Initial multicenter community robotic lobectomy experience: comparisons to a national database.

BACKGROUND: In pulmonary lobectomy, video-assisted thoracoscopic surgery (VATS) offers advantages compared with open thoracotomy. However, various issues have limited its adoption, especially in community settings. Single surgeon studies suggest that completely portal robotic lobectomy (CPRL) may address such limitations. This multicenter study evaluates early CPRL experience in 6 community cardiothoracic surgeons' practices. METHODS: Perioperative data from each surgeon's initial 20, consecutive and unselected cases of CPRL were retrospectively gathered (total n = 120) and compared with the 2009 and 2010 Society of Thoracic Surgeons database for VATS (n = 4,612) and open (n = 5,913) lobectomy. The χ(2) and t test procedures were used and significance was defined at the 95% confidence level (p < 0.05). RESULTS: One hundred sixteen lobectomies (96.7%) were completed robotically with a conversion rate of 3.3%. Preoperative patient characteristics were comparable across the CPRL, VATS, and open groups. The CPRL was equivalent to VATS on all intraoperative and postoperative outcomes, and resulted in significantly lower postoperative blood transfusion rates (0.9% vs 7.8%; p = 0.002), air leaks greater than 5 days (5.2% vs 10.8%; p = 0.05), chest tube duration (3.2 days vs 4.8 days; p < 0.001), and length of stay (4.7 days vs 7.3 days; p < 0.001) when compared with open. For these outcomes, results trended favorably for CPRL over VATS. CONCLUSIONS: This early CPRL experience reveals a minimally invasive lobectomy technique that is safe and reproducible in varied practice settings. Outcomes were equivalent between CPRL and VATS, trending in favor of robotics. The CPRL was superior in several measures compared with open. The absence of patient selection and low conversion rates suggest a broad applicability of this technique.

A pilot study of preoperative gefitinib for early-stage lung cancer to assess intratumor drug concentration and pathways mediating primary resistance.

BACKGROUND: Targeted agents such as tyrosine kinase inhibitors have been extensively studied in preclinical systems and in advanced-stage patients. Little is known about levels of kinase inhibitors found in tumors as opposed to plasma. Similarly, effects of inhibitors on tumor signaling pathways in patient-based materials are unclear. To explore these questions, we conducted a trial of a brief course of preoperative gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, in early-stage non-small cell lung cancer. METHODS: Patient with early-stage non-small cell lung cancer received 4 weeks of gefitinib 250 mg daily before surgical resection. Pre- and posttreatment computerized tomography scans and positron emission tomography scans were used to assess clinical response. Gefitinib and surgical toxicity were evaluated. Tumor tissue was evaluated for gefitinib levels and was compared with plasma gefitinib levels. Activated signaling molecules including EGFR, STAT3, ERK, and AKT were examined in surgically resected tumor tissue. RESULTS: Twenty-three patients participated in the study, and all had surgical resection of tumors. No toxicities unrelated to known effects of gefitinib or surgery were encountered. Twenty-two patients had stable disease, and one had progression in tumor size. There was no correlation with positron emission tomography response and computerized tomography response. Tumor levels of gefitinib were approximately 40-fold higher than plasma levels, indicating potential tumor concentration of gefitinib. Tyrosine phosphorylated STAT3 was abundant in the surgically resected tumor tissue, indicating potential role in primary resistance in vivo. CONCLUSIONS: This study confirms previous preclinical observations that tumor tissues concentrate gefitinib. Persistent STAT3 may be leading to primary resistance to EGFR inhibitors in vivo.

Neoadjuvant chemotherapy for resectable non-small-cell lung cancer.

Lung cancer generally has an unfavorable prognosis. For those with resectable disease, the use of neoadjuvant chemotherapy has the potential to reduce tumor volume, address micrometastatic disease early, and improve outcomes. Randomized trials comparing neoadjuvant platinum-based regimens with surgery alone were able to demonstrate the feasibility and safety of this modality. These trials supported evidence found in phase II trials that utilized third-generation chemotherapies. Still, limitations to these studies exist, such as the inclusion of various disease stages in one study, inter- and intratrial variability of the chemotherapy regimens used, and lack of phase III data comparing neoadjuvant to adjuvant chemotherapy. These heterogeneous factors make it difficult to offer firm recommendations about neoadjuvant chemotherapy. Other matters of contention include the role of postoperative radiation and the concern for increased postoperative complications, especially when a right pneumonectomy is being considered after neoadjuvant chemotherapy. To clarify these issues, well-structured phase III trials comparing adjuvant to neoadjuvant chemotherapy are needed.

Computed tomography response, but not positron emission tomography scan response, predicts survival after neoadjuvant chemotherapy for resectable non-small-cell lung cancer.

PURPOSE: Tumor response is considered a surrogate marker of survival. We investigated whether tumor response based on computed tomography (CT) scan or whole-body [(18)F]fluorodeoxyglucose positron emission tomography (PET) scan after neoadjuvant chemotherapy for resectable non-small-cell lung cancer (NSCLC) is prognostic of survival. PATIENTS AND METHODS: Two consecutive phase II clinical trials were jointly analyzed. Patients underwent CT and PET scans before and after completion of neoadjuvant chemotherapy, followed by surgery. RESULTS: Eighty-nine patients were included. Patients with a partial or complete response based on Response Evaluation Criteria in Solid Tumors categories (n = 33) had a better overall survival than those with stable or progressive disease (n = 56; median survival time, not reached v 36 months, respectively; P = .04). Of all patients, those with response in the highest quartile had 1- and 2-year survival rates of 100% and 81%, respectively, compared with 77% and 61%, respectively, among patients in the lowest quartile. However, on the basis of visual analysis of PET scan, patients with a metabolic response (n = 28) had no significant difference in survival compared with patients without response (n = 61; median survival time, 35.6 months v not reached, respectively; P = .94). In addition, on the basis of a semiquantitative analysis of PET scan, using at least 30% reduction in tumor metabolism as a response (n = 59), we also found no significant difference in survival among those with or without response. CONCLUSION: Among patients with resectable NSCLC treated with neoadjuvant chemotherapy, we found no evidence that tumor response by PET scan after chemotherapy is prognostic of survival; however, response by CT scan was associated with better survival.

Posterior midline approach for single-stage en bloc resection and circumferential spinal stabilization for locally advanced Pancoast tumors. Technical note.

The treatment of Pancoast (superior sulcus) tumors that extensively invade the vertebral column remains controversial. Different surgical approaches involving multistage resection techniques have been previously described for superior sulcus tumors that invade the chest wall and spinal column. Typically a posterior approach to stabilize the spine is followed by a second-stage thoracotomy (posterolateral or trap door) for definitive en bloc resection of stage T4 Pancoast tumors. The authors report and elaborate on a surgical technique successfully used for an en bloc resection as well as spinal stabilization through a single-stage posterior approach without any added morbidity. Two patients with histologically proven Pancoast tumors were treated by single-stage resection and stabilization through a posterior approach at the H. Lee Moffitt Cancer Center. A wedge lung resection or lobectomy was performed by the chest surgeon utilizing the chest wall defect. Placement of an anterior cage (in one case) and posterior cervicothoracic spinal instrumentation (in both cases) was performed during the same operation. Average blood loss was 675 ml and surgical time was 7 hours. The median hospital stay was 9 days (range 7-11 days). Both patients did well postoperatively and were free of recurrence at the 2-year follow-up. Radical resection of Pancoast tumors including lobectomy, chest wall resection, costotransversectomy, and partial or complete vertebrectomy with simultaneous instrumentation for spinal stabilization can be performed through a posterior single-stage approach.

Thymidylate synthase in situ protein expression and survival in stage I nonsmall-cell lung cancer.

BACKGROUND: Thymidylate synthase (TS) is important for maintenance of the intracellular thymidine pool, which is crucial for DNA synthesis and repair. TS messenger RNA and protein levels are predictive of response to 5-fluorouracil-containing therapy for patients with colorectal cancer and gastric cancer. High levels of expression of 2 other genes important in DNA synthesis and repair, RRM1 and ERCC1, are prognostic of survival in early stage nonsmall-cell lung cancer (NSCLC) patients. We hypothesized that intratumoral TS expression would be prognostic of outcome in stage I NSCLC. METHODS: Cytoplasmic tumoral TS was determined by automated in situ protein quantification (AQUA) in 160 patients with completely resected NSCLC that had not received chemotherapy or radiation. It was also determined by real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in 85 similar patients. The 2 datasets were partially overlapping (N=32). The optimal cutpoint was determined by the maximal log-rank method with adjustment of the P-values for multiple looks. RESULTS: TS protein expression was significantly associated with patient survival (P=.0013, adjusted P=.034). The optimal cutpoint was at the 25% percentile; the group with low expression (57.02) had a median OS of 81.3 months. TS mRNA expression was not significantly associated with patient survival or TS protein expression. In a multivariate analysis adjusting for tumor stage, TS remained significantly prognostic of survival (P=.0013, adjusted P=.032). CONCLUSIONS: In situ cytoplasmic TS protein expression in tumors of patients with resected stage I NSCLC is a clinically important determinant of survival.

Phase II study of neoadjuvant chemotherapy with gemcitabine and vinorelbine in resectable non-small cell lung cancer.

OBJECTIVE: We assessed the efficacy of a non-platinum-containing doublet chemotherapy of gemcitabine and vinorelbine as induction therapy prior to surgical resection in patients with stage IB-IIIA and selected stage IIIB non-small cell lung cancer (NSCLC). The primary clinical end point was radiographic disease response rate, and the secondary end points were pathologic response rate, treatment-related toxicity, surgical resectability and outcome, and overall and disease-free survival. METHODS: Patients underwent staging with CT of the chest and upper-abdomen, whole-body F-18 fluorodeoxyglucose positron emission tomography, bronchoscopy, and mediastinoscopy. The patients had to have medically and surgically resectable disease. Chemotherapy consisted of gemcitabine, 1,000 mg/m(2), and vinorelbine, 25 mg/m(2), administered on days 1, 8, 22, and 29. Imaging studies were repeated between days 43 and 50. Disease response was assessed by response evaluation criteria in solid tumors, and patients with resectable disease were offered surgery between days 50 and 70. Patients were followed up every 3 months for 2 years with chest CT. RESULTS: Between January 2000 and March 2004, 27 patients with stage IB NSCLC, 15 patients with stage II NSCLC, and 20 patients with stage III NSCLC were entered. After induction chemotherapy 34% (95% confidence interval [CI], 23 to 48%) had an objective radiographic response, 2% had a complete pathologic response, 90% underwent thoracotomy, and 77% underwent a complete resection. There were four deaths in the 6-week period following surgery, and there were no deaths related to chemotherapy. There were no unexpected morbidities from surgery or chemotherapy. The 1-year and 2-year overall survival rates were 80% (95% CI, 68 to 88%) and 65% (95% CI, 50 to 76%), and the median overall survival was 38.2 months. CONCLUSIONS: Induction chemotherapy with gemcitabine and vinorelbine results in 1-year and 2-year survival rates and a median survival time comparable to those obtained with platinum-containing doublets. However, it appears to be less efficacious in terms of radiographic and pathologic response rates compared with platinum-containing chemotherapy doublets.

Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance.

RRM1 is a gene crucial for determination of the tumor phenotype. It encodes the regulatory subunit of ribonucleotide reductase, and it is a molecular target of gemcitabine. In addition, RRM1 induces PTEN expression and inhibits cell migration, invasion, and metastasis formation. In patients with resected lung cancers, increased levels of RRM1 are highly associated with long survival. In contrast, patients on gemcitabine and cisplatin therapy for advanced disease have a poor survival if RRM1 expression is high presumably because of decreased efficacy of chemotherapy. We analyzed the RRM1 promoter for polymorphisms in an effort to develop a practical and inexpensive assay for RRM1 expression. Two single nucleotide polymorphisms, RR37 and RR524, were discovered. These polymorphisms impacted promoter activity in vitro and had different frequencies in various populations. Promoter allelotypes were highly associated with overall (P = 0.06) and disease-free (P = 0.03) patient survival. The allelotype with the highest predicted activity was associated with the best patient outcome. However, we did not find an association between allelotype and tumoral RRM1 expression. This is likely a result of the limited impact of the described promoter polymorphisms on overall in vivo gene expression. We conclude that clinical studies using RR37 and RR524 for decisions on chemotherapy are premature and that further functional studies on the RRM1 promoter are required to fully elucidate factors controlling RRM1 expression.

RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer.

PURPOSE: RRM1 has important functions in the determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non-small-cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. PATIENTS AND METHODS: A retrospective data set of 49 patients and a prospective data set of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. RESULTS: RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue. RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. CONCLUSION: RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.

Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution.

BACKGROUND: We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor. METHODS: Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib. RESULTS: The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. CONCLUSIONS: In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.