Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Systematic Review.

INTRODUCTION: Thymic epithelial tumors are rare and are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors. The objective of this systematic review was to evaluate the treatment options for patients with thymic epithelial tumors. METHODS: This systematic review was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing surgical, radiotherapy, or systemic treatments against any combination of these treatments in patients with thymic epithelial tumors. Meta-analyses were conducted with clinically homogenous studies. RESULTS: A total of 106 studies were included, mainly from observational studies. There was an overall survival benefit with postoperative radiotherapy for patients with thymic carcinoma (hazard ratio = 0.65, 95% confidence interval: 0.47-0.89) and for patients with thymoma (hazard ratio = 0.70, 95% confidence interval: 0.59-0.82), especially for those with a high risk for mortality. Patients with thymic carcinoma or thymoma had a response to chemotherapy. Selection bias affected the results for studies that evaluated neoadjuvant chemotherapy or minimally invasive surgical techniques. Furthermore, the overall survival benefit found for adjuvant chemotherapy may have been confounded by the administration of postoperative radiotherapy. CONCLUSIONS: For patients with thymoma or thymic carcinoma, the literature is of low quality and subject to bias. There were overall survival benefits with postoperative radiotherapy. The results of this systematic review were used to inform treatment recommendations in a clinical practice guideline. Future large-scale prospective studies that control for confounders are needed.

Toxicity and Efficacy of Multitarget Thoracic Stereotactic Body Radiation Therapy.

PURPOSE: With the increasing use of stereotactic body radiation therapy (SBRT) for primary and metastatic cancer, use of multitarget thoracic (MTT) SBRT is rising. Given the limited safety and efficacy data, we report the experience of this strategy from a large academic center. METHODS AND MATERIALS: Between 2012 and 2021, patients who received SBRT for ≥2 thoracic targets separated by ≤1 year were retrospectively reviewed. The primary endpoint was clinically significant radiation pneumonitis (CSRP) requiring steroids, oxygen, or intubation. Secondary endpoints included local failure (LF), initiation or change of systemic therapy (ICST), progression-free survival, and overall survival. Competing risk analysis was used to evaluate the cumulative incidence of CSRP, LF, and ICST. Univariate and multivariable analyses were performed to look for clinical and dosimetric predictive factors of CSRP and LF. RESULTS: One hundred ninety patients (481 lesions) were treated with MTT SBRT with a median follow-up of 19.7 months. Indications for SBRT were oligometastases (n = 70; 36.8%), oligoprogression (n = 62; 32.6%), curative intent in patients with primary lung cancer (n = 37; 19.5%), and control of dominant areas of metastatic progression (n = 21; 11.0%). The number of irradiated tumors ranged from 2 to 7 and the majority of SBRT courses were delivered simultaneously (88.2%). Overall, 14 patients (7.4%) had CSRP, with 5 cases requiring oxygen. The cumulative incidence of CSRP at 6 and 12 months was 5.3% and 7.6%, respectively. The cumulative incidence of LF at 2 years was 10.5%. The cumulative incidence of ICST at 2 years was 41.1%. Median progression-free survival was 11.8 months and median overall survival was 51.3 months. On multivariable analysis, a higher lung V35Gy (hazard ratio, 2.59; P = .02) was a statistically significant predictor of CSRP and colorectal histology predicted for higher LF (hazard ratio, 2.12; P = .02). CONCLUSIONS: In one of the largest institutional series of MTT SBRT, rates of CSRP and LF were low. Optimizing plans to lower the lung V35Gy may decrease the risk of CSRP.

Surgical, Radiation, and Systemic Treatments of Patients With Thymic Epithelial Tumors: A Clinical Practice Guideline.

INTRODUCTION: The aim of this guideline was to provide recommendations for the most effective therapy for patients with thymic epithelial tumors, including thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETs). This guideline is intended to be used by all health care professionals managing patients with thymic epithelial tumors. METHODS: The guideline was developed by Ontario Health (Cancer Care Ontario)'s Program in Evidence-Based Care and by the Lung Cancer Disease Site Group through a systematic review of the evidence, expert consensus, and formal internal and external reviews. RESULTS: Evidence-based recommendations were developed to improve the management of patients with thymic epithelial tumors. The guideline includes recommendations for surgical, radiation, and systemic treatments for patients with thymoma, thymic carcinoma, and thymic NETs separated by stage of disease using the TNM staging system. Recommendations for patients with thymic NETs were endorsed from the 2021 National Comprehensive Cancer Network Neuroendocrine and Adrenal Tumors Guideline. CONCLUSIONS: This guideline reflects the new staging system for patients with thymoma and thymic carcinoma and includes supporting evidence from the best available studies.

Stereotactic Body Radiation Therapy for Mediastinal and Hilar Lymph Node Metastases.

PURPOSE: Stereotactic body radiation therapy (SBRT) to metastatic mediastinal and hilar lymphadenopathy (MHL) is challenging owing to the proximity of centrally located organs-at-risk. As limited data exist on the safety and efficacy of SBRT for MHL, a retrospective review of clinical outcomes was conducted from a large academic center. METHODS AND MATERIALS: Eligible patients received SBRT to MHL between 2014 to 2019 for the following indications: oligometastases, oligoprogression, or local control of a dominant area of progression. The primary endpoint was grade ≥3 toxicity (Common Terminology Criteria for Adverse Events, version 5.0). The cumulative incidence function evaluated local failure (LF) and starting or changing systemic therapy (SCST). Kaplan-Meier methodology estimated progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-two patients (84 metastases) were included. Median follow-up was 20 months. Primary cancer sites included kidney (53.8%), lung (13.4%), breast (7.7%), and other (25.1%). Indications for SBRT were oligoprogression (n = 35; 67.3%), oligometastases (n = 10; 19.2%), or local failure of a dominant area of progression (n = 7; 13.5%). The majority (n = 31; 59.6%) received SBRT to a single lymph node metastasis. Median SBRT dose was 35 Gy (range, 30-50 Gy) with a median biologically effective dose of 59.5 Gy (range, 48-100 Gy). All treatments were in 5 fractions. Seven grade ≥3 toxicities were experienced by 6 patients (11.5%) and were mostly transient (5/7; 71%). There was a single (1.9%) grade 5 toxicity (radiation pneumonitis). The cumulative incidence of LF was 9.0% at 2 years. The cumulative incidence of SCST was 33.2% and 57.1% at 1 and 2 years, respectively. Median PFS was 4.0 months (95% confidence interval, 2.8-7.3) and median OS was 31.7 months (95% confidence interval, 23.8-87.5). CONCLUSIONS: In one of the largest single institutional series of SBRT for MHL, moderate rates of grade ≥3 toxicity were observed, although the majority were transient. This treatment resulted in low LF rates and potentially delayed SCST for many patients.

Positron emission tomography in staging early lung cancer: a randomized trial.

BACKGROUND: Among patients with early-stage non-small cell lung cancer (NSCLC), preoperative imaging tests are important in defining surgical candidates. OBJECTIVE: To assess whether whole-body positron emission tomography and computed tomography (PET-CT) plus cranial imaging correctly upstages cancer in more patients with NSCLC than does conventional staging plus cranial imaging. DESIGN: Randomized clinical trial with recruitment from June 2004 to August 2007. The centralized, computer-generated, variable block size randomization scheme was stratified by treatment center and cancer stage. Participants, health care providers, and outcome assessors were not blinded to imaging modality assignment. SETTING: 8 hospitals and 5 PET-CT centers in academic institutions. PATIENTS: Eligible patients were older than 18 years; had histologic or cytologic proof of stage I, II, or IIIA NSCLC on the basis of chest radiography and thoracic CT; and had a tumor considered to be resectable. INTERVENTION: PET-CT or conventional staging (abdominal CT and bone scan). All patients also had cranial imaging using CT or magnetic resonance imaging. MEASUREMENTS: The primary outcome was correct upstaging, thereby avoiding stage-inappropriate surgery. Secondary outcomes were incorrect upstaging and incorrect understaging. RESULTS: 170 patients were assigned to PET-CT and 167 to conventional staging. Eight patients (3 who had PET-CT and 5 who had conventional staging) did not have planned surgery. Disease was correctly upstaged in 23 of 167 PET-CT recipients and 11 of 162 conventional staging recipients (13.8% vs. 6.8%; difference, 7.0 percentage points [95% CI, 0.3 to 13.7 percentage points]), thereby sparing these patients from surgery. Disease was incorrectly upstaged in 8 PET-CT recipients and 1 conventional staging recipient (4.8% vs. 0.6%; difference, 4.2 percentage points [CI, 0.5 to 8.6 percentage points]), and it was incorrectly understaged in 25 and 48 patients, respectively (14.9% vs. 29.6%; difference, 14.7 percentage points [CI, 5.7 to 23.4 percentage points]). At 3 years, 52 patients who had PET-CT and 57 patients who had conventional staging had died. LIMITATION: The relatively small sample and the fact that some patients did not have planned surgery limited the ability to determine precise differences in clinical outcomes that were attributable to testing strategies. CONCLUSION: Preoperative staging with PET-CT and cranial imaging identifies more patients with mediastinal and extrathoracic disease than conventional staging, thereby sparing more patients from stage-inappropriate surgery, but the strategy also incorrectly upstaged disease in more patients.

Stereotactic Radiotherapy for Pancreatic Cancer: A Single-Institution Experience.

Introduction Despite treatment advances, the prognosis of locally advanced pancreatic cancer is poor. Treatment remains varied and includes systemic and radiotherapy (RT). Stereotactic body radiotherapy (SBRT), highly conformal high-dose RT per fraction, is an emerging treatment option. Materials and methods We performed a single-institution retrospective review of patients with pancreatic adenocarcinoma treated with SBRT from 2015-2017. The median dose was 27 Gy (range: 21-36 Gy) in three fractions. Endpoints included local progression (RECIST 1.1; Response Evaluation Criteria in Solid Tumors 1.1), distant metastasis, overall survival, and toxicity. Results Forty-one patients were treated, with a median follow-up of eight months. Patients who received SBRT had unresectable (49%), metastatic (17%), or borderline resectable (7%) disease, declined surgery (17%), medically inoperable (7%), or developed local recurrence following the Whipple procedure (2%). The six-month and one-year rates of local progression-free survival, distant metastasis-free survival, and overall survival were 62% and 55%, 44% and 32%, and 70% and 49%, respectively. Five patients (12%) experienced seven late gastrointestinal (GI) grade 3 events. Conclusion  SBRT may be considered a treatment option to achieve local control of pancreatic cancer and is associated with a modest risk of severe late GI toxicities. Systemic therapies remain important, given the proportion of patients who develop distant metastases.

Stereotactic ablative radiotherapy for malignant mediastinal and hilar lymphadenopathy: a systematic review.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) safety and efficacy for mediastinal and hilar lymphadenopathy (MHL) is not yet established, given its potential for toxicity due to the proximity to esophagus and proximal bronchial tree (PBT). This review summarized current reported outcomes of MHL SABR. METHODS: This systematic review, based on the PRISMA guidelines, was performed using MEDLINE® (PubMed®), EMBASE and Cochrane Library databases from inception until December 2018. Studies reporting outcomes from SABR specifically for MHL from all primary malignancies were included. Non- English studies, guidelines, reviews, non-peer reviewed correspondences were excluded. Only the most recent publication and/or largest cohort from a single institution would be included for analysis. RESULTS: From the 222 studies identified, 4 retrospective studies totaling 196 patients were included in the analysis. One study included a small number of patients receiving non-ablative doses of stereotactic radiotherapy (RT). Non-small cell lung cancer (NSCLC) was the most common primary (65%), followed by breast (8%). Median follow-up ranged between 12 and 32 months. Reported dose and fractionation ranged from 21 to 60 Gy in 3-11 fractions, with median BED10 ranged from 46-106 Gy10. Three studies reported local control (LC) rates: study 1, 97% (1-year) and 77% (5-year); study 4, 88% (2-year); and study 2, 69% (6-month) and 66% (16-month). Pooled grade 3-5 toxicity rate according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 was 6% (n=11). Pooled SABR-related mortality (grade 5 toxicity) rate was 2% (n=4). Three SABR-related deaths from esophageal fistulae (2 to trachea, 1 to mediastinum) were reported, with all 3 having prior RT to the subcarinal nodes. CONCLUSIONS: Our review suggested SABR for MHL to be feasible and effective, though there is a potential for serious toxicity especially in the re-irradiation scenario. Multi-institutional and/or prospective studies will help determine the therapeutic benefit of SABR in this high-risk treatment scenario.

Intensity Modulated Radiation Therapy Plus Etoposide/Cisplatin for Patients With Limited Advanced Unresectable Thymic Epithelial Tumors: A Prospective Phase 2 Study.

PURPOSE: This prospective phase 2 study evaluated the efficacy and safety of intensity modulated radiation therapy plus etoposide/cisplatin (EP) for patients with unresectable thymic epithelial tumors (TETs). METHODS AND MATERIALS: Patients with limited advanced unresectable TETs whose lesions could be encompassed within radiation fields were enrolled in this study. Two cycles of EP (75 mg/m2 etoposide and 25 mg/m2 cisplatin on days 1-3 and days 29-31) were administered concurrently with radiation therapy, followed by 2 cycles after radiation therapy. The primary endpoint was the objective response rate. The secondary endpoints were the progression-free survival rate, overall survival rate, and incidence of adverse events. RESULTS: Fifty-six patients were enrolled between June 2011 and May 2018. Twenty-two and 34 patients had thymomas and thymic carcinomas, respectively. The median age was 52 (range, 21-76) years, and 30 patients (53.6%) were men. Eight patients (14.3%) had stage III tumors, 6 (10.7%) had stage IVA tumors, and 42 (75.0%) had stage IVB tumors. The objective response rate was 85.7% (95% confidence interval, 76.3%-95.2%). With a median follow-up of 46 (range, 7-101) months, the 1-, 2-, and 5-year progression-free survival rates were 66.1%, 48.0%, and 29.5%, and the 1-, 2-, and 5-year overall survival rates were 91.0%, 76.2%, and 56.2%, respectively. The most common grade 3 to 4 adverse event was leukopenia (42.9%). Pulmonary fibrosis was also observed (5.3%). CONCLUSIONS: Because intensity modulated radiation therapy with EP is effective and safe for limited advanced unresectable TETs, it could be a suitable treatment option for such patients.

Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review.

Second-line treatment options are limited for patients with advanced non-small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1-positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1-positive tumors).

Radiotherapy With Curative Intent in Patients With Early-stage, Medically Inoperable, Non-Small-cell Lung Cancer: A Systematic Review.

Patients with early-stage non-small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.

How equitable is access to treatment for lung cancer patients? A population-based review of treatment practices in Ontario.

AIM: Guideline concordance is one of the metrics used by the Cancer Quality Council of Ontario and Cancer Care Ontario to assess the quality of cancer care and to drive quality improvement. MATERIALS & METHODS: The rates for lung cancer surgical resection and concordance with the Cancer Care Ontario postoperative adjuvant chemotherapy (AC) guideline were assessed by health region during two time periods (2010-2011 and 2012-2013) according to five equity measures (age, sex, neighborhood income, location of residence and size of immigrant population). RESULTS: Of the patients with stage I/II NSCLC, 52.2% to 63.0% underwent surgical resection in the province of Ontario, Canada; for patients with stage IIIA disease, the rate was 26.4%. The probability of a surgical resection decreased substantially with age; only 26.9% of those with potentially resectable (stage I-IIIA) disease over 80 years underwent surgery. The use of postoperative AC increased modestly over the time of the study but the rate of use varied widely by health region (34.6 to 84.6%). Patients in rural areas were as likely to receive AC as urban dwellers; however, older aged patients (≥65 years) and those from the lowest income neighborhoods were significantly less likely to receive AC. CONCLUSION: Surgical rates and the use of AC vary by health region in Ontario and by age and level of neighborhood income despite universal access in a publicly funded health care system. The reasons for this variance are unclear but warrant further study.Presented in part at the 15th World Conference on Lung Cancer, Sydney, Australia, 27-30 October 2013.

Adjuvant Systemic Therapy and Adjuvant Radiation Therapy for Stage I to IIIA Completely Resected Non-Small-Cell Lung Cancers: American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice Guideline Update.

Purpose The panel updated the American Society of Clinical Oncology (ASCO) adjuvant therapy guideline for resected non-small-cell lung cancers. Methods ASCO convened an update panel and conducted a systematic review of the literature, investigating adjuvant therapy in resected non-small-cell lung cancers. Results The updated evidence base covered questions related to adjuvant systemic therapy and included a systematic review conducted by Cancer Care Ontario current to January 2016. A recent American Society for Radiation Oncology guideline and systematic review, previously endorsed by ASCO, was used as the basis for recommendations for adjuvant radiation therapy. An update of these systematic reviews and a search for studies related to radiation therapy found no additional randomized controlled trials. Recommendations Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stage IIA, IIB, or IIIA disease who have undergone complete surgical resections. For individuals with stage IB, adjuvant cisplatin-based chemotherapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a medical oncologist, is recommended to assess benefits and risks of adjuvant chemotherapy for each patient. The guideline provides information on factors other than stage to consider when making a recommendation for adjuvant chemotherapy, including tumor size, histopathologic features, and genetic alterations. Adjuvant chemotherapy is not recommended for patients with stage IA disease. Adjuvant radiation therapy is not recommended for patients with resected stage I or II disease. In patients with stage IIIA N2 disease, adjuvant radiation therapy is not recommended for routine use. However, a postoperative multimodality evaluation, including a consultation with a radiation oncologist, is recommended to assess benefits and risks of adjuvant radiation therapy for each patient with N2 disease. Additional information is available at www.asco.org/lung-cancer-guidelines and www.asco.org/guidelineswiki .

The role of radiation therapy in malignant pleural mesothelioma: a systematic review.

INTRODUCTION: Radiation therapy may offer patients presenting with malignant pleural mesothelioma (MPM) symptom palliation and improvements in quality of life. This systematic review will address the role of radiation therapy in the management of MPM. METHODS: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials were selected and assessed. RESULTS: Three small randomized controlled trials compared prophylactic external beam radiation therapy to no radiation therapy for patients with thoracic tracts caused by drainage tubes or diagnostic procedures. None of those trials reported any serious adverse effects. A pooled analysis found no significant reduction in the frequency of procedure tract metastases. Four non-comparative studies have shown that hemithoracic irradiation alone resulted in significant toxicity, including radiation-induced pulmonary fibrosis, radiation pneumonitis, and bronchopleural fistula, without any survival benefit. Few of the identified studies reported on symptom control, and no studies included formal measures of quality of life. CONCLUSION: There is limited evidence for the role of radiotherapy in the management of patients with MPM. Future studies including radiotherapy for the treatment of such patients should include formal measures of quality of life and symptom control.

The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review.

PURPOSE: This review addresses the role of high-dose-rate endobronchial brachytherapy (HDREB) for symptom palliation in patients with non-small-cell lung cancer. METHODS AND MATERIALS: Relevant trials were identified through a systematic search of the literature. RESULTS: Twenty-nine trials were eligible. Six randomized trials involved HDREB alone or with external beam radiation therapy (EBR) or laser therapy. Median and 1-year survival ranged from 4 to 10 months and from 11% to 38%, respectively. Symptoms controlled by HDREB were dyspnea, cough, chest pain, and hemoptysis. Fatal hemoptysis ranged from 7% to 22%. Better overall symptom palliation and fewer retreatments were required in previously untreated patients using EBR alone or EBR with HDREB. CONCLUSIONS: EBR alone is more effective than HDREB for symptom palliation in previously untreated patients with endobronchial non-small-cell lung cancer. HDREB with EBR seems to provide better symptom relief than EBR alone. HDREB is recommended for symptomatic patients with recurrent endobronchial obstruction previously treated by EBR, providing it is technically feasible.

The Use of Systemic Treatment in the Maintenance of Patients with Non-Small Cell Lung Cancer: A Systematic Review.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression and potentially increase overall survival. Secondarily, it may increase the proportion of patients eligible for second-line therapy at the time of progression. The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for phase III randomized controlled trials comparing maintenance systemic treatment against another systemic treatment or placebo in patients with stage IIIB or IV NSCLC who had received a minimum of four prior cycles of platinum-based chemotherapy. Meta-analyses were conducted with clinically homogenous trials. RESULTS: Fourteen randomized controlled trials with 22 publications were included. The overall survival benefit was strongest for maintenance therapy with pemetrexed for patients with nonsquamous NSCLC (hazard ratio = 0.74, 95% confidence interval: 0.64-0.86) but not significant for patients with squamous NSCLC. There was also an overall survival benefit with maintenance therapy with epidermal growth factor receptor tyrosine kinase inhibitors, but the magnitude of the benefit was smaller than with pemetrexed (hazard ratio = 0.84, 95% confidence interval: 0.75-0.94). Docetaxel or gemcitabine as maintenance chemotherapies did not have an impact on overall survival. CONCLUSION: For patients with advanced, stable stage IIIB/IV NSCLC whose disease has not progressed after four to six cycles of platinum-based chemotherapy, the overall survival benefits were strongest for pemetrexed maintenance therapy followed by epidermal growth factor receptor tyrosine kinase inhibitor maintenance therapy.

A Phase II Trial of Erlotinib and Concurrent Palliative Thoracic Radiation for Patients With Non-Small-Cell Lung Cancer.

BACKGROUND: The downstream signaling pathways of the epidermal growth factor receptor might influence radiation resistance. Data from preclinical work support the hypothesis that erlotinib concurrent with radiation therapy (RT) might increase cancer cell killing. The present trial was designed to examine the efficacy and toxicity of combined erlotinib and palliative chest thoracic RT in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with newly diagnosed stage III-IV (American Joint Committee on Cancer, version 6) or recurrent NSCLC received 3 weeks of erlotinib at a dose of 150 mg daily, starting 1 week before palliative thoracic RT to 30 Gy in 10 fractions within 2 weeks. The primary outcome was a change in the quality of life, as measured by the Lung Cancer Symptom Scale (LCSS) question on the "symptoms of lung cancer" from baseline to 4 weeks after treatment. RESULTS: A total of 40 patients were recruited from 2 institutions. Of the 40 patients, 22 (55%) were men, with an average age of 71 years, and 60% had stage IV disease. A total of 26 patients (65%) completed the full course of erlotinib, and 35 (88%) completed the planned RT. Twenty-five patients (62.5%) reported LCSS scores at 4 weeks after treatment, with an average change (improvement) of -12.5 U (95% confidence interval, -23.0 to -1.9; 2P = .023). This was less than the a priori hypothesis of a change of -17.5 U. The median overall and progression-free survival was 5.2 and 3.2 months, respectively. CONCLUSION: The present single-arm, phase II trial did not demonstrate additional symptomatic benefit from concurrent erlotinib therapy with standard palliative thoracic RT for patients with locally advanced or metastatic NSCLC.

Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control (ABC).

PURPOSE: The active breathing control (ABC) device allows for temporary immobilization of respiratory motion by implementing a breath hold at a predefined relative lung volume and air flow direction. The purpose of this study was to quantitatively evaluate the ability of the ABC device to immobilize peripheral lung tumors at a reproducible position, increase total lung volume, and thereby reduce lung mass within the planning target volume (PTV). MATERIALS AND METHODS: Ten patients with peripheral non-small-cell lung cancer tumors undergoing radiotherapy had CT scans of their thorax with and without ABC inspiration breath hold during the first 5 days of treatment. Total lung volumes were determined from the CT data sets. Each peripheral lung tumor was contoured by one physician on all CT scans to generate gross tumor volumes (GTVs). The lung density and mass contained within a 1.5-cm PTV margin around each peripheral tumor was calculated using CT numbers. Using the center of the GTV from the Day 1 ABC scan as the reference, the displacement of subsequent GTV centers on Days 2 to 5 for each patient with ABC applied was calculated in three dimensions. RESULTS: With the use of ABC inspiration breath hold, total lung volumes increased by an average of 42%. This resulted in an average decrease in lung mass of 18% within a standard 1.5-cm PTV margin around the GTV. The average (+/- standard deviation) displacement of GTV centers with ABC breath hold applied was 0.3 mm (+/- 1.8 mm), 1.2 mm (+/- 2.3 mm), and 1.1 mm (+/- 3.5 mm) in the lateral direction, anterior-posterior direction, and superior-inferior direction, respectively. CONCLUSIONS: Results from this study indicate that there remains some inter-breath hold variability in peripheral lung tumor position with the use of ABC inspiration breath hold, which prevents significant PTV margin reduction. However, lung volumes can significantly increase, thereby decreasing the mass of lung within a standard PTV.

Accelerated hypofractionation for early-stage non-small-cell lung cancer.

PURPOSE: To describe the outcome of treating early-stage non-small-cell lung cancer (NSCLC) with an accelerated hypofractionated course of radiotherapy. METHODS AND MATERIALS: A policy of treating early-stage NSCLC with a dose of 48 Gy in 12 once-daily fractions without elective irradiation of radiologically uninvolved regional nodes was adopted in 1996. We describe the outcome in 33 patients with NSCLC treated with this dose-fractionation schedule. RESULTS: The median patient age was 72.0 years. Most patients (75.8%) were not surgical candidates because of medical comorbidities or old age. For staging, 97.0% underwent CT of the thorax, and mediastinoscopy was performed in 6.1%. All patients had Stage T1-T2N0, except for 4 patients with positive nodes based on pathologically involved or clinically enlarged lymph nodes adjacent to the primary tumor. The overall survival rate was 80.1% at 1 year and 46.0% at 2 years. The median survival was 22.6 months. The cause-specific survival rate was 89.8% at 1 year and 54.1% at 2 years. The recurrence-free survival rate was 66.4% at 1 year and 40.0% at 2 years. Lateral radiotherapy field margins of <2 cm predicted for inferior overall survival, cause-specific survival, and recurrence-free survival on univariate and multivariate analyses (p <0.05). The most commonly reported toxicities were acute dermatitis (30.3%) and late cutaneous/subcutaneous fibrosis (24.2%). CONCLUSION: Accelerated hypofractionation for early-stage NSCLC appears to be safe and produces promising early results. Very small radiotherapy field margins may lead to an inferior outcome. Prospective studies are needed to determine the optimal dose-fractionation schedule.

The impact of (18)FDG-PET on target and critical organs in CT-based treatment planning of patients with poorly defined non-small-cell lung carcinoma: a prospective study.

PURPOSE: To prospectively study the impact of coregistering (18)F-fluoro-deoxy-2-glucose hybrid positron emission tomographic (FDG-PET) images with CT images on the planning target volume (PTV), target coverage, and critical organ dose in radiation therapy planning of non-small-cell lung carcinoma. METHODS AND MATERIALS: Thirty patients with poorly defined tumors on CT, referred for radical radiation therapy, underwent both FDG-PET and CT simulation procedures on the same day, in radiation treatment position. Image sets were coregistered using external fiducial markers. Three radiation oncologists independently defined the gross tumor volumes, using first CT data alone and then coregistered CT and FDG-PET data. Standard margins were applied to each gross tumor volume to generate a PTV, and standardized treatment plans were designed and calculated for each PTV. Dose-volume histograms were used to evaluate the relative effect of FDG information on target coverage and on normal tissue dose. RESULTS: In 7 of 30 (23%) cases, FDG-PET information changed management strategy from radical to palliative. In 5 of the remaining 23 (22%) cases, new FDG-avid nodes were found within 5 cm of the primary tumor and were included in the PTV. The PTV defined using coregistered CT and FDG-PET would have been poorly covered by the CT-based treatment plan in 17--29% of cases, depending on the physician, implying a geographic miss had only CT information been available. The effect of FDG-PET on target definition varied with the physician, leading to a reduction in PTV in 24-70% of cases and an increase in 30-76% of cases. The relative change in PTV ranged from 0.40 to 1.86. On average, FDG-PET information led to a reduction in spinal cord dose but not in total lung dose, although large differences in dose to the lung were seen for a few individuals. CONCLUSION: The coregistration of planning CT and FDG-PET images made significant alterations to patient management and to the PTV. Ultimately, changes to the PTV resulted in changes to the radiation treatment plans for the majority of cases. Where possible, we would recommend that FDG-PET data be integrated into treatment planning of non-small-cell lung carcinoma, particularly for three-dimensional conformal techniques.

A mixed methods approach to understand variation in lung cancer practice and the role of guidelines.

INTRODUCTION: Practice pattern data demonstrate regional variation and lower than expected rates of adherence to practice guideline (PG) recommendations for the treatment of stage II/IIIA resected and stage IIIA/IIIB unresected non-small cell lung cancer (NSCLC) patients in Ontario, Canada. This study sought to understand how clinical decisions are made for the treatment of these patients and the role of PGs. METHODS: Surveys and key informant interviews were undertaken with clinicians and administrators. RESULTS: Participants reported favorable ratings for PGs and the evidentiary bases underpinning them. The majority of participants agreed more patients should have received treatment and that regional variation is problematic. Participants estimated that up to 30% of patients are not good candidates for treatment and up to 20% of patients refuse treatment. The most common barrier to implementing PGs was the lack of organizational support by clinical administrative leadership. There was concern that the trial results underpinning the PG recommendations were not generalizable to the typical patients seen in clinic. The qualitative analysis yielded five themes related to physicians' decision making: the unique patient, the unique physician, the family, the clinical team, and the clinical evidence. A dynamic interplay between these factors exists. CONCLUSION: Our study demonstrates the challenges inherent in (i) the complexity of clinical decision making; (ii) how quality of care problems are perceived and operationalized; and (iii) the clinical appropriateness and utility of PG recommendations. We argue that systematic and rigorous methodologies to help decision makers mitigate or negotiate these challenges are warranted.