Full Dose SBRT in Combination With Mediastinal Chemoradiation for Locally Advanced, Non-Small Cell Lung Cancer: A Practical Guide for Planning, Dosimetric Results From a Phase 2 Study, and a Treatment Planning Guide for the Phase 3 NRG Oncology LU-008 Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) has been used with high effectiveness in early-stage non-small cell lung cancer (NSCLC) but has not been studied extensively in locally advanced NSCLC. We conducted a phase 2 study delivering SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes for patients with node-positive locally advanced NSCLC. This manuscript serves as both a guide to planning techniques used on this trial and the subsequent phase 3 study, NRG Oncology LU-008, and to report patient dosimetry and toxicity results. METHODS AND MATERIALS: We initiated a phase 2 multicenter single arm study evaluating SBRT to the primary tumor (50-54 Gy in 3-5 fractions) followed by conventionally fractionated chemoradiation to 60 Gy in 2 Gy fractions with doublet chemotherapy to the involved lymph nodes for patients with stage III or unresectable stage II NSCLC. Patients eligible for adjuvant immunotherapy received up to 12 months of durvalumab. We report a detailed guide for the entire treatment process from computed tomography simulation through treatment planning and delivery. The dosimetric outcomes from the 60 patients who completed therapy on study are reported both for target coverage and normal structure doses. We also report correlation between radiation-related toxicities and dosimetric parameters. RESULTS: Sixty patients were enrolled between 2017 and 2022. Planning techniques used were primarily volumetric modulated arc therapy for SBRT to the primary tumor and conventionally fractionated radiation to the involved nodes, with a minority of cases using dynamic conformal arc technique or static dynamic multileaf collimator intensity modulated radiation therapy. Grade 2 or higher pneumonitis was associated with lung dose V5 Gy > 70% and grade 2 or higher pulmonary toxicity was associated with lung dose V10 Gy > 50%. Only 3 patients (5%) experienced grade 3 or higher pneumonitis. Grade 2 or higher esophagitis was associated with esophageal doses, including mean dose > 20 Gy, V60 Gy > 7%, and D1cc > 55 Gy. Only 1 patient (1.7%) experienced grade 3 esophagitis. CONCLUSIONS: SBRT to the primary tumor followed by conventionally fractionated chemoradiation to the involved lymph nodes is feasible with planning techniques as described. Radiation-related toxicity on this phase 2 study was low. This manuscript serves as a guideline for the recently activated NRG Oncology LU-008 phase 3 trial evaluating this experimental regimen.

Dosimetric Analysis of Intra-Fraction Motion Detected by Surface-Guided Radiation Therapy During Linac Stereotactic Radiosurgery.

Purpose: Stereotactic radiosurgery (SRS) immobilization with an open face mask is more comfortable and less invasive than frame based, but concerns about intrafraction motion must be addressed. Surface-guided radiation therapy (SGRT) is an attractive option for intrafraction patient monitoring because it is continuous, has submillimeter accuracy, and uses no ionizing radiation. The purpose of this study was to investigate the dosimetric consequences of uncorrected intrafraction patient motion detected during frameless linac-based SRS. Methods and Materials: Fifty-five SRS patients were monitored during treatment using SGRT between January 1, 2017, and September 30, 2020. If SGRT detected motion >1 mm, imaging was repeated and the necessary shifts were made before continuing treatment. For the 25 patients with intrafraction 3-dimensional vector shifts of ≥1 mm, we moved the isocenter in the planning system using the translational shifts from the repeat imaging and recalculated the plans to determine the dosimetric effect of the shifts. Planning target volume (PTV) coverage, minimum gross tumor volume (GTV) dose (relative and absolute), and normal brain V12 were evaluated. Wilcoxon signed rank tests were used to compare planned and simulated dosimetric parameters and median 2 sample tests were used to investigate these differences between cone and multileaf collimator (MLC) plans. Results: For simulated plans, V12 increased by a median of 0.01 cc (P = .006) and relative GTV minimum dose and PTV coverage decreased by a median of 15.8% (P < .001) and 10.2 % (P < .001), respectively. Absolute minimum GTV dose was found to be significantly lower in the simulated plans (P < .001). PTV coverage decreased more for simulated cone plans than for simulated MLC plans (11.6% vs 4.7%, P = .011) but median V12 differences were found to be significantly larger for MLC plans (-0.34 cc vs -0.01 cc, P = .011). Differences in GTV minimum dose between cone and MLC plans were not statistically significant. Conclusions: SGRT detected clinically meaningful intrafraction motion during frameless SRS, which could lead to large underdoses and increased normal brain dose if uncorrected.

Volumetric Modulated Arc Therapy (VMAT) Craniospinal Irradiation (CSI) for Children and Adults: A Practical Guide for Implementation.

PURPOSE: Volumetric modulated arc therapy (VMAT) craniospinal irradiation (CSI) has been shown to have significant dosimetric advantages compared to 3-dimensional conformal therapy but is a technically complex process. We sought to develop a guide for all aspects of the VMAT CSI process and report patient dosimetry results. METHODS AND MATERIALS: We initiated VMAT CSI in 2017 and have regularly revised our standard operating procedure for this process since then. Herein, we report a detailed template for the entire VMAT CSI process from initial patient setup and immobilization at time of computed tomography (CT) simulation to contouring and treatment planning, quality assurance, and therapy delivery. The records of 12 patients who were treated with VMAT CSI were also retrospectively reviewed. RESULTS: Patient age ranged from 2 to 59 years with 5 pediatric patients (age <18 years), 5 young adults (age 18-35 years), and 2 older adults (age >35 years). The majority of patients (67%) had medulloblastoma. CSI dose ranged from 21.6 to 36 Gy, with a median of 36 Gy. The median CSI planning target volume was 2383 cc with a median V95% of 99.8% and median 0.03 cc hotspot of 112.5%. The average V107% was 7.4% and the average conformality index was 1.01. CONCLUSIONS: VMAT CSI has potentially significant dosimetric and acute toxicity advantages compared to 3-dimensional conformal. However, proper procedures need to be in place throughout the process in order to be able to realize these potential advantages. We herein describe our detailed standard operating procedure for VMAT CSI. Recognizing the scarcity of proton beam centers in many areas, VMAT CSI represents a feasible treatment with more widespread availability.

The Association Between Radiation Therapy Dose and Overall Survival in Patients With Intracranial Infiltrative Low-Grade Glioma Treated With Concurrent and/or Adjuvant Chemotherapy.

PURPOSE: Previous trials have shown no benefit for radiation therapy (RT) dose escalation when RT is given as adjuvant monotherapy for infiltrative low-grade glioma (LGG). However, the current standard of care for high-risk LGG is RT with concurrent and/or adjuvant chemotherapy. The effect of RT dose escalation on overall survival (OS) in the setting of concurrent and/or adjuvant chemotherapy is not well established. METHODS AND MATERIALS: We used the National Cancer Database to select records for adult patients with intracranial grade 2 LGG diagnosed between 2004 and 2015. Patients must have received adjuvant external beam RT with concurrent and/or adjuvant chemotherapy. RT dose level was categorized as standard (45-54 Gy) or high (>54-65 Gy). Multivariable and propensity score matched analyses were used. RESULTS: The study cohort consisted of 1043 patients, of whom 644 (62%) received standard dose (median, 54 Gy) and 399 (38%) received high-dose RT (median, 60 Gy). RT dose level was not associated with OS (hazard ratio, 1.2; P = .1) in multivariable analysis. Propensity score matching yielded 380 matched pairs (n = 760). There was no difference in OS for high-dose versus standard-dose RT in the matched cohort (5-year OS 64% vs 69%; P = .14) or in the 2 prespecified subgroups of astrocytoma histology and 1p/19q noncodeleted. CONCLUSIONS: Adjuvant RT dose escalation above 54 Gy in the setting of concurrent and/or adjuvant chemotherapy was not associated with improved OS for patients with infiltrative LGG in this National Cancer Database retrospective study. This was also true for the subgroups with less chemotherapy-sensitive disease, including astrocytoma histology and 1p/19q noncodeleted, although these analyses were limited by small size. Methods to improve OS other than RT dose escalation in the setting of concurrent and/or adjuvant chemotherapy should be considered for patients with poor-prognosis LGG.

The utilization of immunotherapy with radiation therapy in lung cancer: a narrative review.

Despite decreasing smoking rates, lung cancer remains the leading cause of death from cancer in the United States. Radiation therapy has been established as an effective locoregional therapy for both early stage and locally advanced disease and is known to stimulate local immune response. Past treatment paradigms have established the role of combining cytotoxic chemotherapy regimens and radiation therapy to help address the local and systemic nature of lung cancer. However, these regimens have limitations in their tolerability due to toxicity. Additionally, cytotoxic chemotherapy has limited efficacy in preventing systemic spread of lung cancer. Newer systemic agents such as immune checkpoint inhibitors have shown improved survival in metastatic and locally advanced lung cancer and have the advantage of more limited toxicity profiles compared to cytotoxic chemotherapy. Furthermore, improved overall response rates and systemic tumor responses have been observed with the combination of radiation therapy and immunotherapy, leading to numerous active clinical trials evaluating the combination of immune checkpoint inhibition with radiotherapy. This comprehensive review discusses the current clinical data and ongoing studies evaluating the combination of radiation therapy and immunotherapy in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

The effect of adjuvant radiotherapy on overall survival in adults with intracranial ependymoma.

BACKGROUND: Adult intracranial ependymoma is rare, and the role for adjuvant radiotherapy (RT) is not well defined. METHODS: We used the National Cancer Database (NCDB) to select adults (age ≥ 22 years) with grade 2 to 3 intracranial ependymoma status postresection between 2004 and 2015 and treated with adjuvant RT vs observation. Four cohorts were generated: (1) all patients, (2) grade 2 only, (3) grade 2 status post-subtotal resection only, (4) and grade 3 only. The association between adjuvant RT use and overall survival (OS) was assessed using multivariate Cox and propensity score matched analyses. RESULTS: A total of 1787 patients were included in cohort 1, of which 856 patients (48%) received adjuvant RT and 931 (52%) were observed. Approximately two-thirds of tumors were supratentorial and 80% were grade 2. Cohorts 2, 3, and 4 included 1471, 345, and 316 patients, respectively. There was no significant association between adjuvant RT use and OS in multivariate or propensity score matched analysis in any of the cohorts. Older age, male sex, urban location, higher comorbidity score, earlier year of diagnosis, and grade 3 were associated with increased risk of death. CONCLUSIONS: This large NCDB study did not demonstrate a significant association between adjuvant RT use and OS for adults with intracranial ependymoma, including for patients with grade 2 ependymoma status post-subtotal resection. The conflicting results regarding the efficacy of adjuvant RT in this patient population highlight the need for high-quality studies to guide therapy recommendations in adult ependymoma.

Use of surface-guided radiation therapy in combination with IGRT for setup and intrafraction motion monitoring during stereotactic body radiation therapy treatments of the lung and abdomen.

BACKGROUND AND PURPOSE: Multiple techniques can be used to assist with more accurate patient setup and monitoring during Stereotactic body radiation therapy (SBRT) treatment. This study analyzes the accuracy of 3D surface mapping with Surface-guided radiation therapy (SGRT) in detecting interfraction setup error and intrafraction motion during SBRT treatments of the lung and abdomen. MATERIALS AND METHODS: Seventy-one patients with 85 malignant thoracic or abdominal tumors treated with SBRT were analyzed. For initial patient setup, an alternating scheme of kV/kV imaging or SGRT was followed by cone beam computed tomography (CBCT) for more accurate tumor volumetric localization. The CBCT six degree shifts after initial setup with each method were recorded to assess interfraction setup error. Patients were then monitored continuously with SGRT during treatment. If an intrafractional shift in any direction >2 mm for longer than 2 sec was detected by SGRT, then CBCT was repeated and the recorded deltas were compared to those detected by SGRT. RESULTS: Interfractional shifts after SGRT setup and CBCT were small in all directions with mean values of <5 mm and < 0.5 degrees in all directions. Additionally, 25 patients had detected intrafraction motion by SGRT during a total of 34 fractions. This resulted in 25 (73.5%) additional shifts of at least 2 mm on subsequent CBCT. When comparing the average vector detected shift by SGRT to the resulting vector shift on subsequent CBCT, no significant difference was found between the two. CONCLUSIONS: Surface-guided radiation therapy provides initial setup within 5 mm for patients treated with SBRT and can be used in place of skin marks or planar kV imaging prior to CBCT. In addition, continuous monitoring with SGRT during treatment was valuable in detecting potentially clinically meaningful intrafraction motion and was comparable in magnitude to shifts from additional CBCT scans. PTV margin reduction may be feasible for SBRT in the lung and abdomen when using SGRT for continuous patient monitoring during treatment.

Preoperative stereotactic radiosurgery before planned resection of brain metastases: updated analysis of efficacy and toxicity of a novel treatment paradigm.

OBJECTIVEPreoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS and may lower the risk of radiation necrosis (RN) and leptomeningeal disease (LMD) recurrence. The study goal was to report the efficacy and toxicity of preoperative SRS in an expanded patient cohort with longer follow-up period relative to prior reports.METHODSThe records for patients with brain metastases treated with preoperative SRS and planned resection were reviewed. Patients with classically radiosensitive tumors, planned adjuvant whole brain radiotherapy, or no cranial imaging at least 1 month after surgery were excluded. Preoperative SRS dose was based on lesion size and was reduced approximately 10-20% from standard dosing. Surgery generally followed within 48 hours.RESULTSThe study cohort consisted of 117 patients with 125 lesions treated with single-fraction preoperative SRS and planned resection. Of the 117 patients, 24 patients were enrolled in an initial prospective trial; the remaining 93 cases were consecutively treated patients who were retrospectively reviewed. Most patients had a single brain metastasis (70.1%); 42.7% had non-small cell lung cancer, 18.8% had breast cancer, 15.4% had melanoma, and 11.1% had renal cell carcinoma. Gross total resection was performed in 95.2% of lesions. The median time from SRS to surgery was 2 days, the median SRS dose was 15 Gy, and the median gross tumor volume was 8.3 cm3. Event cumulative incidence at 2 years was as follows: cavity local recurrence (LR), 25.1%; distant brain failure, 60.2%; LMD, 4.3%; and symptomatic RN, 4.8%. The median overall survival (OS) and 2-year OS rate were 17.2 months and 36.7%, respectively. Subtotal resection (STR, n = 6) was significantly associated with increased risk of cavity LR (hazard ratio [HR] 6.67, p = 0.008) and worsened OS (HR 2.63, p = 0.05) in multivariable analyses.CONCLUSIONSThis expanded and updated analysis confirms that single-fraction preoperative SRS confers excellent cavity local control with very low risk of RN or LMD. Preoperative SRS has several potential advantages compared to postoperative SRS, including reduced risk of RN due to smaller irradiated volume without need for cavity margin expansion and reduced risk of LMD due to sterilization of tumor cells prior to spillage at the time of surgery. Subtotal resection, though infrequent, is associated with significantly worse cavity LR and OS. Based on these results, a randomized trial of preoperative versus postoperative SRS is being designed.

External validity of two nomograms for predicting distant brain failure after radiosurgery for brain metastases in a bi-institutional independent patient cohort.

Patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) are at increased risk of distant brain failure (DBF). Two nomograms have been recently published to predict individualized risk of DBF after SRS. The goal of this study was to assess the external validity of these nomograms in an independent patient cohort. The records of consecutive patients with BM treated with SRS at Levine Cancer Institute and Emory University between 2005 and 2013 were reviewed. Three validation cohorts were generated based on the specific nomogram or recursive partitioning analysis (RPA) entry criteria: Wake Forest nomogram (n = 281), Canadian nomogram (n = 282), and Canadian RPA (n = 303) validation cohorts. Freedom from DBF at 1-year in the Wake Forest study was 30% compared with 50% in the validation cohort. The validation c-index for both the 6-month and 9-month freedom from DBF Wake Forest nomograms was 0.55, indicating poor discrimination ability, and the goodness-of-fit test for both nomograms was highly significant (p < 0.001), indicating poor calibration. The 1-year actuarial DBF in the Canadian nomogram study was 43.9% compared with 50.9% in the validation cohort. The validation c-index for the Canadian 1-year DBF nomogram was 0.56, and the goodness-of-fit test was also highly significant (p < 0.001). The validation accuracy and c-index of the Canadian RPA classification was 53% and 0.61, respectively. The Wake Forest and Canadian nomograms for predicting risk of DBF after SRS were found to have limited predictive ability in an independent bi-institutional validation cohort. These results reinforce the importance of validating predictive models in independent patient cohorts.

Single-Fraction Stereotactic Radiosurgery (SRS) Alone Versus Surgical Resection and SRS for Large Brain Metastases: A Multi-institutional Analysis.

PURPOSE: Stereotactic radiosurgery (SRS) dose is limited by brain metastasis (BM) size. The study goal was to retrospectively determine whether there is a benefit for intracranial outcomes and overall survival (OS) for gross total resection with single-fraction SRS versus SRS alone for patients with large BMs. METHODS AND MATERIALS: A large BM was defined as ≥4 cm3 (2 cm in diameter) prior to the study. We reviewed the records of consecutive patients treated with single-fraction SRS alone or surgery with preoperative or postoperative SRS between 2005 and 2013 from 2 institutions. RESULTS: Overall, 213 patients with 223 treated large BMs were included; 66 BMs (30%) were treated with SRS alone and 157 (70%) with surgery and SRS (63 preoperatively and 94 postoperatively). The groups (SRS vs surgery and SRS) were well balanced except regarding lesion volume (median, 5.9 cm3 vs 9.6 cm3; P<.001), median number of BMs (1.5 vs 1, P=.002), median SRS dose (18 Gy vs 15 Gy, P<.001), and prior whole-brain radiation therapy (33% vs 5%, P<.001). The local recurrence (LR) rate was significantly lower with surgery and SRS (1-year LR rate, 36.7% vs 20.5%; P=.007). There was no difference in radiation necrosis (RN) by resection status, but there was a significantly increased RN rate with postoperative SRS versus with preoperative SRS and with SRS alone (1-year RN rate, 22.6% vs 5% and 12.3%, respectively; P<.001). OS was significantly higher with surgery and SRS (2-year OS rate, 38.9% vs 19.8%; P=.01). Both multivariate adjusted analyses and propensity score-matched analyses demonstrated similar results. CONCLUSIONS: In this retrospective study, gross total resection with SRS was associated with significantly reduced LR compared with SRS alone for patients with large BMs. Postoperative SRS was associated with the highest rate of RN. Surgical resection with SRS may improve outcomes in patients with a limited number of large BMs compared with SRS alone. Further studies are warranted.

External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases.

BACKGROUND: A scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm3, with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population. METHODS: We reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence. RESULTS: The low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm3 (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53). CONCLUSION: The 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted.

Novel radiotherapy approaches for lung cancer: combining radiation therapy with targeted and immunotherapies.

Targeted therapies and immunotherapies have quickly become fixtures in the treatment armamentarium for metastatic non-small cell lung cancer (NSCLC). Targeted therapies directed against epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, and ROS-1 rearrangements have demonstrated improved progression free survival (PFS) and, in selected populations, improved overall survival (OS) compared with cytotoxic chemotherapy. Immunotherapies, including checkpoint inhibitor monoclonal antibodies against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), have now also demonstrated improved survival compared with chemotherapy. The use of these novel systemic agents in non-metastatic patient populations and in combination with radiation therapy is not well defined. As radiation therapy has become more effective and more conformal with fewer toxicities, it has increasingly been used in the oligometastatic or oligoprogression setting. This has allowed improvement in PFS and potentially OS, and in the oligoprogressive setting may overcome acquired drug resistance of a specific lesion(s) to allow patients to remain on their targeted therapies. Molecularly targeted therapies and immunotherapies for patients with metastatic NSCLC have demonstrated much success. Advances in radiation therapy and stereotactic body radiotherapy, radiation therapy have led to combination strategies with targeted therapies among patients with lung cancer. Radiation therapy has also been combined with immunotherapies predominantly in the metastatic setting. In the metastatic population, radiation therapy has the ability to provide durable local control and also augment the immune response of systemic agents, which may lead to an abscopal effect of immune-mediated tumor response in disease sites outside of the radiation field in select patients.

Dosimetric and motion analysis of margin-intensive therapy by stereotactic ablative radiotherapy for resectable pancreatic cancer.

BACKGROUND: The retroperitoneal margin is a common site of positive surgical margins in patients with resectable pancreatic cancer. Preoperative margin-intensive therapy (MIT) involves delivery of a single high dose of ablative radiotherapy (30 Gy) focused on this surgically inaccessible margin, utilizing stereotactic techniques in an effort to reduce local failure following surgery. In this study, we investigated the motion of regional organs at risk (OAR) utilizing 4DCT, evaluated the dosimetric effects of abdominal compression (AC) to reduce regional motion, and compared various planning techniques to optimize MIT. METHODS: 10 patients were evaluated with 4DCT scans. All 10 patients had scans using AC and seven of the 10 patients had scans both with and without AC. The peak respiratory abdominal organ and major vessel centroid excursion was measured. A "sub-GTV" region was defined by a radiation oncologist and surgical oncologist encompassing the retroperitoneal margin typically lateral and posterior to the superior mesenteric artery (SMA), and a 3-5 mm margin was added to constitute the PTV. Identical 3D non-coplanar SABR (3DSABR) plans were designed for the average compression and non-compression scans. Compression scans were planned with 3DSABR, coplanar IMRT (IMRT), and Cyberknife (CK) planning techniques. Dose volume analysis was undertaken for various endpoints, comparing OAR doses with and without AC and for different planning methods. RESULTS: The mean PTV size was 20.2 cm3. Regional vessel motion of the SMA, celiac trunk, and renal vessels was small (< 5 mm) and not significantly impacted by AC. Mean pancreatic motion was > 5 mm, so AC has been used in all patients enrolled thus far. AC did not significantly increase OAR dose including the stomach and traverse colon. There were several statistically significant differences in the doses to OARs as a function of the type of planning modality used. CONCLUSIONS: AC does not significantly reduce the limited motion of structures in close proximity to the MIT target and does not significantly increase the dose to OARs that can be displaced by the compression plate. The treatment planning techniques evaluated in this study have different advantages with no clearly superior method in our analysis. Dose to adjacent vessels may be reduced with 3DSABR or IMRT techniques, while conformality is increased with IMRT or CK.

Stereotactic ablative radiation therapy for primary lung tumors.

Stereotactic ablative radiotherapy, also known as stereotactic body radiation therapy, has been developed as an innovative therapy for stage I non-small cell lung cancer and has now emerged as a standard treatment option for medically inoperable patients through careful analysis utilizing prospective, multi-institutional trials. This article reviews and updates the evidence for use of stereotactic ablative radiotherapy in medically inoperable patients with stage I lung cancer, its extension of use to medically operable patients, and the toxicities associated with this emerging technique.

Stereotactic body radiation therapy: evaluation of setup accuracy and targeting methods for a new couch integrated immobilization system.

A new stereotactic frame system was designed at Indiana University to utilize the precision motion control of newer accelerator couches and treat obese patients previously untreatable in other frame systems during stereotactic body radiation therapy (SBRT). The repositioning accuracy and target reproducibility of this frame was evaluated in the treatment of both lung and liver tumors. The external coordinate system on the new frame was validated using a phantom system. Translational motions were carried out using couch motors. Five patients were treated with SBRT and twenty-three verification CT scans were acquired. The displacement of the gross tumor volume (GTV) and adjacent vertebral body between the original CT scan and the verification CT scans was determined. The mean setup accuracy for the patient study was less than 5 mm. Mean displacement of the GTV was 3.0 mm (0.0-6.0 mm) in the lateral (x) direction, 4.1 mm (0.0-8.9 mm) in the superior-inferior (y) direction, and 2.6 mm (0.0-10.0 mm) in the cranio-caudal (z) direction. Comparison of vertebral body position showed mean displacement of 2.4 mm (0.0 to 8.0 mm), 1.9 mm (0.0 mm to 2.0 mm), and 0.9 mm (0.0 to 5.0 mm) for the same shift directions. Repositioning could be accurately carried out from an initial reference position using the treatment couch controllers. Adequate set-up accuracy using a frame system capable of accommodating wide girth patients was achieved and was comparable to other published studies for narrower frames. With these results, a 5 mm expansion for PTV margins remains the standard for our institution.

Four-dimensional computed tomography scan analysis of tumor and organ motion at varying levels of abdominal compression during stereotactic treatment of lung and liver.

PURPOSE: To investigate the effectiveness of different abdominal compression levels on tumor and organ motion during stereotactic body radiotherapy of lower lobe lung and liver tumors using four-dimensional (4D)-CT scan analysis. METHODS AND MATERIALS: Three 4D-CT scans were acquired for 10 patients first using with no compression and then compared with two different levels of abdominal compression. The position of the tumor and various organs were defined at the peak inspiratory and expiratory phases and compared to determine the maximum motion. RESULTS: Mean (+/-SD) medium compression force (MC) and high compression force (HC) were 47.6 +/- 16.0 N and 90.7 +/- 27.1 N, respectively. Mean overall tumor motion was 13.6 mm (2sigma [2 sigma] 11.5-15.6), 8.3 mm (2sigma 6.0-10.5), and 7.2 mm (2sigma 5.4-9.0) for no compression, MC, and HC, respectively. A significant difference in the control of both superior-inferior (SI) and overall motion of tumors was seen with the application of MC and HC when compared with no compression (p < 0.0001 for both). High compression force improved SI and overall tumor motion compared with MC, but this was only significant for SI motion (p = 0.04 and p = 0.06). Significant control of organ motion was only seen in the pancreas (p = 0.01). CONCLUSIONS: Four-dimensional CT shows significant control of both lower lobe lung and liver tumors using abdominal compression. High levels of compression improve SI tumor motion when compared with MC.

Modification of gene products involved in resistance to apoptosis in metastatic colon cancer cells: roles of Fas, Apaf-1, NFkappaB, IAPs, Smac/DIABLO, and AIF.

BACKGROUND: Colon cancer becomes resistant to apoptosis as it acquires metastatic potential. SW480 and SW620 colon cancer cells were established from the same patient at different stages of tumor progression. The stage III colorectal cancer cell line (SW620) is more resistant to apoptosis. In the present report, we investigated the apoptotic gene products that might account for colon cancer evasion of immune attack and chemoradioresistance-induced apoptosis. METHODS: SW480 and SW620 cells were used for this experiment. Type 1 apoptosis was induced by CH-11. Type 2 apoptosis was induced by cisplatin and ionizing radiation. Apoptosis was determined by caspase-3 activity and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling. Gene products Fas, TRAIL, c-FLIP, Bid, BAX, Bcl-2, Bcl-xL, Apaf-1, nuclear factor-kappa B, Smac/DIABLO, apoptosis inducing factor, and the inhibitors of apoptosis were investigated by immunocytochemistry and Western blot analyses. RESULTS: SW620 cell lines were more resistant to both Type 1 and Type 2 apoptosis induced by CH-11, cisplatin, and ionizing radiation, respectively. Examination of the extrinsic pathway demonstrated Fas receptor to be down-regulated in SW620. Apaf-1 was decreased in SW620 cells; while other members of the mitochondrial pathway including Bax, Bid, Bcl-xL, and Bcl-2 demonstrated minimal alterations of protein levels in both cell lines. Survivin and XIAP protein levels were increased in SW620 cells, which correlated with nuclear expression of nuclear factor-kappa B in SW620 cells but not SW480. Mitochondrial-released factors including Smac/DIABLO and apoptosis inducing factor were increased in SW480 cells. CONCLUSIONS: SW620 cells have acquired genetic defects both in the intrinsic and extrinsic pathways of apoptosis, which may explain in part the ability of colon cancer cells to escape the immune system and to become chemoradioresistant. These genes may be potential targets for chemoradiosensitization in advanced colorectal cancer.

Predictors of distant metastasis and mortality in patients with stage II colorectal cancer.

The aim of our study was to determine clinical factors that predicted distant metastasis and mortality in patients with stage II colorectal cancer (CRC). A retrospective review of all patients admitted to the Dallas Veteran's Affairs Medical Center from 1998 to 2002 with stage II CRC was performed. Factors associated with distant metastasis and mortality were assessed by univariate analysis. Independent predictors of mortality and distant metastasis were assessed by multivariate analysis. Fifty-five patients with stage II CRC were identified (96% men, age 65 +/- 1.2 years old). Univariate analysis demonstrated that patients with distant metastasis (n = 13) had a history of alcohol intake (54% vs 20%; P = 0.029), less history of angiotensin-converting enzyme inhibitor use for the management of hypertension (31% vs 67%; P = 0.029), greater incidence of a rectal location for cancer (54% vs 12%; P = 0.004), an abdominoperineal resection (APR) for surgical management of their cancers (23% vs 0%; P = 0.011), and less negative lymph nodes examined during surgical resection (9 +/- 2.2 vs 15 +/- 1.2, P = 0.022). Follow-up of at least 3 years revealed 14 mortalities. Survivors had a less preoperative serum carcinoembryonic antigen level (5.9 +/- 0.9 vs 19.1 +/- 8.6; P = 0.031), an average less tumor depth involvement (T stage: 3.0 +/- 0.03 vs 3.2 +/- 0.11; P = 0.065), more negative lymph nodes examined at the time of surgical resection (14.0 +/- 1.3 vs 10.0 +/- 1.7; P = 0.058), less incidence of rectal cancer (21% vs 43%; P = 0.060), and none had undergone an APR (0% vs. 21%; P = 0.010). Multivariate analysis revealed that alcohol intake (P = 0.014; odds ration [OR] = 5.3), patients undergoing an APR (P = 0.011; OR = 25), and less frequency of angiotensin-converting enzyme inhibitor use (P = 0.007; OR = 4.5) independently predicted distant metastasis, whereas preoperative carcinoembryonic antigen (P = 0.038; OR = 2.8) and patients undergoing an APR (P = 0.019; OR = 25) independently predicted mortality.

Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management.

Avastin (Bevacizumab) is a recently developed monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that increases survival in patients with metastatic colorectal cancer. Bowel perforation is a known risk factor of unknown etiology associated with the use of Avastin. In this report, the incidence, risk factors, typical presentation, and management of patients with this complication is described.