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.

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.

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 .

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).

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.

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.

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.

Phase II study of accelerated hypofractionated three-dimensional conformal radiotherapy for stage T1-3 N0 M0 non-small cell lung cancer: NCIC CTG BR.25.

BACKGROUND: A multi-institutional phase II trial was performed to assess a hypofractionated accelerated radiotherapy regimen for early stage non-small cell lung cancer (NSCLC) in an era when stereotactic body radiotherapy was not widely available. METHODS: Eighty patients with biopsy-proven, peripherally located, T1-3 N0 M0 NSCLC were enrolled. Eligible patients received 60 Gy in 15 fractions using a three-dimensional conformal technique without inhomogeneity correction. The gross tumour volume (GTV) was the primary tumor only, and the planning target volume (PTV) margin was 1.0 to 1.5cm. The primary endpoint was the 2-year primary tumor control rate. Toxicities were measured using the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: The median follow-up of patients was 49 months (range = 21-63 months). The median age of patients was 75.9 years. The actuarial rate of primary tumor control was 87.4% (95% confidence interval [CI] = 76.2% to 93.5%) at 2 years. Overall survival was 68.7% (95% CI = 57.2% to 77.6%) at 2 years. The actuarial rates of developing regional and distant relapse at 2 years were 8.8% (95% CI = 4.1% to 18.7%) and 21.6% (95% CI = 13.5% to 33.5%), respectively. Tumor size greater than 3cm was associated with an increased risk of developing distant relapse (hazard ratio = 3.11; 95% CI = 1.30 to 7.42; two-sided log-rank test P = .007). The most common grade 3+ toxicities were fatigue (6.3%), cough (7.5%), dyspnea (13.8%), and pneumonitis (10.0%) CONCLUSIONS: Conformal radiotherapy to a dose of 60 Gy in 15 fractions resulted in favorable primary tumor control and overall survival rates in patients with T1-3 N0 M0 NSCLC. Severe toxicities were uncommon with this relatively simple treatment technique.

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.

Improving the quality of lung cancer care in Ontario: the lung cancer disease pathway initiative.

BACKGROUND: Before 2008, Cancer Care Ontario (CCO) undertook provincial cancer control quality-improvement initiatives on a programmatic basis. CCO has now added Disease Pathway Management (DPM) to its quality improvement strategy, with the intent of achieving high-quality care, processes, and patient experience across the patient pathway for specific cancers. OBJECTIVES: The three goals of DPM are: to describe and share evidence-based best practice along the cancer continuum for specific cancers; identify quality-improvement priorities for specific cancers and catalyze action; monitor performance against best practice for specific cancers. The objective of this article is to describe the process by which the CCO lung cancer (LC) DPM was initiated and some of its early successes. METHODS: In 2009, LC DPM began with a draft LC disease pathway map and the establishment of five multidisciplinary working groups, each focused on a phase of the LC patient journey: prevention, screening, and early detection; diagnosis; treatment; palliative care, end-of-life care, and survivorship; and patient experience. The working groups held 25 meetings of 2-hour duration and developed concepts for 17 quality-improvement projects across the patient journey. Eight were selected for detailed discussion at a provincial consensus conference, which provided input on priorities for action. A report on the priorities for action was prepared and widely circulated, and regional roadshows were held in all 14 regions of the province of Ontario. Region-specific data on incidence, stage, treatment compliance, and wait times among other issues relevant to LC, were shared with the regional care providers at these roadshows. Funding was provided by CCO to address opportunities for regional improvement based on the data and the priorities identified. RESULTS: The LC disease pathways were refined through substantial multidisciplinary discussion, and the diagnostic pathway was posted on CCO's Web site in February 2012. The treatment pathways for small-cell LC and non-small-cell LC were posted in November 2012. LC Diagnostic Assessment Units/Programs have been initiated in 14 regions, and educational materials on dyspnea management, including a patient video, are available on CCO's Web site. An audit has been undertaken to better understand the barriers to the uniform uptake of specific evidence-based practices across the province, and the results will be reported shortly. The proportion of LC patients, whose symptoms are assessed at least once a month, using a standardized symptom assessment instrument (Edmonton Symptom Assessment System), has improved through the DPM. CONCLUSION: Through CCO's LC DPM initiative, Regional Cancer Programs have become aware of their performance on a range of LC-specific performance and quality metrics and have been motivated to undertake quality-improvement initiatives. Standardized diagnostic and treatment pathways have been developed. Ongoing measurement of a broad range of metrics, including stage-specific survival, guideline concordance, and measures of the patient experience will help determine the benefit of this major initiative.

Positron emission tomography-computed tomography compared with invasive mediastinal staging in non-small cell lung cancer: results of mediastinal staging in the early lung positron emission tomography trial.

INTRODUCTION: Patients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. Fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment. METHODS: In this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy. RESULTS: All 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48-85%), and specificity was 94% (95% CI, 88-97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43-80%) and 95% (95% CI, 90-98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure. CONCLUSIONS: PET-CT assessment of the mediastinum is associated with a clinically relevant false-positive rate. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT.

Autocontouring and manual contouring: which is the better method for target delineation using 18F-FDG PET/CT in non-small cell lung cancer?

UNLABELLED: Previously, we showed that a CT window and level setting of 1,600 and -300 Hounsfield units, respectively, and autocontouring using an (18)F-FDG PET 50% intensity level correlated best with pathologic results. The aim of this study was to compare this autocontouring with manual contouring, to determine which method is better. METHODS: Seventeen patients with non-small cell lung cancer underwent (18)F-FDG PET/CT before surgery. The maximum diameter on pathologic examination was determined. Seven sets of gross tumor volumes (GTVs) were defined. The first set (GTV(CT)) was contoured manually using only CT information. The second set (GTV(Auto)) was autocontoured using a 50% intensity level for (18)F-FDG PET images. The third set (GTV(Manual)) was manually contoured using a visual method on PET images. The other 4 sets combined CT and (18)F-FDG PET images fused to one another to become composite volumes: GTV(CT+Auto), GTV(CT+Manual), GTV(CT-Auto), and GTV(CT-Manual). To quantitate the degree to which CT and (18)F-FDG PET defined the same region of interest, a matching index was calculated for each case. The maximum diameter of GTV was compared with the maximum diameter on pathologic examination. RESULTS: The median GTV(CT), GTV(Auto), GTV(Manual), GTV(CT+Auto), GTV(CT+Manual), GTV(CT-Auto), and GTV(CT-Manual) were 6.96, 2.42, 4.37, 7.46, 10.17, 2.21, and 3.38 cm(3), respectively. The median matching indexes of GTV(CT) versus GTV(CT+Auto), GTV(Auto) versus GTV(CT+Auto), GTV(CT) versus GTV(CT+Manual), and GTV(Manual) versus GTV(CT+Manual) were 0.86, 0.65, 0.88, and 0.81, respectively. Compared with the maximum diameter on pathologic examination, the correlations of GTV(CT), GTV(Auto), GTV(Manual), GTV(CT+Auto), and GTV(CT+Manual) were 0.87, 0.83, 0.93, 0.86, and 0.94, respectively. CONCLUSION: The matching index was higher for manual contouring than for autocontouring using a 50% intensity level on (18)F-FDG PET images. When using a 50% intensity level to contour the target of non-small cell lung cancer, one should also consider using manual contouring of (18)F-FDG PET to check for any missed disease.

First-line systemic chemotherapy in the treatment of advanced non-small cell lung cancer: a systematic review.

INTRODUCTION: Non-small cell lung cancer (NSCLC) frequently presents at an incurable stage, and a majority of patients will be considered for palliative chemotherapy at some point in their disease. This article reviews the growing evidence for first-line treatment in NSCLC. METHODS: Studies of first-line chemotherapy regimens including new agents (docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, erlotinib, and gefitinib) were identified through Medline, Embase, the Cochrane databases, and web sites of guideline organizations. RESULTS: Two evidence-based guidelines, 10 systematic reviews, and forty-six randomized trials were eligible for inclusion. Randomized studies suggest that platinum-based doublets (platinum plus new agent) are the standard of care for first-line systemic therapy. No one new agent is clearly superior for use in combination with a platinum agent. The survival advantage of platinum-based doublets over nonplatinum combinations or older combinations is modest. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, although multiple exclusion criteria limit the applicability of these data to a subset of patients. In patients at least 70 years of age or with Eastern Collaborative Oncology Group performance status 2, a new single agent is an alternative. Treatment beyond four to six cycles impedes quality of life without prolonging life. Emerging data suggest that the choice of chemotherapy agent may be influenced by histologic subtype. CONCLUSION: In NSCLC, a combination of a platinum agent plus a new agent continues to be the standard of care. As differences between regimens are small, toxicity and patient preference should help guide regimen choice.

PET CT thresholds for radiotherapy target definition in non-small-cell lung cancer: how close are we to the pathologic findings?

PURPOSE: Optimal target delineation threshold values for positron emission tomography (PET) and computed tomography (CT) radiotherapy planning is controversial. In this present study, different PET CT threshold values were used for target delineation and then compared pathologically. METHODS AND MATERIALS: A total of 31 non-small-cell lung cancer patients underwent PET CT before surgery. The maximal diameter (MD) of the pathologic primary tumor was obtained. The CT-based gross tumor volumes (GTV(CT)) were delineated for CT window-level thresholds at 1,600 and -300 Hounsfield units (HU) (GTV(CT1)); 1,600 and -400 (GTV(CT2)); 1,600 and -450 HU (GTV(CT3)); 1,600 and -600 HU (GTV(CT4)); 1,200 and -700 HU (GTV(CT5)); 900 and -450 HU (GTV(CT6)); and 700 and -450 HU (GTV(CT7)). The PET-based GTVs (GTV(PET)) were autocontoured at 20% (GTV(20)), 30% (GTV(30)), 40% (GTV(40)), 45% (GTV(45)), 50% (GTV(50)), and 55% (GTV(55)) of the maximal intensity level. The MD of each image-based GTV in three-dimensional orientation was determined. The MD of the GTV(PET) and GTV(CT) were compared with the pathologically determined MD. RESULTS: The median MD of the GTV(CT) changed from 2.89 (GTV(CT2)) to 4.46 (GTV(CT7)) as the CT thresholds were varied. The correlation coefficient of the GTV(CT) compared with the pathologically determined MD ranged from 0.76 to 0.87. The correlation coefficient of the GTV(CT1) was the best (r=0.87). The median MD of GTV(PET) changed from 5.72 cm to 2.67 cm as the PET thresholds increased. The correlation coefficient of the GTV(PET) compared with the pathologic finding ranged from 0.51 to 0.77. The correlation coefficient of GTV(50) was the best (r=0.77). CONCLUSION: Compared with the MD of GTV(PET), the MD of GTV(CT) had better correlation with the pathologic MD. The GTV(CT1) and GTV(50) had the best correlation with the pathologic results.