, which can be used to manipulate tumour dose, and/or normal lung dose. To demonstrate the potential benefits of LED-SBRT, the DOSXYZnrc (National Research Council of Canada, Ottawa, ON) Monte Carlo (MC) software was used to calculate dose within a cylindrical phantom and a typical lung patient. 6 MV or 18 MV x-ray fields were focused onto a small tumour volume (diameter ∼1 cm). For the phantom, square fields of 1 × 1 cm2, 3 × 3 cm2, or 5 × 5 cm2 were applied. However, in the patient, 3 × 1 cm2, 3 × 2 cm2, 3 × 2.5 cm2, or 3 × 3 cm2 field sizes were used in simulations to assure target coverage in the superior–inferior direction. To mimic a 180° SBRT arc in the (symmetric) phantom, a single beam profile was calculated, rotated, and beams were summed at 1° segments to accumulate an arc dose distribution. For the patient, a 360° arc was modelled with 36 equally weighted (and spaced) fields focused on the tumour centre. A planning target volume (PTV) was generated by considering the extent of tumour motion over the patient's breathing cycle and set-up uncertainties. All patient dose results were normalized such that at least 95% of the PTV received at least 54 Gy (i.e. D95 = 54 Gy). Further, we introduce ‘LED maps’ as a novel clinical tool to compare the magnitude of LED resulting from the various SBRT arc plans. Results from the phantom simulation suggest that the best lung sparing occurred for RT parameters that cause severe LED. For equal tumour dose coverage, normal lung dose (2 cm outside the target region) was reduced from 92% to 23%, comparing results between the 18 MV (5 × 5 cm2) and 18 MV (1 × 1 cm2) arc simulations. In addition to reduced lung dose for the 18 MV (1 × 1 cm2) arc, maximal tumour dose increased beyond 125%. Thus, LED can create steep dose gradients to spare normal lung, while increasing tumour dose levels (if desired). In the patient simulation, a LED-optimized arc plan was designed using either 18 MV (3 × 1 cm2) or 6 MV (3 × 3cm2) beams. Both plans met the D95 dose coverage requirement for the target. However, the LED-optimized plan increased the maximum, mean, and minimum dose within the PTV by as much as 80 Gy, 11 Gy, and 3 Gy, respectively. Despite increased tumour dose levels, the 18 MV (3 × 1 cm2) arc plan improved or maintained the V20, V5, and mean lung dose metrics compared to the 6 MV (3 × 3 cm2) simulation. We conclude that LED-SBRT has the potential to increase dose gradients, and dose levels within a small lung tumour. The magnitude of tumour dose increase or lung sparing can be optimized through manipulation of RT parameters (e.g. beam energy and field size).

Cytosolic PhospholipaseA2 Inhibition with PLA-695 Radiosensitizes Tumors in Lung Cancer Animal Models

Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2) is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR) significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and induced cell death and attenuated invasion by tumor cells (LLC &A549). In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA2 in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.

TH-A-137-09: Gated Lung SRS/SBRT with Conical Collimators

Purpose: To investigate the use of conical collimator equipped linacs to treat small lung tumors (< 3 cm in diameter) with gated stereotactic radio-surgery (SRS) or stereotactic body radio-therapy (SBRT) and to compare the performance of this modality with other treatment options currently being used. Methods: A phantom simulating chest and lung motion was used to test the effectiveness of gating a linac equipped with conical collimators. Dose to a simulated lung lesion was planned, delivered using cones, and measured with an ionization chamber and film. Plans designed using traditional modalities for treatment of a single, small lung lesion were then compared with plans using conical collimators to determine if any advantages exist when using conical collimators. Results: Conical collimator equipped linacs may be used with respiratory gating during SRS/SBRT. For Varian Trilogy linacs, using beam arcs with cones rather than static beams would require software modifications that prevent minor-interlocks from reinitiating the beam after gantry motion is stopped due to gating. A significant advantage was found when using static beams with cylindrical collimators to treat small lung lesions where the healthy tissue at risk is limited by mean dose to the tissue. It is possible to deliver 30% higher doses to the target lesion under these circumstances. When the healthy tissue at risk is limited by maximum dose to surrounding critical structures, such as the spinal cord, using the cone collimators does not provide a significant advantage over other modalities. Conclusion: The results show that, depending on the type of sensitivity exhibited by the tissue at risk, use of conical collimators with gated static beam SRS/SBRT on small lung tumors would allow delivery of higher target doses than conventional modalities, while still sparing surrounding normal tissue from damaging dose levels.