Therapy For Advanced Lung Cancer Research Articles

State of the Art: Response Assessment in Lung Cancer in the Era of Genomic Medicine

Tumor response assessment has been a foundation for advances in cancer therapy. Recent discoveries of effective targeted therapy for specific genomic abnormalities in lung cancer and their clinical application have brought revolutionary advances in lung cancer therapy and transformed the oncologist's approach to patients with lung cancer. Because imaging is a major method of response assessment in lung cancer both in clinical trials and practice, radiologists must understand the genomic alterations in lung cancer and the rapidly evolving therapeutic approaches to effectively communicate with oncology colleagues and maintain the key role in lung cancer care. This article describes the origin and importance of tumor response assessment, presents the recent genomic discoveries in lung cancer and therapies directed against these genomic changes, and describes how these discoveries affect the radiology community. The authors then summarize the conventional Response Evaluation Criteria in Solid Tumors and World Health Organization guidelines, which continue to be the major determinants of trial endpoints, and describe their limitations particularly in an era of genomic-based therapy. More advanced imaging techniques for lung cancer response assessment are presented, including computed tomography tumor volume and perfusion, dynamic contrast material-enhanced and diffusion-weighted magnetic resonance imaging, and positron emission tomography with fluorine 18 fluorodeoxyglucose and novel tracers. State-of-art knowledge of lung cancer biology, treatment, and imaging will help the radiology community to remain effective contributors to the personalized care of lung cancer patients.

Anti-Cancer Therapy of Advanced Lung Cancer in Elderly Patients

Lung cancer is not only the most common cancer of the elderly but is also the leading cause of cancer related mortality in Korea. Therefore, the elderly form a large subgroup of patients with advanced lung cancer. Aging is associated with co-morbidities, poor performance status, and impaired organ function. These problems can cause uncertainty when selecting the optimal treatment for advanced lung cancer, and some elderly patients could be undertreated. Patients with non-squamous histology lung cancer, regardless of age or performance status, should be tested for epidermal growth factor receptor (EGFR) mutations; patients with EGFR mutations such as del 19 or L858R are able to receive EGFR tyrosine kinase inhibitors. The treatment options for elderly patients with lung cancer include best supportive care, single agent chemotherapy, platinum-based doublet chemotherapy, and targeted therapy. The optimum therapeutic option for elderly individuals with advanced lung cancer must be selected carefully, taking into account both the risks and benefits. (Korean J Med 2014;87:537-541)

“EXHALE”: exercise as a strategy for rehabilitation in advanced stage lung cancer patients: a randomized clinical trial comparing the effects of 12 weeks supervised exercise intervention versus usual care for advanced stage lung cancer patients

BackgroundLung cancer is the leading cause of cancer death in North America and Western Europe. Patients with lung cancer in general have reduced physical capacity, functional capacity, poor quality of life and increased levels of anxiety and depression. Intervention studies indicate that physical training can address these issues. However, there is a lack of decisive evidence regarding the effect of physical exercise in patients with advanced lung cancer. The aim of this study is to evaluate the effects of a twelve weeks, twice weekly program consisting of: supervised, structured training in a group of advanced lung cancer patients (cardiovascular and strength training, relaxation).Methods/DesignA randomized controlled trial will test the effects of the exercise intervention in 216 patients with advanced lung cancer (non-small cell lung cancer (NSCLC) stage IIIb - IV and small cell lung cancer (SCLC) extensive disease (ED)). Primary outcome is maximal oxygen uptake (VO2peak). Secondary outcomes are muscle strength (1RM), functional capacity (6MWD), lung capacity (Fev1) and patient reported outcome (including anxiety, depression (HADS) and quality of life (HRQOL)).DiscussionThe present randomized controlled study will provide data on the effectiveness of a supervised exercise intervention in patients receiving systemic therapy for advanced lung cancer. It is hoped that the intervention can improve physical capacity and functional level, during rehabilitation of cancer patients with complex symptom burden and help them to maintain independent function for as long as possible.Trial registrationhttp://ClinicalTrials.gov, NCT01881906

Clinical evaluation of targeted arterial perfusion of verapamil and chemotherapeutic drugs in interventional therapy of advanced lung cancer

PurposeTo assess the clinical efficacy of targeted arterial perfusion of verapamil and chemotherapeutic agents in the interventional therapy of lung cancer.MethodsForty patients with advanced lung cancer underwent treatment with targeted arterial perfusion of verapamil and chemotherapeutic agents using Seldinger technique. Interventional therapy was performed once a month, and each subject received interventional treatment for 2 or more cycles. The therapeutic efficacy was evaluated 2 months post-treatment.ResultsOut of 40 patients with advanced lung cancer, 5 cases achieved complete remission (CR) and 29 cases achieved partial remission (PR), with a total effectiveness (CR + PR) rate of 85 %. Besides, 32 cases achieved significantly alleviated clinical symptoms, and 29 cases had decreased clinical tumor stage. All subjects had stable karnofsky performance status score and body weight. Among the 40 patients, 13 cases had leucopenia, 10 cases had gastrointestinal reactions, 3 cases presented with elevated alanine aminotransferase/aspartate aminotransferase ratio, and 3 cases had fever. However, all these side effects relieved quickly. No elevation of BUN/Cr ratio and allergic reactions was observed. No significant changes in cardiac function and electrocardiogram were noticed after the treatment.ConclusionsTargeted arterial perfusion of verapamil and chemotherapeutic drugs can improve the clinical symptoms of patients with advanced lung cancer and increase the efficacy of chemotherapeutic agents, thereby providing an opportunity for radiotherapy or surgical treatment for advanced lung cancer.

Maintenance Therapy for Advanced Lung Cancer: Who, What, and When?

A 60-year-old woman with hypertension, dyslipidemia, and 35-pack-year smoking history is referred for treatment of advanced non-small-cell lung cancer (NSCLC). She initially presented after a transient ischemic attack, when a chest radiograph demonstrated a right lung mass. Computed tomography (CT) of the chest revealed a 5-cm right upper lobe mass, without mediastinal adenopathy, and a 6-cm cystic mass in the spleen. Additional imaging showed no brain metastasis. Endobronchial ulstrasound-guided core biopsies of the lung mass and ipsilateral mediastinal nodes confirmed a poorly differentiated non-small-cell carcinoma. Immunohistochemical stains were positive for napsin A and thyroid transcription factor 1, suggestive of adenocarcinoma (Fig 1). Molecular analysis identified a KRAS G12C mutation. A positron emission tomography (PET) -CT scan demonstrated [(18)F]fluorodeoxyglucose uptake in the right upper lobe mass and splenic lesion (Fig 2A). CT-guided fine-needle aspiration of the splenic lesion was performed and revealed metastatic carcinoma, consistent with the lung primary. Treatment with carboplatin plus pemetrexed was initiated, without bevacizumab because of the recent transient ischemic attack; carboplatin was selected over cisplatin because of similar concerns. The patient received two cycles of chemotherapy without complications, and repeat imaging showed decrease in size of the lung mass and splenic lesion (Figs 2B and 2C). After four cycles of chemotherapy, a chest CT showed ongoing response (Fig 2D). Her Eastern Cooperative Oncology Group performance status remained 0.

MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.

Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2

In the past decade, we have observed exciting advances in lung cancer therapy, including the development of targeted therapies. However, additional strategies for early detection and tumor-based therapy are still essential in improving patient outcomes. EGF receptor (EGFR) and MET (the receptor tyrosine kinase for hepatocyte growth factors) are cell-surface tyrosine kinase receptors that have been implicated in diverse cellular processes and as regulators of several microRNAs (miRNAs), thus contributing to tumor progression. Here, we demonstrate a biological link between EGFR, MET, and the miRNA cluster 23a ~ 27a ~ 24-2. We show that miR-27a regulates MET, EGFR, and Sprouty2 in lung cancer. In addition, we identify both direct and indirect mechanisms by which miR-27a can regulate both MET and EGFR. Thus, we propose a mechanism for MET and EGFR axis regulation that may lead to the development of therapeutics in lung cancer.

Salvage surgery for a super-responder by gefitinib therapy for advanced lung cancer

Salvage surgery after gefitinib therapy in a 66-year-old female with cT4N1M1a lung adenocarcinoma in the right middle lobe, which had gene mutation of epidermal growth factor receptor, is presented. The patient had bulky hilar lymph nodes, pleural dissemination, and pulmonary metastases in the ipsilateral lobes. After 3 courses of chemotherapy, the patient was treated with gefitinib, resulting in partial response, i.e. only the primary tumor and the middle lobe atelectasis remained. We performed the middle lobe lobectomy aimed at local control and pathological confirmation of the remaining tumor. Because the hilum of the middle lobe was occupied with scar tissue, its pulmonary vein had to be cut within the pericardium and its pulmonary artery and bronchus had to be transected simultaneously with a stapler. Pathological stage was yp-T2aN0N0 with Ef 2. For salvage surgery after good response to gefitinib therapy, it should be taken care to expose pulmonary vessels.

Activity and safety of CPBev regimen (cisplatinum, pemetrexed, and bevacizumab) as first-line therapy for locally advanced or metastatic adenocarcinoma of the lung: Final results of a phase II study.

e18026 Background: During the past five years the paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs-regimen containing both these agents and cis-platinum, we conducted a multi-institutional phase II study started on november 2007. Methods: chemonaive patients with non-squamous non-small cell lung cancer were considered eligible We adopt the two-stage of Simon model as statistical design of the study; activity of the regime, expressed as overall response rate and safety were the main end-points. Administered doses were 75 and 500 mg/p.s.m for cis-platinum and pemetrexed respectively and 7.5 mg./kg for Bevacizumab, for 3 - 6 cycles. G-CSF were administered only after the first cycle of therapy, whereas vitamin supplementation started from day 1 of the first cycle. No maintenance therapy was allowed. Results: We registered 9 partial responses among the first 15 patients treated so, accordingly with the design of the study, we completed the enrollment up to 32 patients. Patients characteristics are: male/female: 20/12, median age (years): 59 (r. 36 - 77), ECOG-WHO/PS 0/1: 21/11. One hundred eighty-three cycles of CPBev were administered: we registered only 13 cases of grade 3 adverse events. No grade 4 toxicities were observed. One case of allergic reaction to cis-platinum were observed. In terms of response rate, we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). Results in terms of outcome parameters expressed by progression-free and overall survival will be presented at the meeting. Conclusions: On the basis of our data, CPBev have a good toxicity profile and seems to be extremely active in advanced non-squamous lung carcinomas.

Abstract 3726: Allyl isothiocyanate (AITC), a naturally occurring compound, combined with platinum-based therapies enhances apoptosis in vitro, and inhibits lung tumor growth in vivo

Abstract Lung cancer is the leading cause of cancer-related death in the United States, and it is estimated more than 220,000 new cases will be diagnosed in 2011. The first-line therapy for advanced lung cancer almost always contains a platinum-based chemotherapeutic agent, regardless of the disease's histological profile. In vitro studies have shown that isothiocyanate compounds can sensitize lung cancer cells to cisplatin treatment, however the underlying mechanisms have not been well defined and until now, there have been no in vivo demonstrations to support the in vitro results. Our lab recently discovered that allyl isothiocyanate (AITC), a naturally occurring isothiocyanate molecule found in cruciferous vegetables such as horseradish and mustard seeds, can sensitize lung cancer cells to cisplatin treatment. Our data demonstrate that the combination of cisplatin and AITC can induce apoptosis more effectively than cisplatin alone. Furthermore, drug combination index (CI) analysis from cancer cell-based ex vivo studies showed synergistic effects between AITC and cisplatin in defined dose ranges. Mechanistic studies revealed that combination treatment of cisplatin and AITC decreases the expression of survivin and Bcl-2 and concomitantly increases caspase-3 activation, PARP cleavage and DNA fragmentation, hallmarks of apoptosis. Most importantly, our data demonstrate that cisplatin, in combination with orally administered AITC, shows significantly improved suppression of lung tumor growth in human lung tumor xenograft mouse models compared to cisplatin or AITC alone. Given its oral bioavailability and potential to overcome cisplatin resistance, AITC shows promise as a chemotherapeutic-sensitizer for the treatment of advanced lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3726. doi:1538-7445.AM2012-3726

MiR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222

Non-small cell lung cancer (NSCLC) accounts for ∼80% of all lung cancers. Although some advances in lung cancer therapy have been made, patient survival is still quite poor. Two microRNAs, miR-221 and miR-222, upregulated by the MET proto-oncogene, have been already described to enhance cell survival and to induce TNF-related apoptosis-inducing ligand (TRAIL) resistance in NSCLC cell lines, through the downregulation of p27(kip1), PTEN and TIMP3. Here, we further investigated this pathway and showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in NSCLC cells through the c-Jun-mediated downregulation of miR-221 and miR-222. Moreover, we found that miR-130a reduced migratory capacity of NSCLC. A better understanding of MET-miR-221 and 222 axis regulation in drug resistance is the key in developing new strategies in NSCLC therapy.

Whole blood transcriptomics analysis of 24h responses to bevacizumab/erlotinib in nonsquamous non-small cell lung cancer: A multicenter phase II trial SAKK19/05.

e21069 Background: It is essential to understand the mechanisms of action of new therapies in advanced lung cancer. The SAKK investigated the response to bevacizumab/erlotinib (BE) on disease stabi...

Abstract PL01-03: The landscape of cancer prevention: Personalized approach in lung cancer

Abstract PL01-03: The landscape of cancer prevention: Personalized approach in lung cancer

Chemotherapy Significantly Increases the Risk of Radiation Pneumonitis in Radiation Therapy of Advanced Lung Cancer

The reported rate of developing radiation pneumonitis (RP) in patients receiving definitive radiation therapy (RT) for lung cancer is 5% to 36%. However, this incidence is probably underreported because of the nonspecific symptoms of RP that may be erroneously attributed to another cardiovascular or respiratory disorder. The objective of this study was to evaluate the incidence of RP in lung cancer patients receiving RT or chemoradiation therapy. Of the 110 patients that were reviewed, 86 were chosen for a retrospective analysis. A diagnosis of RP was made based on clinical assessment in the first 6 to 12 months after RT. Radiation pneumonitis was graded as per Radiation Therapy Oncology Group grading criteria. The incidence of developing grade 2 or higher RP was significantly associated with addition of chemotherapy. The incidence of RP in patients receiving chemotherapy was 62.7% (42/67) versus 15.8% (3/19) in patients receiving no chemotherapy (P < 0.001). However, there was no significant effect of the type or sequence of chemotherapy on the incidence of RP. The risk of developing RP is 5 times greater in patients receiving chemotherapy when compared with those not receiving this treatment (hazard ratio: 5.0; 95% confidence interval 1.5, 16.1). In addition, patients in age group 61 to 70 years had a significantly increased risk of developing RP compared with patients of age 60 or younger (hazard ratio: 3.0; 95% confidence interval: 1.4, 6.5). Histology and radiation dose were not significant factors in development of RP. The incidence of RP in patients receiving external-beam RT is significantly increased with addition of chemotherapy and 61 to 70 year age group.

Targeted Radiopharmaceutical Therapy for Advanced Lung Cancer: Phase I Trial of Rhenium Re188 P2045, a Somatostatin Analog

Both small cell and non-small cell lung cancer overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analog that binds with high affinity to SSTR and can be labeled with Tc-99m to gauge receptor prevalence or with Re-188 for 2.1 MeV beta radiotherapy. To evaluate the safety of this approach, a phase I dose-escalation study of Re-188 P2045 in SSTR-positive lung cancer was performed. Patients were required to have stage IIIb or IV or recurrent non-small cell lung cancer or extensive stage or recurrent small cell lung cancer, performance status 0 to 1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive and projected renal dose of radiation from Re-188 P2045 was less than 20 Gy, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated 30 mCi/m2, 60 mCi/m2, and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose-limiting toxicity was defined as > or = grade 3 nonhematologic toxicity or grade 4 hematologic toxicity. Fifteen patients were enrolled. The median age was 61 years. Fourteen patients had > or = 2 prior chemotherapy regimens. All were imaged with Tc-99m P2045, eight patients received Re-188 P2045. The most common toxicity was mild lymphopenia. The trial was halted at the 90 mCi/m2 level when three patients were projected to have renal radiation doses above 20 Gy. The monoclonal antibody was not determined, and no responses were seen. Five of the eight patients (62.5%, 95% CI: 24-91%) had stable disease for at least 8 weeks, all of whom entered the study with progressive disease. Median overall survival was 11.5 months. This trial demonstrated that Re-188 P2045 was well tolerated. Tc-99m P2045 imaging allows identification of patients who may benefit from this treatment. Although responses were not seen, survival for these heavily pretreated patients is interesting and merits further research.

Is there a role for maintenance therapy in non-small-cell lung cancer? An emerging issue

Standard treatment of advanced non-small-cell lung cancer consists of platinum-based (doublet) polychemotherapy. The treatment should last for a maximum of four to six cycles. Several randomized clinical trials and some meta-analyses showed that a longer duration of treatment does not lead to an increase in survival. Recent data with new-generation agents (chemo- or targeted therapies) suggest that a maintenance treatment until progression of disease in patients with response or stable disease after the first cycles of induction (platinum-based) chemotherapy confers an advantage in time-to-progression or even overall survival (with pemetrexed) compared with no maintenance treatment. The advent of new agents and the better selection of patients according to histology or mutation of specific tyrosine kinase receptors (e.g., EGF receptor) seems to increase the therapeutic options and improve the prognosis in the advanced disease setting. The paradigm of the duration of therapy in advanced lung cancer appears to change from the use of second-line treatment only at progression of disease to an early introduction of an alternative (second-line) therapy as consolidation and chronic phase of maintenance.

A phase I study of gemcitabine plus palliative radiation therapy for advanced lung cancer

To determine the maximum-tolerated dose (MTD) and antitumor activity of twice-weekly gemcitabine when combined with palliative-dose thoracic radiation therapy (RT) in patients with recurrent or progressive lung cancer. Patients were enrolled in a dose-escalating study of gemcitabine with a starting dose level of 40 mg/m(2) given as 30-minute infusions twice weekly concurrent with RT. The RT dose was 30 Gy in 10 fractions, 5 fractions per week. A total of 18 patients were enrolled on three dose levels: 40, 50, and 65 mg/m(2). Four patients came off study early due to rapid progression of disease and therefore were not evaluated. The MTD of gemcitabine was found to be 50 mg/m(2). Dose-limiting toxicities were grade-4 esophagitis in one patient and grade-4 neutropenia in another patient. Overall response included 1 partial response (PR). Local response included six PR, four minor response (MR), three stable disease (SD), and one progressive disease (PD). The MTD of gemcitabine with concominant palliative thoracic radiation therapy is 50 mg/m(2) twice weekly. The DLTs observed were grade-4 esophagitis and grade-4 myelotoxicity at 65 mg/m(2).

Targeted radiopharmaceutical therapy for advanced lung cancer: Phase I trial of rhenium Re188 somatostatin analogue P2045

7672 Background: Both small cell (SCLC) and non-small cell lung cancer (NSCLC) overexpress somatostatin receptors (SSTR). P2045 peptide is an 11-amino acid somatostatin analogue that binds with high affinity to SSTR. The analogue can be labeled with Tc-99m to gauge receptor prevalence, or with Re-188 for 2.1MeV beta radiotherapy. To evaluate the safety of this approach a phase I dose-escalation study of Re-188 P2045 in SSTR positive lung cancer was performed. Methods: Patients (pts) were required to have progressive advanced lung cancer, PS 0–1, and normal organ function. There were no limitations on the number of prior therapies. Tumor SSTR was detected with Tc-99m P2045. If positive, treatment with escalating doses of Re-188 P2045 was instituted. Three doses were evaluated, 30 mCi/m2, 60 mCi/m2 and 90 mCi/m2. A single dose of Re-188 P2045 was allowed. Dose limiting toxicity was defined as ≥ grade 3 non-hematologic toxicity, grade 4 hematologic toxicity or projected renal radiation dose of &gt;20 Gy. Results: 15 pts entered, 7 M, 8 F, median age 61y, 9-PS0, 6 PS1. 13 NSCLC, 2 SCLC. 14 pts had ≥ 2 prior chemotherapy regimens. 1 pt refused standard therapy. All pts were imaged with Tc-99m P2045, 8 pts received Re-188 P2045. The 7 pts who did not proceed to Re-188 P2045 were due to rapid progression (n=2) non-uptake of Tc 99m P2045 (n=2) or projected renal radiation dose above the 20 Gy limit (n=3). All pts treated with Re-188 P2045 (4 at 30 mCi/m2, 3 at 60 mCi/m2 and 1 at 90 mCi/m2) had NSCLC. The major toxicity was grade 1 or 2 lymphopenia. No dose limiting toxicities were seen. All tumors imaged by Tc-99m had uptake of Re- 188. The trial was halted at the 90 mCi/m2 level when 3 pts had projected renal radiation doses above 20Gy. No responses were seen. 5 of the 8 pts (62.5%, 95% CI: 24%, 91%) had stable disease at 8 weeks, all of whom entered with progressive disease.. Median overall survival was 11.5 mo. Conclusions: 1) Re-188 P2045 was well-tolerated. 2) Tc-99m P2045 imaging allows identification of pts who may benefit from Re-188 P2045. 3) While responses were not seen, survival for these heavily pretreated pts is encouraging. 4) Further exploration of this approach utilizing amino acid infusion to ameliorate potential renal toxicity is warranted. No significant financial relationships to disclose.

Operative complications and early mortality after induction therapy for lung cancer

Induction therapy for advanced lung cancer allows improvement of completeness of resection and survival. However, predictive risk factors for postoperative complications and early mortality remain controversial. We report our 14-year experience with this combined approach. One hundred and thirty-nine patients (100 males and 39 females) underwent induction therapy and surgery for stage IIIA and B lung cancer. The mean age was 58.4+/-7.7 years. We retrospectively collected demographic data, preoperative functional parameters, type of operation, associated disorders, staging, induction regimen (chemotherapy alone or associated with radiotherapy). Univariate and multivariate analyses were performed to identify predictors of postoperative complications and early mortality. One hundred and nine patients received chemotherapy (mainly based on cisplatin and gemcitabine) and 30 received chemoradiotherapy (median dose 50Gy). Complications developed in 49 patients (35%). The most frequent was persistent air leakage (23-30% of the lobectomies), followed by cardiac complications, respiratory failure, and infections. Five patients (3.5%) died in the postoperative period and four of them had received pneumonectomy (mortality for pneumonectomy: 12.5%). The statistical analysis demonstrated that only pneumonectomy was associated with an increased mortality risk with no differences between intra- and extrapericardial dissection or right and left pneumonectomy. Induction therapy seems to be associated with an increased incidence of air leakage; the risk of other complications is acceptable. Pneumonectomy is associated with an increased risk of mortality and should be performed in selected patients.

Nucleotide-based therapies targeting clusterin chemosensitize human lung adenocarcinoma cells bothin vitroandin vivo

AbstractIntroduction: Lung cancer is highly lethal and resistant to most anticancer interventions. Treatment resistance is mediated, in part, by enhanced expression of cell survival proteins that help facilitate tumor progression. Clusterin is a stress-associated cytoprotective protein up-regulated by various apoptotic triggers in many cancers and confers treatment resistance when overexpressed. The objectives in this study were to evaluate clusterin expression levels in human lung cancer tissue, and to test effects of clusterin silencing using antisense oligonucleotides (ASOs) and short interfering double-stranded RNAs (siRNAs) on chemosensitivity in human lung cancer A549 cells. Methods: Clusterin immunostaining was evaluated in a tissue microarray of 149 spotted human lung cancers. The effects of clusterin ASO or siRNA treatment on clusterin expression and chemosensitivity to paclitaxel was examined in A549 cells in vitro while the ability of clusterin ASO to chemosensitize in vivo was evaluated in immunocompromised mice bearing A549 tumors. Results: More than 80% of human non-small cell lung cancers are immunoreactive for clusterin. Clusterin ASO or siRNA decreased clusterin mRNA expression in A549 cells &amp;gt;75% in a dose-dependent, sequence-specific manner, and significantly enhanced chemosensitivity to paclitaxel in vitro. Characteristic apoptotic DNA laddering was observed after combined treatment with ASO plus paclitaxel, but not with either agent alone. In vivo administration of clusterin ASO, compared to mismatch control oligonucleotide, synergistically enhanced the effects of paclitaxel or gemcitibine to significantly delay A549 tumor growth. Conclusion: These findings identify clusterin as a valid therapeutic target in strategies employing novel multimodality therapy for advanced lung cancer.