A Prospective Phase II Study of Induction Carboplatin and Vinorelbine followed by Concomitant Topotecan and Accelerated Radiotherapy (ART) in Locally Advanced Non-small Cell Lung Cancer (NSCLC)

BackgroundSurvival of locally advanced/unresectable non-small cell lung cancer (NSCLC) has improved with the use of concurrent radiation and chemotherapy over the past decades, but local and distant failure remain high. In addition, a key limiting factor in combining chemotherapy with accelerated radiotherapy (ART) is severe esophagitis. We investigated the toxicity, response rate, and overall survival (OS) with induction carboplatin and vinorelbine followed by concomitant topotecan and ART in patients with locally advanced/unresectable NSCLC.MethodsIn this phase II trial, stage IIIA or IIIB NSCLC patients with a Karnofsky performance score >60 were eligible. Patients received induction carboplatin (area under the curve = 5.5) on days 1 and 22, and vinorelbine (25 mg/m2) on days 1, 8, 22, and 29. During the concurrent chemoradiation, patients received intravenous topotecan (0.5 mg/m2) on days 43 to 47, days 57 to 61, and days 71 to 75 before the morning radiotherapy (RT) fraction. RT was administered in an accelerated fashion at 2 Gy per fraction, twice daily for five consecutive days, every other week, to a cumulative dose of 60 Gy during a 5-week period.ResultsThirty-seven patients were accrued; of these, 35 were evaluable. Overall response rate was 71% (14% complete response, 57% partial response). Six of 35 (17%) patients had stable disease. Four (11%) patients progressed during treatment. At a median follow-up of 45 months for surviving patients, the median survival based on Kaplan–Meier estimates is 17.9 months. OS at 1, 2, and 3 years is 62%, 41%, and 33%, respectively. Actuarial 5-year OS is 21%. The median time to first relapse is 12.2 months (9.1–24.7 months). There were no cases of grade 3 or 4 esophagitis.ConclusionsThis combined-modality regimen yielded encouraging OS rates, with no severe esophagitis. Using four-dimensional RT treatment planning, we plan to further evaluate altered fractionation RT and chemotherapy for this group of patients

(P44) Is Prophylactic Cranial Irradiation Necessary in Stage I-IIA Small Cell Lung Cancer Patients? A Single Institution Experience

Background: The advent of screening chest computed tomography (CT) for high-risk patients has increased the patient population presenting with early-stage small cell lung cancer (SCLC). While surgical resection continues to be standard of care, stereotactic body radiation therapy (SBRT) is an option for non-surgical candidates. Although the effectiveness of PCI in patients with limited stage SCLC has been well established, decreasing the brain metastasis incidence from approximately 70% to 30%, the role of PCI in early-stage SCLC (T1-T2) has not been fully elucidated. This study reports our experience omitting PCI in early-stage SCLC. Objectives: This study reports our experience omitting PCI in early stage SCLC. Methods: Fourteen patients with early-stage SCLC, nine patients with clinical stage I (T1) and five patients with stage IA (T2) SCLC, ranging in age from 54-81 years old, treated with surgical resection or SBRT from July 2015 to May 2021 at our institution, were retrospectively reviewed. Positron emission tomography (PET) was used in the staging of 93% of patients. All patients had initial negative brain MRI and opted not to receive PCI. 71% of the patients had brain scan surveillance for follow-up. Risk factors including age, gender, and tumor size, were analyzed for overall survival (OS), loco-regional recurrence (LRR), and distant metastasis (DM) using the Log-rank test. Results: With a median follow-up of 13 months (range 2-63), none of our patients developed metastases to the brain. Adjuvant chemotherapy, with a mean of 4 cycles (2-6) was administered to 13 out of 14 patients (92%). The 2-year OS, LRR and DM estimates were 47% [95% CI (0.14, 0.75)], 57% [95% CI (0.19, 0.82)], and 51% [95% CI (0.17, 0.77)], respectively. The OS and the frequency of LRR were not found to be correlated with age, gender, or tumor size. DM was significantly higher in males vs females (P=0.016). Conclusions: Our experience in patients with Stage I-IIA SCLC treated with surgery or SBRT did not demonstrate any development of brain metastases. As PCI carries long term risks of neurotoxicity, close surveillance with regular brain imaging may be a reasonable alternative. Adjuvant systemic therapy remains an important component of treatment

Technical note: Comparison of the internal target volume (ITV) contours and dose calculations on 4DCT, average CBCT, and 4DCBCT imaging for lung stereotactic body radiation therapy (SBRT)

PURPOSE: To investigate the differences between internal target volumes (ITVs) contoured on the simulation 4DCT and daily 4DCBCT images for lung cancer patients treated with stereotactic body radiotherapy (SBRT) and determine the dose delivered on 4D planning technique. METHODS: For nine patients, 4DCBCTs were acquired before each fraction to assess tumor motion. An ITV was contoured on each phase of the 4DCBCT and a union of the 10 ITVs was used to create a composite ITV. Another ITV was drawn on the average 3DCBCT (avgCBCT) to compare with current clinical practice. The Dice coefficient, Hausdorff distance, and center of mass (COM) were averaged over four fractions to compare the ITVs contoured on the 4DCT, avgCBCT, and 4DCBCT for each patient. Planning was done on the average CT, and using the online registration, plans were calculated on each phase of the 4DCBCT and on the avgCBCT. Plan dose calculations were tested by measuring ion chamber dose in the CIRS lung phantom. RESULTS: The Dice coefficients were similar for all three comparisons: avgCBCT-to-4DCBCT (0.7 ± 0.1), 4DCT-to-avgCBCT (0.7 ± 0.1), and 4DCT-to-4DCBCT (0.7 ± 0.1); while the mean COM differences were also comparable (2.6 ± 2.2mm, 2.3 ± 1.4mm, and 3.1 ± 1.1mm, respectively). The Hausdorff distances for the comparisons with 4DCBCT (8.2 ± 2.9mm and 8.1 ± 3.2mm) were larger than the comparison without (6.5 ± 2.5mm). The differences in ITV D95% between the treatment plan and avgCBCT calculations were 4.3 ± 3.0% and -0.5 ± 4.6%, between treatment plan and 4DCBCT plans, respectively, while the ITV V100% coverages were 99.0 ± 1.9% and 93.1 ± 8.0% for avgCBCT and 4DCBCT, respectively. CONCLUSION: There is great potential for 4DCBCT to evaluate the extent of tumor motion before treatment, but image quality challenges the clinician to consistently delineate lung target volumes

Development and evaluation of a clinical model for lung cancer patients using stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning

The purpose of this study was to describe the development of a clinical model for lung cancer patients treated with stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning, and to evaluate the model performance and applicability to different planning techniques, tumor locations, and beam arrangements. 105 SBRT plans for lung cancer patients previously treated at our institution were included in the development of the knowledge-based model (KBM). The KBM was trained with a combination of IMRT, VMAT, and 3D CRT techniques. Model performance was validated with 25 cases, for both IMRT and VMAT. The full KBM encompassed lesions located centrally vs. peripherally (43:62), upper vs. lower (62:43), and anterior vs. posterior (60:45). Four separate sub-KBMs were created based on tumor location. Results were compared with the full KBM to evaluate its robustness. Beam templates were used in conjunction with the optimizer to evaluate the model\u27s ability to handle suboptimal beam placements. Dose differences to organs-at-risk (OAR) were evaluated between the plans gener-ated by each KBM. Knowledge-based plans (KBPs) were comparable to clinical plans with respect to target conformity and OAR doses. The KBPs resulted in a lower maximum spinal cord dose by 1.0 ± 1.6 Gy compared to clinical plans, p = 0.007. Sub-KBMs split according to tumor location did not produce significantly better DVH estimates compared to the full KBM. For central lesions, compared to the full KBM, the peripheral sub-KBM resulted in lower dose to 0.035 cc and 5 cc of the esophagus, both by 0.4Gy ± 0.8Gy, p = 0.025. For all lesions, compared to the full KBM, the posterior sub-KBM resulted in higher dose to 0.035 cc, 0.35 cc, and 1.2 cc of the spinal cord by 0.2 ± 0.4Gy, p = 0.01. Plans using template beam arrangements met target and OAR criteria, with an increase noted in maximum heart dose (1.2 ± 2.2Gy, p = 0.01) and GI (0.2 ± 0.4, p = 0.01) for the nine-field plans relative to KBPs planned with custom beam angles. A knowledge-based model for lung SBRT consisting of multiple treatment modalities and lesion loca-tions produced comparable plan quality to clinical plans. With proper training and validation, a robust KBM can be created that encompasses both IMRT and VMAT techniques, as well as different lesion locations

Phase I trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer

The safety of oncolytic adenovirus-mediated suicide and interleukin-12 (IL 12) gene therapy was evaluated in metastatic pancreatic cancer patients. In this phase I study, a replication-competent adenovirus (Ad5-yCD/mutTK(SR39) rep-hIL-12) expressing yCD/mutTK(SR39) (yeast cytidine deaminase/mutant S39R HSV-1 thymidine kinase) and human IL-12 (IL 12) was injected into tumors of 12 subjects with metastatic pancreatic cancer (T2N0M1-T4N1M1) at escalating doses (1 × 10(11), 3 × 10(11), or 1 × 10(12) viral particles). Subjects received 5-fluorocytosine (5-FC) therapy for 7 days followed by chemotherapy (FOLFIRINOX or gemcitabine/albumin-bound paclitaxel) starting 21 days after adenovirus injection. The study endpoint was toxicity through day 21. Experimental endpoints included measurements of serum IL 12, interferon gamma (IFNG), and CXCL10 to assess immune system activation. Peripheral blood mononuclear cells and proliferation markers were analyzed by flow cytometry. Twelve patients received Ad5-yCD/mutTK(SR39) rep-hIL-12 and oral 5-FC. Approximately 94% of the 121 adverse events observed were grade 1/2 requiring no medical intervention. Ad5-yCD/mutTK(SR39) rep-hIL-12 DNA was detected in the blood of two patients. Elevated serum IL 12, IFNG, and CXCL10 levels were detected in 42%, 75%, and 92% of subjects, respectively. Analysis of immune cell populations indicated activation after Ad5-yCD/mutTK(SR39) rep-hIL-12 administration. The median survival of patients in the third cohort is 18.1 (range, 3.5-20.0) months. The study maximum tolerated dose (MTD) was not reached

The Influence of Dosimetric Parameters on Quality of Life for Early Stage Non-small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Background: Lung stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage non-small cell lung cancer (NSCLC) patients who are medically inoperable. The influence of radiation dose/volume parameters on quality of life is not known. Our hypothesis is that clinically meaningful declines in quality of life over time will be associated with increased radiation lung dose/volume parameters. Objectives: To investigate clinical toxicity and quality of life (QOL) outcomes of stage I NSCLC patients after SBRT as a function of radiation dose/volume parameters. Methods: In this IRB-approved study, 55 stage I NSCLC patients who received SBRT (12 Gy x 4) and completed QOL forms were analyzed. Clinical symptoms and QOL were measured at baseline and at 3, 6, 12, 18, 24, and 36 months post-SBRT. Clinical toxicity was graded using the common terminology criteria for adverse effects (CTCAE v4.0). Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) instrument. Dosimetric parameters, including the mean lung radiation dose (MLD), and the volume of normal lung receiving \u3e 5, 10, 13 or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student\u27s t-test and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxicities. Kaplan-Meier method was used to estimate rates of local control (LC), disease free survival (DFS), and overall survival (OS). Results: With a median follow-up of 24 months, the 3 year LC, DFS, and OS were 93%, 65% and 84%, respectively, with 5.5% grade 3 toxicity and no grade 4 or 5 toxicities. Clinically meaningful declines in patient reported QOL (FACT-TOI, lung cancer subscale, physical well-being, and/or functional well-being) post-treatment significantly correlated with increased dosimetric parameters, such as V10, V13, and V20. Conclusions: While lung SBRT is associated with excellent LC and minimal clinical toxicity for early stage NSCLC, clinically meaningful declines in QOL significantly correlated with increasing lung dose/volume parameters. This suggests that further improvements in the techniques of lung SBRT have the potential to further enhance patients\u27 QOL following this treatment

The Influence of Dosimetric Parameters on Quality of Life for Early Stage Non-small Cell Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy

Background: Lung stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage non-small cell lung cancer (NSCLC) patients who are medically inoperable. The influence of radiation dose/volume parameters on quality of life is not known. Our hypothesis is that clinically meaningful declines in quality of life over time will be associated with increased radiation lung dose/volume parameters. Objectives: To investigate clinical toxicity and quality of life (QOL) outcomes of stage I NSCLC patients after SBRT as a function of radiation dose/volume parameters. Methods: In this IRB-approved study, 55 stage I NSCLC patients who received SBRT (12 Gy x 4) and completed QOL forms were analyzed. Clinical symptoms and QOL were measured at baseline and at 3, 6, 12, 18, 24, and 36 months post-SBRT. Clinical toxicity was graded using the common terminology criteria for adverse effects (CTCAE v4.0). Quality of life was followed using the validated Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI) instrument. Dosimetric parameters, including the mean lung radiation dose (MLD), and the volume of normal lung receiving \u3e 5, 10, 13 or 20 Gy (V5, V10, V13, and V20) were measured from the radiation treatment plan. Student\u27s t-test and Pearson correlation analyses were used to examine the relationships between radiation lung metrics and clinically meaningful changes in QOL and/or clinical toxicities. Kaplan-Meier method was used to estimate rates of local control (LC), disease free survival (DFS), and overall survival (OS). Results: With a median follow-up of 24 months, the 3 year LC, DFS, and OS were 93%, 65% and 84%, respectively, with 5.5% grade 3 toxicity and no grade 4 or 5 toxicities. Clinically meaningful declines in patient reported QOL (FACT-TOI, lung cancer subscale, physical well-being, and/or functional well-being) post-treatment significantly correlated with increased dosimetric parameters, such as V10, V13, and V20. Conclusions: While lung SBRT is associated with excellent LC and minimal clinical toxicity for early stage NSCLC, clinically meaningful declines in QOL significantly correlated with increasing lung dose/volume parameters. This suggests that further improvements in the techniques of lung SBRT have the potential to further enhance patients\u27 QOL following this treatment

Racial Differences in Treatments and Toxicity in Non-Small Cell Lung Cancer Patients Treated with Thoracic Radiation Therapy

Background: Racial disparities are of particular concern for lung cancer patients given historical differences in surgery rates for African-American lung cancer patients that resulted in lower overall survival and higher recurrence rates compared with rates in White patients. Objectives: The overall objective of this study was to examine racial differences in thoracic radiation therapy (RT) treatments and toxicities in a large cohort of patients from a multi-institutional consortium database of non-small cell lung cancer (NSCLC) patients. Methods: A large multi-institutional statewide prospectively collected patient-level database of locally advanced (stage II or III) NSCLC patients who received thoracic RT from March 2012 to November 2019 was analyzed to assess the associations between race and treatment and toxicity variables. Race (White or African-American) was defined by patient self-report or if not available then by the electronic medical record system classification. Race categories other than White or African-American comprised a small minority of patients and were excluded from this analysis. Patient-reported toxicity was determined by validated tools including the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Provider-reported toxicity was determined by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Uni-variable and multi-variable regression models were then fitted to assess relationships between primary outcomes by race and indicators of high-quality treatment and secondary analysis of symptoms. Spearman rank correlation coefficients were calculated between provider reported toxicity and similar patient reported outcomes for each race category. Results: A total of 1441 patients from 24 institutions with mean age of 68 years (range 38-94) were evaluated; 226 patients were African-American, of whom 61% were treated at three facilities. Race was not significantly associated with RT treatment approach, use of concurrent chemotherapy, or the dose to the planning target volume (PTV) or organs at risk including the heart and lungs. However, there was increased patient-reported general pain in African-American patients (compared with White patients) at several time points including pre-RT (22% (vs 15%), P=0.02) and at the end of RT (30% (vs 17%), P=0.001). African-American patients were significantly less likely to have provider-reported grade 2+ radiation pneumonitis (odds ratio (OR) 0.36, P=0.03), despite similar levels of patient-reported respiratory toxicities such as cough and shortness of breath and even after controlling for known patient and treatment-related factors. Correlation coefficients between provider- and patient-reported toxicities were generally similar across race categories. Conclusions: In this large multi-institutional observational study, we reassuringly found no evidence of differences in radiation treatment or chemotherapy approaches by race, in contrast to historical differences by race in surgical care that led to worse survival and outcomes in minority race patients. However, we did unexpectedly find that African-American race was associated with lower odds of provider-reported grade 2+ radiation pneumonitis despite similar patient-reported toxicities of shortness of breath and cough. There are several possibilities for this finding including that pneumonitis is a multifactorial diagnosis that relies on clinical as well as radiologic information and clinical information alone may be insufficient. The Spearman correlation analysis also revealed stronger correlations between patient- and provider-reported toxicities in White patients compared with African-American patients, particularly for trouble swallowing/esophagitis. These findings together for pneumonitis and esophagitis discouragingly suggest possible under-recognition of symptoms in black patients. Further investigation is now warranted to better understand how these findings impact the care of racially diverse lung cancer patients

Characteristics of a novel treatment system for linear accelerator–based stereotactic radiosurgery

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond Dmax were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2–1.8 mm (80%-20%) and 1.9–3.8 mm (90%-10%) relative to 10X FFF, which has 1.2–2.2mm and 2.3–5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment