Jessica S. Donington

Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors.

Background: The purpose of this study was to report initial results of a phase I study using single-fraction stereotactic radiotherapy (RT) in patients with inoperable lung tumors. Methods: Eligible patients included those with inoperable T1-2N0 non-small cell lung cancer (NSCLC) or solitary lung metastases. Treatments were delivered by means of the CyberKnife. All patients underwent computed tomography-guided metallic fiducial placement in the tumor for image-guided targeting. Nine to 20 patients were treated per dose cohort starting at 15 Gy/fraction followed by dose escalation of 5 to 10 Gy to a maximal dose of 30 Gy/fraction. A minimal 3-month period was required between each dose level to monitor toxicity. Results: Thirty-two patients (21 NSCLC and 11 metastatic tumors) were enrolled. At 25 Gy, pulmonary toxicity was noted in patients with prior pulmonary RT and treatment volumes greater than 50 cc; therefore, dose escalation to 30 Gy was applied only to unirradiated patients and treatment volume less than 50 cc. Ten patients received doses less than 20 Gy, 20 received 25 Gy, and two received 30 Gy. RT-related complications were noted for doses greater than 25 Gy and included four cases of grade 2 to 3 pneumonitis, one pleural effusion, and three possible treatment-related deaths. The 1-year freedom from local progression was 91% for dose greater than 20 Gy and 54% for dose less than 20 Gy in NSCLC (p = 0.03). NSCLC patients had significantly better freedom from relapse (p = 0.003) and borderline higher survival than those with metastatic tumors (p = 0.07). Conclusions: Single-fraction stereotactic RT is feasible for selected patients with lung tumors. For those with prior thoracic RT, 25 Gy may be too toxic. Higher dose was associated with improved local control. Longer follow-up is necessary to determine the treatment efficacy and toxicity.

An Evaluation of Tumor Oxygenation and Gene Expression in Patients with Early Stage Non–Small Cell Lung Cancers

Background: To directly assess tumor oxygenation in resectable non–small cell lung cancers (NSCLC) and to correlate tumor pO2 and the selected gene and protein expression to treatment outcomes. Methods: Twenty patients with resectable NSCLC were enrolled. Intraoperative measurements of normal lung and tumor pO2 were done with the Eppendorf polarographic electrode. All patients had plasma osteopontin measurements by ELISA. Carbonic anhydrase-IX (CA IX) staining of tumor sections was done in the majority of patients (n = 16), as was gene expression profiling (n = 12) using cDNA microarrays. Tumor pO2 was correlated with CA IX staining, osteopontin levels, and treatment outcomes. Results: The median tumor pO2 ranged from 0.7 to 46 mm Hg (median, 16.6) and was lower than normal lung pO2 in all but one patient. Because both variables were affected by the completeness of lung deflation during measurement, we used the ratio of tumor/normal lung (T/L) pO2 as a reflection of tumor oxygenation. The median T/L pO2 was 0.13. T/L pO2 correlated significantly with plasma osteopontin levels (r = 0.53, P = 0.02) and CA IX expression (P = 0.006). Gene expression profiling showed that high CD44 expression was a predictor for relapse, which was confirmed by tissue staining of CD44 variant 6 protein. Other variables associated with the risk of relapse were T stage (P = 0.02), T/L pO2 (P = 0.04), and osteopontin levels (P = 0.001). Conclusions: Tumor hypoxia exists in resectable NSCLC and is associated with elevated expression of osteopontin and CA IX. Tumor hypoxia and elevated osteopontin levels and CD44 expression correlated with poor prognosis. A larger study is needed to confirm the prognostic significance of these factors.

American College of Chest Physicians and Society of Thoracic Surgeons Consensus Statement for Evaluation and Management for High-Risk Patients with Stage I Non-small Cell Lung Cancer

BACKGROUND The standard treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy with systematic mediastinal lymph node evaluation. Unfortunately, up to 25% of patients with stage I NSCLC are not candidates for lobectomy because of severe medical comorbidity. METHODS A panel of experts was convened through the Thoracic Oncology Network of the American College of Chest Physicians and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons. Following a literature review, the panel developed 13 suggestions for evaluation and treatment through iterative discussion and debate until unanimous agreement was achieved. RESULTS Pretreatment evaluation should focus primarily on measures of cardiopulmonary physiology, as respiratory failure represents the greatest interventional risk. Alternative treatment options to lobectomy for high-risk patients include sublobar resection with or without brachytherapy, stereotactic body radiation therapy, and radiofrequency ablation. Each is associated with decreased procedural morbidity and mortality but increased risk for involved lobe and regional recurrence compared with lobectomy, but direct comparisons between modalities are lacking. CONCLUSIONS Therapeutic options for the treatment of high-risk patients are evolving quickly. Improved radiographic staging and the diagnosis of smaller and more indolent tumors push the risk-benefit decision toward parenchymal-sparing or nonoperative therapies in high-risk patients. Unbiased assessment of treatment options requires uniform reporting of treatment populations and outcomes in clinical series, which has been lacking to date.

hsa-miR-29c* Is Linked to the Prognosis of Malignant Pleural Mesothelioma

The inability to forecast outcomes for malignant mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach. We investigated whether specific microRNAs (miR) could segregate a largely surgically treated group of mesotheliomas into good or bad prognosis categories. A training set of 44 and a test set of 98 mesothelioma tumors were analyzed by a custom miR platform, along with 9 mesothelioma cell lines and 3 normal mesothelial lines. Functional implications as well as downstream targets of potential prognostic miRs were investigated. In both the training and test sets, hsa-miR-29c* was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Increased expression of hsa-miR-29c* predicted a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was shown through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. A single miR has the potential to be a prognostic biomarker in mesothelioma, and validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future.

A pilot cohort study of the determinants of longitudinal opioid use after surgery.

BACKGROUND: Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery. METHODS: Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done. RESULTS: Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%–87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%–71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%–58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity. CONCLUSIONS: Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

Sublobar Resection: A Movement from the Lung Cancer Study Group

The 1995 Lung Cancer Study Group consensus recommending lobectomy for stage I non-small cell lung cancer (NSCLC) has directed lung cancer resections since its publication. However, enhancements in imaging technology over the last decade have produced larger cohorts of patients presenting with localized, early-stage disease. Today, multislice computer tomography is widely available, capable of detecting NSCLC at smaller sizes, with improved spatial resolution, and is used in screening programs for high-risk individuals. Furthermore, the maturation of minimally invasive surgical resection (video-assisted thoracoscopic surgery) has reduced perioperative morbidity and mortality, improved postoperative lung function, and demonstrated equivalent oncologic effectiveness to open surgery. The mandatory use of lobectomy for patients with small stage IA NSCLC is now being challenged. Numerous single-institution trials have demonstrated that well-selected use of sublobar resection can afford comparable survival and recurrence rates to lobectomy, particularly in high-risk patients. Currently, a prospective, randomized multi-institutional phase III trial is being conducted by the Cancer and Lymphoma Group B (CALGB 140503) to determine whether patients with small (≤2 cm) peripheral NSCLC tumors can safely undergo sublobar resection while maintaining rates of survival and recurrence that are comparable to lobectomy. This review summarizes the literature from the past 15 years to assist in applying those conclusions to future research innovation.

The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer.

Introduction: It can be difficult to distinguish between a second primary and a metastasis in patients with lung cancer who have more than one pulmonary site of cancer. Methods: A systematic review of the literature was conducted by a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee to develop recommendations to identify second primary lung cancers. The process entailed review of knowledge relating to the mechanism of metastasis, determination of clonality, and outcomes of patients with resected tumors. Results: It is easier to determine that two tumors are different than that they are the same; finding similarities does not establish that they are the same. For example, most second primary lung cancers are of the same histotype. Few criteria are reliable by themselves; these include different histologic cancer types or matching DNA breakpoints by sequencing and a comprehensive histologic assessment of resected specimens. Characteristics that are suggestive but associated with potential misclassification include the presence or absence of biomarkers, imaging characteristics, and the presence or absence of nodal involvement. Conclusions: Clinical and pathologic (i.e., after resection) criteria are presented to identify two foci as separate primary lung cancers versus a metastasis. Few features are definitive; many commonly used characteristics are suggestive but associated with a substantial rate of misclassification. Careful review by a multidisciplinary tumor board, considering all available information, is recommended.

Reduction of Elevated Plasma Osteopontin Levels With Resection of Non–Small-Cell Lung Cancer

PURPOSE Plasma osteopontin (OPN) levels in advanced non-small-cell lung cancer (NSCLC) correlate with therapeutic response and survival, but the utility of plasma OPN for diagnosis and monitoring of early-stage NSCLC has not been investigated. We hypothesize that plasma OPN levels are elevated in early-stage NSCLC and decrease with resection. PATIENTS AND METHODS Presurgery plasma OPN levels (in ng/mL) were measured by enzyme-linked immunosorbent assay (ELISA) in a discovery set of 60 patients with early-stage NSCLC and were compared with data from 56 cancer-free smokers. Presurgery OPN was validated in an independent cohort of 96 patients with resectable NSCLC. The presurgery levels in the latter cohort were compared with matched postsurgery levels. Perioperative OPN levels were correlated with demographics, tumor characteristics, and perioperative events. OPN was monitored during follow-up. Results Discovery set presurgery NSCLC OPN (271 +/- 31 ng/mL) was higher than smokers (40 +/- 2 ng/mL; P = .001). Presurgery OPN was similar in the NSCLC validation cohort (324 ng/mL +/- 20 ng/mL; P = .134). Postsurgery OPN (256 ng/mL +/- 21 ng/mL) measured at mean of 9.8 weeks (range, 2 to 46 weeks) was lower than presurgery OPN (P = .005). Time from surgery significantly impacted postsurgery OPN: OPN < or = 6 weeks postsurgery (303 n/mL +/- 26 ng/mL) was higher than OPN greater than 6 weeks postsurgery (177 ng/mL +/- 29 ng/mL; P = .003). Multivariate analysis noted correlations between albumin and creatinine to presurgery OPN and use of thoracotomy to postsurgery OPN. Recurrence rate was 5% at 29 weeks mean follow-up. OPN at recurrence was elevated from postsurgery nadir. CONCLUSION Plasma OPN levels are elevated in early-stage NSCLC. They are reduced after resection and appear to increase with recurrence. Plasma OPN may have utility as a biomarker in early-stage NSCLC.

The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification

Introduction: Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. Methods: A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. Results: Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor—T3 for a same‐lobe, T4 for a same‐side (different lobe), and M1a for an other‐side location—with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic‐type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same‐side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. Conclusion: We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

Lung cancer osteopontin isoforms exhibit angiogenic functional heterogeneity

OBJECTIVE Osteopontin is a multifunctional phosphoprotein with an important but poorly understood role in non-small cell lung cancer pathogenesis. We hypothesize that osteopontin isoforms (OPNa, OPNb, and OPNc) have divergent roles in non-small-cell lung cancer angiogenesis and divergent impact on vascular endothelial growth factor secretion. METHODS We examined mRNA expression using reverse transcriptase-polymerase chain reaction primers for 3 osteopontin isoforms in non-small-cell lung cancer and immortalized bronchial epithelial cell lines, and correlated expression with osteopontin secretion into media detected by enzyme-linked immunosorbent assay. Angiogenic properties conferred by osteopontin isoforms were evaluated by transfecting cDNA plasmids specific to each isoform and controls into non-small-cell lung cancer cell lines, H153 and H358 (low endogenous osteopontin) and A549 and H460 (high endogenous osteopontin), analyzing conditioned media on a bovine capillary endothelial platform, and measuring vascular endothelial growth factor levels by enzyme-linked immunosorbent assay. RESULTS OPNa mRNA expression correlated with osteopontin secretion in cell lines (r = 0.912, P = .0006). OPNa overexpression significantly increased tubule length compared with controls, OPNb had a similar, but less pronounced effect, and OPNc significantly decreased tubule length compared with controls in each cell line. OPNa overexpression was associated with significant increases in vascular endothelial growth factor secretion, whereas OPNb had no effect and OPNc overexpression was associated with significant decreases in vascular endothelial growth factor compared with controls in each cell line. CONCLUSION We demonstrated divergent effects of osteopontin isoforms on non-small-cell lung cancer angiogenesis and vascular endothelial growth factor secretion. OPNa overexpression was associated with increased bovine capillary endothelial tubule length and vascular endothelial growth factor secretion, whereas OPNc was associated with decreases in both. These findings may lead to therapeutic strategies for selective isoform inhibition in non-small cell lung cancer.