Seminars in Cardiothoracic and Vascular Anesthesia http://scv.sagepub.com/
The Year in Thoracic Surgery: Highlights From 2013 Daine T. Bennett and Michael J. Weyant SEMIN CARDIOTHORAC VASC ANESTH 2014 18: 24 originally published online 5 February 2014 DOI: 10.1177/1089253214521529 The online version of this article can be found at: http://scv.sagepub.com/content/18/1/24
Published by: http://www.sagepublications.com
Additional services and information for Seminars in Cardiothoracic and Vascular Anesthesia can be found at: Email Alerts: http://scv.sagepub.com/cgi/alerts Subscriptions: http://scv.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://scv.sagepub.com/content/18/1/24.refs.html
>> Version of Record - Mar 12, 2014 OnlineFirst Version of Record - Feb 5, 2014 What is This?
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
521529 research-article2014
SCVXXX10.1177/1089253214521529Seminars in Cardiothoracic and Vascular AnesthesiaBennett and Weyant
The Perioperative Year in Review-2013
The Year in Thoracic Surgery: Highlights From 2013
Seminars in Cardiothoracic and Vascular Anesthesia 2014, Vol. 18(1) 24–28 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253214521529 scv.sagepub.com
Daine T. Bennett, MD1 and Michael J. Weyant, MD1
Abstract Over the course of 2013, many important studies have been published affecting the care of thoracic surgery patients. Novel chemotherapeutics are being developed to target specific tumor mutations. The utilization of robotic-assisted surgery continues to expand within this exciting field as well. Improved data on endobronchial ultrasound staging and sublobar resections for non–small cell lung cancer as well as postoperative surveillance after esophagectomy have also been reported. This review summarizes important publications of the past year influencing the practice of thoracic surgery today. Keywords thoracic surgery, robotic-assisted, videoscopic-assisted, esophagectomy, lung cancer, targeted therapy, segmentectomy, wedge resection, salvage therapy, endobronchial ultrasound, mediastinal staging
Introduction The field of thoracic surgery continues to have exciting, innovative research published that affects daily practice. The year 2013 was no exception. With the number of articles available, it is difficult to remain current on all areas under investigation in the evolving field of thoracic surgery. The purpose of this article is to highlight some of the pertinent articles published in 2013 in thoracic surgery that are of interest to cardiothoracic anesthesiologists and thoracic surgeons alike. As with other articles in this series of Seminars in Cardiothoracic and Vascular Anesthesia, this article is not meant to be a comprehensive review of all the literature published in 2013 but more a discussion of selected, quality articles addressing current issues and innovations in the field of thoracic surgery. It was difficult to narrow the selection down to so few articles and acknowledge biases related to selecting the following articles from the pool of so many high-quality articles. While videoscopic-assisted thoracoscopic surgery (VATS) has been well established in thoracic surgery, robotic-assisted surgery has recently become more popular among thoracic surgeons. Comparative research between robotic-assisted and VATS pulmonary resections with regard to clinical outcomes and costs is starting to be published. More recently, robotic surgery is being implemented into minimally invasive esophagectomy cases with papers on technique and feasibility starting to be published. Directed therapy for non–small cell lung cancer (NSCLC) is another exciting area of research with a drug targeting a new mutational aberration recently being approved for use. Endobronchial ultrasound for preoperative mediastinal
staging in NSCLC continues to have data supporting and solidifying its role in the management of thoracic patients. Some light has been shed on the effects of mortality from wedge resection versus segementectomy for those patients who cannot tolerate a lobectomy for NSCLC. Last, the results from surveillance and salvage therapy in patients with esophageal adenocarcinoma who have undergone trimodality therapy was published in the largest cohort of patients to date that questions the utility of intensive surveillance strategies. The following review summarizes important findings from these articles published over the past year as well as a discussion of the associated strengths and weaknesses. The reader is encouraged to reference these articles for more details on the important updates in thoracic surgery during 2013.
Robotic-Assisted Versus VideoscopicAssisted Thoracoscopic Surgery VATS has previously been established as having improved perioperative outcomes over open thoracotomy. Now robotic-assisted thoracic surgery (RATS) is emerging as a 1
University of Colorado School of Medicine, Department of Surgery, Division of Cardiothoracic Surgery, Aurora, Colorado, USA Corresponding Author: Michael J. Weyant, Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, University of Colorado Denver-Anschutz Medical Campus, 12631 East 17th Ave, MS C310, Aurora, CO 80045, USA. Email: [email protected]
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
25
Bennett and Weyant viable option for minimally invasive pulmonary resections. While there are many proponents of the new technology, limited data evaluating outcomes with the new technique have been published to date. Swanson and colleagues1 performed a retrospective review of the Premier multihospital database to evaluate clinical and economic outcomes of patients undergoing wedge resection or lobectomy by either VATS or RATS. They included all patients older than 8 years who underwent surgery between 2009 and 2011. Cases were identified according to International Classification of Disease, Ninth edition (ICD-9). The planned statistical analysis included comparisons of length of stay, operative time, adverse events, and hospital costs. A total of 15 502 patients who underwent a wedge resection or lobectomy were identified. Of these 14 837 were VATS and only 665 were RATS. Due to the large discrepancy between the 2 groups, a propensity scoring system was used to match RATS patients with comparable VATS patients. Propensity scoring was calculated based on a number of variables including severity of disease, age, gender, comorbidities, size of hospital, and status as a teaching hospital. The final number of patients analyzed was 295 lobectomies and 325 wedge resections per group for both VATS and RATS. The odds ratio of adverse events between VATS and RATS was not significantly different in either wedge resection or lobectomy. Also hospital length of stay was comparable between the 2 groups. Operating time for lobectomy was slightly longer for RATS than VATS, 4.49 hours versus 4.23 hours (P = .0959) and was significantly longer for wedge resection, 3.26 hours compared with 2.86 hours (P = .0003). Hospital costs were significantly higher for RATS with both operations. RATS compared with VATS cost $25 040 and $20 476, respectively, for lobectomy (P < .0001) and $19 592 and $16 600, respectively, for wedge resection (P = .0001). The authors note that these were direct hospital costs for the procedures and did not include the greater than 1 million dollar investment to purchase the daVinci robot nor the cost of the annual service contract. Strengths of the study include that the database used includes cases representing a broad geographic and demographic sampling of US hospitals and that the data are reasonably recent. The use of propensity score-matched cases removes some of the confounding from a retrospective review, but it remains inferior to a prospective randomized trial. Also the database was designed for billing purposes, which makes it difficult to obtain certain clinical data. The authors also acknowledge the learning curve involved with implementing robotic technology noting that the cost and operative time data may equilibrate as surgeons become more efficient with the technology.1
Endobronchial UltrasonographyTransbronchial Needle Aspiration Adequate mediastinal nodal staging for NSCLC reduces the number of nontherapeutic pulmonary resections and is important for accurate prognoses and treatment plans. Alternatives to the highly invasive mediastinoscopy technique have been under study for the past several years. These include positron emission tomography-computed tomography (PET-CT), endoscopic ultrasonography-fine needle aspiration (EUS), and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS). EBUS has been shown to have comparable diagnostic results to mediastinoscopy in some studies; however, the feasibility, accuracy, and safety of this technique have not been evaluated in the veteran population. Cornwell and colleagues2 performed a retrospective review of prospectively collected data from single-center Veterans Affairs Medical Center (VA) of patients undergoing lobectomy from 2009 to 2012. All patients underwent PET-CT, and those with concerning results went for EBUS staging. The primary outcome measures were feasibility, safety, accuracy, and negative predictive value of EBUS. The pathology results from surgical hilar and mediastinal resections were used at the gold standard. The authors identified 166 patients who underwent pulmonary lobectomy for NSCLC during this time period. Patients with sublobar resections were excluded. Of these 104 patients had PET-CT only and 62 went on for EBUS staging. The accuracy of EBUS staging was 93.5% with a negative predictive value of 92.6%. EBUS failed to adequately stage 8 patients in total; however, 4 of these patients had diseased lymph nodes in areas inaccessible to EBUS. The PET-CT only group demonstrated an accuracy of 74% and a negative predictive value of 74%. The negative predictive value of EBUS (92.6%) was significantly better than PET-CT only (74%) (P = .004). The nontherapeutic resection rate was lower for the EBUS group (8.1%) than the PET-CT only group (12.5%), but this result was not significant (P = .37). There were no significant complications related to EBUS staging procedures. This was the first study evaluating feasibility and effectiveness of EBUS in the veteran population. While the results from this study were comparable to other studies, these data demonstrate that this evolving technique can be applied in a VA setting. Most of the previous reports have come from highly specialized, tertiary care centers. The authors also point out the importance of accurate staging with EBUS, which prevents patients from undergoing nontherapeutic, invasive pulmonary resections, which is especially important in the high-risk veteran population.2
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
26
Seminars in Cardiothoracic and Vascular Anesthesia 18(1)
Segmentectomy Versus Wedge Lobectomy remains the standard of care for patients with NSCLC in those who can physiologically tolerate the procedure. In patients who are not lobectomy candidates, the optimal surgical management with wedge resection versus segmentectomy is still debated. While some studies have compared pathologic margins, this report by Smith and colleagues3 evaluated survival benefits between the 2 procedures. Unfortunately, there have been no randomized trials to date to evaluate survival outcomes between these 2 groups. In this study, the authors use a national database and propensity score matched cohorts to study a sampling of patients from across the country and analyze wellmatched patients. The authors queried the Surveillance, Epidemiology and End Results (SEER) database for patients who underwent either wedge resection or segmentectomy for NSCLC with tumors ≤3 cm between 1998 and 2006. They identified a total of 3525 patients with 704 (20%) receiving segmentectomy and the remaining undergoing wedge resection. Propensity scores were calculated based on age, sex, race, marital status, and tumor characteristics. The baseline characteristics revealed significantly larger tumor size and more lymph nodes sampled in the segmentectomy cohort. For all posed questions, the authors evaluated overall survival as well as lung cancer–specific survival. They also ran each analysis using a Cox regression model, which adjusted for propensity score and number of lymph nodes sampled, as well as a matched analysis based on propensity score. The findings of this study demonstrated improved survival for segmentectomy over wedged resection in almost every category analyzed. Included below are the data based on the adjusted Cox regression model as the propensity matched analyses showed similar results. In the primary analysis, segmentectomy demonstrated significant improvement in both overall survival (hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.69-0.96) and lung cancer– specific survival (HR = 0.76; 95% CI = 0.61-0.94). As secondary analyses, the authors evaluated survival between the 2 surgical techniques based on TIa tumors and age less than or greater than 70. In patients with tumors less than 2 cm segmentectomy continued to show improved overall survival (HR = 0.84; 95% CI = 0.68-0.99) and lung cancer–specific survival (HR = 0.82; 95% CI = 0.62-1.00). Concerning patients less than 70 years old, there was also an overall survival benefit (HR = 0.74; 95% CI = 0.560.96) and a lung cancer–specific survival benefit (HR = 0.79; 95% CI = 0.57-1.00). In patients older than 70 years, the overall survival benefit was not significant (HR = 0.85; 95% CI = 0.69-1.05); however, lung cancer–specific survival remained significant (HR = 0.73; 95% CI = 0.53-0.97).
This study provides evidence in support of segmentectomy over wedge resection in patients who are unfit for lobar resection. While the authors demonstrate an improved study design by using propensity scoring of retrospective data, they admit that there remains a need for a randomized study to more fully answer the question.3
Targeted Therapy for NSCLC Chemotherapeutic agents for NSCLC have been drastically improving over recent years. Standard platinum-based chemotherapy are no longer the only treatment option. Ongoing research has identified many mutational subtypes of NSCLC that serve as potential therapeutic targets. Epidermal growth factor receptor (EGFR) is one such mutation in which protein kinase inhibitors have been developed to target this mutation. Erlotinib and afatinib are 2 protein kinase inhibitors currently approved for the treatment of NSCLC with susceptible EGFR mutations. Unfortunately, not all tumors with the EGFR mutation respond to the drugs, and those that do frequently acquire resistance within 1 year. There are a number of agents currently undergoing phase I/II trials that are directed at other potential therapeutic targets. These mutational variants include HER2, BRAF, RET, MEK1/2, PI3K, MET, FGFR, and VEGF.4 Recently, a new drug, crizotinib, targeting anaplastic lymphoma kinase (ALK), has been approved. The results of a phase III trial comparing crizotinib to chemotherapy with patients with metastatic or locally advanced NSCLC containing the ALK mutation were published in June 2013 issue of the New England Journal of Medicine. Crizotinib is administered orally and targets mutations in ALK, MET, and ROS1 tyrosine kinases. Earlier phase trials had demonstrated a 60% response rate in ALK-positive tumors and progression-free survival of 8.1 to 9.7 months while traditional single-agent chemotherapies generally yield 10% response with 2- to 3-month progression-free survival. This randomized, controlled, open label, phase III trial compared crizotinib with standard chemotherapy. Eligibility criteria included patients at least 18 years old with locally advanced or metastatic NSCLC positive for ALK mutation with progressive disease after 1 round of prior platinumbased chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive oral crizotinib or intravenous therapy of either pemetrexed or docetaxel. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status and whether or not prior EGFR kinase inhibitor therapy had been administered. The primary end point was radiographic evidence of disease progression or death. Secondary end points included overall survival, rate of partial and complete responses, safety, and patient-reported outcomes. Treatment was continued until disease progression was documented based on Response Evaluation Criteria in Solid Tumors (RECIST) standards.
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
27
Bennett and Weyant The study randomized a total of 347 patients with 173 to crizotinib and 174 to chemotherapy. In the chemotherapy group, 99 received pemetrexed and 72 received docetaxel. The results of the primary end point demonstrated an improvement in median progression-free survival with crizotinib over both chemotherapies with a hazard ratio for death or progression of disease in crizotinib of 0.49 (95% CI = 0.37-0.64; P < .001). Also, crizotinib was superior to each drug individually with a hazard ratio of 0.59 (95% CI = 0.43-0.80; P < .001) compared with pemetrexed and 0.30 (95% CI = 0.21-0.43; P < .001) compared with docetaxel. The response rate to crizotinib (66%) was significantly higher than both pemetrexed (29%) and docetaxel (9%) (P < .001). The median overall survival was 20.3 months with crizotinib and 22.8 months with chemotherapy, resulting in a nonsignificant hazard ratio for death with crizotinib of 1.02 (95% CI = 0.68-1.54; P = .54). Adverse events that were at least 5% higher for chemotherapy compared with crizotinib were fatigue, alopecia, dyspnea, and rash. Adverse events that were at least 5% higher with crizotinib compared with chemotherapy were vision disorder, nausea, vomiting, diarrhea, constipation, edema, dizziness, upper respiratory infection, and elevated liver aminotransferase levels. Of note, 2% of patients receiving chemotherapy experienced grade 3 or 4 elevated aminotransferase levels compared with 16% of patients receiving crizotinib, with 1 patient dying of liver failure. Based on patient survey data, patients with crizotinib demonstrated a significantly improved global quality of life as well as significant improvement in median time to deterioration regarding cough, dyspnea, or chest pain. The authors conclude that in patients with ALK-positive NSCLC crizotinib therapy increased tumor response rates, prolonged progression-free survival, and improved quality of life when compared with standard chemotherapy. They note that the higher rate of adverse events in the crizotinib group was likely in part due to the longer median treatment duration with crizotinib compared with chemotherapy (31 weeks vs 12 weeks). Also, patients who crossed over from standard chemotherapy to crizotinib after demonstrating progressive disease introduced confounding into the overall survival analysis. This study was supported by the maker of crizotinib, Pfizer.5
Surveillance After Trimodality Treatment of Esophageal Cancer Esophageal cancer is a devastating disease with an almost equivalent annual incidence and death rate of around 16 000 people per year. In the United States, adenocarcinoma is the most common type. Patients with locoregional disease are frequently treated with trimodality therapy consisting of chemoradiation followed by esophagectomy. Surveillance
is frequently continued afterwards; however, the protocols are not standardized and guidelines are mostly based on expert opinion. The goal of surveillance is to identify patients with locoregional recurrence without metastatic disease who may benefit from salvage chemoradiation or surgery. The effectiveness of this management has only been evaluated by a limited number of single-center, retrospective reviews. Sudo and colleagues6 at the MD Anderson Cancer Center performed a retrospective review of prospectively collected data of 518 patients. All patients had undergone trimodality therapy and been followed with the standardized, conservative surveillance program at that institution. The authors’ primary goal was to assess outcomes for those patients who received salvage therapy after recurrence as well as type and timing of recurrences. This was the largest cohort of patients published on the subject to date. Patients analyzed in this data set had been diagnosed with localized esophageal adenocarcinoma and treated with trimodality therapy consisting of radiotherapy and chemotherapy with a fluoropyrimidine and either a platinum or taxane compound followed by esophagectomy. The surveillance protocol was a PET-CT and blood tests every 3 months for a year, then 6 months for 2 years, followed by yearly for at least 5 years. Also endoscopy was performed every 6 months for 18 months followed by yearly. For the 518 patients, the overall median follow-up time was 29 months and 55 months for those still alive. Of the 518 patients, 215 relapsed with 188 having distant, metastatic disease and 27 with locoregional disease only. Eleven of these patients had recurrence only in the esophageal lumen of which 8 were diagnosed by PET-CT. Sixtythree percent of locoregional recurrences (17 patients) occurred within 2 years and 89% (24 patients) occurred within 3 years. These 27 patients were 5% of the total 518 patients undergoing surveillance who could have potentially benefited from salvage therapy. Of these 27 patients, 12 were eligible for chemoradiation salvage therapy, 4 received surgical reoperation, and 11 were treated palliatively. Of the 12 patients treated with chemoradiation, 5 survived more than 2 years. Of the 4 treated with surgical resection, 3 survived more than 2 years. All patients treated surgically had significant perioperative morbidity, and all developed distant metastases. The median overall survival of the 27 patients with locoregional disease was 17 months. The median survival of those treated palliatively was 5 months. The authors provide a nice discussion on the utility of surveillance after trimodality therapy for esophageal adenocarcinoma. Per the institution’s protocol described above, the patients would have undergone numerous
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
28
Seminars in Cardiothoracic and Vascular Anesthesia 18(1)
PET-CT scans and endoscopies, which are both costly and uncomfortable. This surveillance went out to at least 5 years, but they noted that 89% of recurrences were identified within 3 years. They suggest that endoscopy may only be needed when imaging findings are concerning given costs and risks associated with the procedure and that most recurrences were identified with PET-CT. Overall only 5% of the 518 patients were identified with locoregional disease. Of these 27 patients, 16 were eligible for some type of salvage therapy and only 8 survived more than 2 years (1.5% of 518 patients). With so few patients benefiting from such extensive surveillance and treatment, the authors question the utility of the aggressive management. However, they recognize that there are few studies available to develop evidence-based surveillance guidelines.6
esophagectomy. The perioperative results of this study are comparable to others, albeit they are all small, single-center case series. This is a very exciting new field of thoracic surgery, which has plenty of room for advancement. It will be interesting to see data comparing it to traditional operations as this novel technique continues to become more refined and more prevalent.7
Conclusion The field of thoracic surgery continues to evolve and advance. Advancement with novel surgical techniques as well as chemotherapeutics continues to improve. The volume of quality research continues to increase and will only serve to improve the patient care provided to this population. Declaration of Conflicting Interests
Robotic Esophagectomy Robotic-assisted surgery is becoming increasingly more prevalent in many areas of surgery. This has also been true most recently in esophageal operations. Most of the current literature report feasibility and effectiveness in singlecenter early experience with the technique. Many articles report some type of hybrid approach. The report by Sarkaria and colleagues7 at Memorial Sloan-Kettering are included here as they report on a novel technique using robotic techniques for both the thoracic and abdominal portions of the procedure and demonstrate their experience with 21 consecutive patients over a 1-year period during 2011. The technical details of both the thoracic and abdominal portions of the procedure are well documented in the article but are beyond the scope of this review. Of note this is the first report of a series of patients undergoing totally robotic-assisted minimally invasive esophagectomy. Two surgeons primarily performed all procedures. The cohort of patients was mostly male and had a median age of 62 years old. The median operative time, including repositioning, was 556 minutes, which decreased to 414 minutes for the last 5 cases. Ten of the 21 required conversion to laparoscopic assist and 5 of those eventually required conversion to an open operation. However, none of the last 5 patients required conversion to open operations. Five of the patients experienced grade III or greater complications, and 1 patient died on postoperative day 70 due to respiratory failure after anastomotic leak. The median number of lymph nodes sampled was 20 (range 10-49). Seventeen patients achieved an R0 resection. Four patients obtained an R1 resection, but one of those was a radial margin of a patient who did not undergo neoadjuvant therapy. This is the first report of a series of patients undergoing completely robotic-assisted minimally invasive
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Swanson SJ, Miller DL, McKenna RJ, et al. Comparing robot-assisted thoracic surgical lobectomy with conventional video-assisted thoracic surgical lobectomy and wedge resection: results from a multihospital database (Premier) [published online November 7, 2013]. J Thorac Cardiovasc Surg. doi:10.1016/j.jtcvs.2013.09.046. 2. Cornwell LD, Bakaeen FG, Lan CKW, et al. Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy for preoperative nodal staging of lung cancer in a veteran population. JAMA Surg. 2013;148:1024-1029. 3. Smith CB, Swanson SJ, Mhango G, Wisnivesky JP. Survival after segmentectomy and wedge resection in stage I nonsmall-cell lung cancer. J Thorac Oncol. 2013;8:73-78. 4. Liu SV, Subramaniam D, Cyriac GC, Abdul-Khalek FJ, Giaccone G. Emerging protein kinase inhibitors for nonsmall cell lung cancer [published online December 20, 2013]. Expert Opin Emerg Drugs. doi:10.1517/14728214.2 014.873403. 5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394. 6. Sudo K, Taketa T, Correa AM, et al. Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies. J Clin Oncol. 2013;31:4306-4310. 7. Sarkaria IS, Rizk NP, Finley DJ, et al. Combined thoracoscopic and laparoscopic robotic-assisted minimally invasive esophagectomy using a four-arm platform: experience, technique and cautions during early procedure development. Eur J Cardiothorac Surg. 2013;43:e107-e115.
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
The Year in Thoracic Surgery: Highlights From 2013 Daine T. Bennett and Michael J. Weyant SEMIN CARDIOTHORAC VASC ANESTH 2014 18: 24 originally published online 5 February 2014 DOI: 10.1177/1089253214521529 The online version of this article can be found at: http://scv.sagepub.com/content/18/1/24
Published by: http://www.sagepublications.com
Additional services and information for Seminars in Cardiothoracic and Vascular Anesthesia can be found at: Email Alerts: http://scv.sagepub.com/cgi/alerts Subscriptions: http://scv.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://scv.sagepub.com/content/18/1/24.refs.html
>> Version of Record - Mar 12, 2014 OnlineFirst Version of Record - Feb 5, 2014 What is This?
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
521529 research-article2014
SCVXXX10.1177/1089253214521529Seminars in Cardiothoracic and Vascular AnesthesiaBennett and Weyant
The Perioperative Year in Review-2013
The Year in Thoracic Surgery: Highlights From 2013
Seminars in Cardiothoracic and Vascular Anesthesia 2014, Vol. 18(1) 24–28 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1089253214521529 scv.sagepub.com
Daine T. Bennett, MD1 and Michael J. Weyant, MD1
Abstract Over the course of 2013, many important studies have been published affecting the care of thoracic surgery patients. Novel chemotherapeutics are being developed to target specific tumor mutations. The utilization of robotic-assisted surgery continues to expand within this exciting field as well. Improved data on endobronchial ultrasound staging and sublobar resections for non–small cell lung cancer as well as postoperative surveillance after esophagectomy have also been reported. This review summarizes important publications of the past year influencing the practice of thoracic surgery today. Keywords thoracic surgery, robotic-assisted, videoscopic-assisted, esophagectomy, lung cancer, targeted therapy, segmentectomy, wedge resection, salvage therapy, endobronchial ultrasound, mediastinal staging
Introduction The field of thoracic surgery continues to have exciting, innovative research published that affects daily practice. The year 2013 was no exception. With the number of articles available, it is difficult to remain current on all areas under investigation in the evolving field of thoracic surgery. The purpose of this article is to highlight some of the pertinent articles published in 2013 in thoracic surgery that are of interest to cardiothoracic anesthesiologists and thoracic surgeons alike. As with other articles in this series of Seminars in Cardiothoracic and Vascular Anesthesia, this article is not meant to be a comprehensive review of all the literature published in 2013 but more a discussion of selected, quality articles addressing current issues and innovations in the field of thoracic surgery. It was difficult to narrow the selection down to so few articles and acknowledge biases related to selecting the following articles from the pool of so many high-quality articles. While videoscopic-assisted thoracoscopic surgery (VATS) has been well established in thoracic surgery, robotic-assisted surgery has recently become more popular among thoracic surgeons. Comparative research between robotic-assisted and VATS pulmonary resections with regard to clinical outcomes and costs is starting to be published. More recently, robotic surgery is being implemented into minimally invasive esophagectomy cases with papers on technique and feasibility starting to be published. Directed therapy for non–small cell lung cancer (NSCLC) is another exciting area of research with a drug targeting a new mutational aberration recently being approved for use. Endobronchial ultrasound for preoperative mediastinal
staging in NSCLC continues to have data supporting and solidifying its role in the management of thoracic patients. Some light has been shed on the effects of mortality from wedge resection versus segementectomy for those patients who cannot tolerate a lobectomy for NSCLC. Last, the results from surveillance and salvage therapy in patients with esophageal adenocarcinoma who have undergone trimodality therapy was published in the largest cohort of patients to date that questions the utility of intensive surveillance strategies. The following review summarizes important findings from these articles published over the past year as well as a discussion of the associated strengths and weaknesses. The reader is encouraged to reference these articles for more details on the important updates in thoracic surgery during 2013.
Robotic-Assisted Versus VideoscopicAssisted Thoracoscopic Surgery VATS has previously been established as having improved perioperative outcomes over open thoracotomy. Now robotic-assisted thoracic surgery (RATS) is emerging as a 1
University of Colorado School of Medicine, Department of Surgery, Division of Cardiothoracic Surgery, Aurora, Colorado, USA Corresponding Author: Michael J. Weyant, Section of General Thoracic Surgery, Division of Cardiothoracic Surgery, University of Colorado Denver-Anschutz Medical Campus, 12631 East 17th Ave, MS C310, Aurora, CO 80045, USA. Email: [email protected]
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
25
Bennett and Weyant viable option for minimally invasive pulmonary resections. While there are many proponents of the new technology, limited data evaluating outcomes with the new technique have been published to date. Swanson and colleagues1 performed a retrospective review of the Premier multihospital database to evaluate clinical and economic outcomes of patients undergoing wedge resection or lobectomy by either VATS or RATS. They included all patients older than 8 years who underwent surgery between 2009 and 2011. Cases were identified according to International Classification of Disease, Ninth edition (ICD-9). The planned statistical analysis included comparisons of length of stay, operative time, adverse events, and hospital costs. A total of 15 502 patients who underwent a wedge resection or lobectomy were identified. Of these 14 837 were VATS and only 665 were RATS. Due to the large discrepancy between the 2 groups, a propensity scoring system was used to match RATS patients with comparable VATS patients. Propensity scoring was calculated based on a number of variables including severity of disease, age, gender, comorbidities, size of hospital, and status as a teaching hospital. The final number of patients analyzed was 295 lobectomies and 325 wedge resections per group for both VATS and RATS. The odds ratio of adverse events between VATS and RATS was not significantly different in either wedge resection or lobectomy. Also hospital length of stay was comparable between the 2 groups. Operating time for lobectomy was slightly longer for RATS than VATS, 4.49 hours versus 4.23 hours (P = .0959) and was significantly longer for wedge resection, 3.26 hours compared with 2.86 hours (P = .0003). Hospital costs were significantly higher for RATS with both operations. RATS compared with VATS cost $25 040 and $20 476, respectively, for lobectomy (P < .0001) and $19 592 and $16 600, respectively, for wedge resection (P = .0001). The authors note that these were direct hospital costs for the procedures and did not include the greater than 1 million dollar investment to purchase the daVinci robot nor the cost of the annual service contract. Strengths of the study include that the database used includes cases representing a broad geographic and demographic sampling of US hospitals and that the data are reasonably recent. The use of propensity score-matched cases removes some of the confounding from a retrospective review, but it remains inferior to a prospective randomized trial. Also the database was designed for billing purposes, which makes it difficult to obtain certain clinical data. The authors also acknowledge the learning curve involved with implementing robotic technology noting that the cost and operative time data may equilibrate as surgeons become more efficient with the technology.1
Endobronchial UltrasonographyTransbronchial Needle Aspiration Adequate mediastinal nodal staging for NSCLC reduces the number of nontherapeutic pulmonary resections and is important for accurate prognoses and treatment plans. Alternatives to the highly invasive mediastinoscopy technique have been under study for the past several years. These include positron emission tomography-computed tomography (PET-CT), endoscopic ultrasonography-fine needle aspiration (EUS), and endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS). EBUS has been shown to have comparable diagnostic results to mediastinoscopy in some studies; however, the feasibility, accuracy, and safety of this technique have not been evaluated in the veteran population. Cornwell and colleagues2 performed a retrospective review of prospectively collected data from single-center Veterans Affairs Medical Center (VA) of patients undergoing lobectomy from 2009 to 2012. All patients underwent PET-CT, and those with concerning results went for EBUS staging. The primary outcome measures were feasibility, safety, accuracy, and negative predictive value of EBUS. The pathology results from surgical hilar and mediastinal resections were used at the gold standard. The authors identified 166 patients who underwent pulmonary lobectomy for NSCLC during this time period. Patients with sublobar resections were excluded. Of these 104 patients had PET-CT only and 62 went on for EBUS staging. The accuracy of EBUS staging was 93.5% with a negative predictive value of 92.6%. EBUS failed to adequately stage 8 patients in total; however, 4 of these patients had diseased lymph nodes in areas inaccessible to EBUS. The PET-CT only group demonstrated an accuracy of 74% and a negative predictive value of 74%. The negative predictive value of EBUS (92.6%) was significantly better than PET-CT only (74%) (P = .004). The nontherapeutic resection rate was lower for the EBUS group (8.1%) than the PET-CT only group (12.5%), but this result was not significant (P = .37). There were no significant complications related to EBUS staging procedures. This was the first study evaluating feasibility and effectiveness of EBUS in the veteran population. While the results from this study were comparable to other studies, these data demonstrate that this evolving technique can be applied in a VA setting. Most of the previous reports have come from highly specialized, tertiary care centers. The authors also point out the importance of accurate staging with EBUS, which prevents patients from undergoing nontherapeutic, invasive pulmonary resections, which is especially important in the high-risk veteran population.2
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
26
Seminars in Cardiothoracic and Vascular Anesthesia 18(1)
Segmentectomy Versus Wedge Lobectomy remains the standard of care for patients with NSCLC in those who can physiologically tolerate the procedure. In patients who are not lobectomy candidates, the optimal surgical management with wedge resection versus segmentectomy is still debated. While some studies have compared pathologic margins, this report by Smith and colleagues3 evaluated survival benefits between the 2 procedures. Unfortunately, there have been no randomized trials to date to evaluate survival outcomes between these 2 groups. In this study, the authors use a national database and propensity score matched cohorts to study a sampling of patients from across the country and analyze wellmatched patients. The authors queried the Surveillance, Epidemiology and End Results (SEER) database for patients who underwent either wedge resection or segmentectomy for NSCLC with tumors ≤3 cm between 1998 and 2006. They identified a total of 3525 patients with 704 (20%) receiving segmentectomy and the remaining undergoing wedge resection. Propensity scores were calculated based on age, sex, race, marital status, and tumor characteristics. The baseline characteristics revealed significantly larger tumor size and more lymph nodes sampled in the segmentectomy cohort. For all posed questions, the authors evaluated overall survival as well as lung cancer–specific survival. They also ran each analysis using a Cox regression model, which adjusted for propensity score and number of lymph nodes sampled, as well as a matched analysis based on propensity score. The findings of this study demonstrated improved survival for segmentectomy over wedged resection in almost every category analyzed. Included below are the data based on the adjusted Cox regression model as the propensity matched analyses showed similar results. In the primary analysis, segmentectomy demonstrated significant improvement in both overall survival (hazard ratio [HR] = 0.81; 95% confidence interval [CI] = 0.69-0.96) and lung cancer– specific survival (HR = 0.76; 95% CI = 0.61-0.94). As secondary analyses, the authors evaluated survival between the 2 surgical techniques based on TIa tumors and age less than or greater than 70. In patients with tumors less than 2 cm segmentectomy continued to show improved overall survival (HR = 0.84; 95% CI = 0.68-0.99) and lung cancer–specific survival (HR = 0.82; 95% CI = 0.62-1.00). Concerning patients less than 70 years old, there was also an overall survival benefit (HR = 0.74; 95% CI = 0.560.96) and a lung cancer–specific survival benefit (HR = 0.79; 95% CI = 0.57-1.00). In patients older than 70 years, the overall survival benefit was not significant (HR = 0.85; 95% CI = 0.69-1.05); however, lung cancer–specific survival remained significant (HR = 0.73; 95% CI = 0.53-0.97).
This study provides evidence in support of segmentectomy over wedge resection in patients who are unfit for lobar resection. While the authors demonstrate an improved study design by using propensity scoring of retrospective data, they admit that there remains a need for a randomized study to more fully answer the question.3
Targeted Therapy for NSCLC Chemotherapeutic agents for NSCLC have been drastically improving over recent years. Standard platinum-based chemotherapy are no longer the only treatment option. Ongoing research has identified many mutational subtypes of NSCLC that serve as potential therapeutic targets. Epidermal growth factor receptor (EGFR) is one such mutation in which protein kinase inhibitors have been developed to target this mutation. Erlotinib and afatinib are 2 protein kinase inhibitors currently approved for the treatment of NSCLC with susceptible EGFR mutations. Unfortunately, not all tumors with the EGFR mutation respond to the drugs, and those that do frequently acquire resistance within 1 year. There are a number of agents currently undergoing phase I/II trials that are directed at other potential therapeutic targets. These mutational variants include HER2, BRAF, RET, MEK1/2, PI3K, MET, FGFR, and VEGF.4 Recently, a new drug, crizotinib, targeting anaplastic lymphoma kinase (ALK), has been approved. The results of a phase III trial comparing crizotinib to chemotherapy with patients with metastatic or locally advanced NSCLC containing the ALK mutation were published in June 2013 issue of the New England Journal of Medicine. Crizotinib is administered orally and targets mutations in ALK, MET, and ROS1 tyrosine kinases. Earlier phase trials had demonstrated a 60% response rate in ALK-positive tumors and progression-free survival of 8.1 to 9.7 months while traditional single-agent chemotherapies generally yield 10% response with 2- to 3-month progression-free survival. This randomized, controlled, open label, phase III trial compared crizotinib with standard chemotherapy. Eligibility criteria included patients at least 18 years old with locally advanced or metastatic NSCLC positive for ALK mutation with progressive disease after 1 round of prior platinumbased chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive oral crizotinib or intravenous therapy of either pemetrexed or docetaxel. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status and whether or not prior EGFR kinase inhibitor therapy had been administered. The primary end point was radiographic evidence of disease progression or death. Secondary end points included overall survival, rate of partial and complete responses, safety, and patient-reported outcomes. Treatment was continued until disease progression was documented based on Response Evaluation Criteria in Solid Tumors (RECIST) standards.
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
27
Bennett and Weyant The study randomized a total of 347 patients with 173 to crizotinib and 174 to chemotherapy. In the chemotherapy group, 99 received pemetrexed and 72 received docetaxel. The results of the primary end point demonstrated an improvement in median progression-free survival with crizotinib over both chemotherapies with a hazard ratio for death or progression of disease in crizotinib of 0.49 (95% CI = 0.37-0.64; P < .001). Also, crizotinib was superior to each drug individually with a hazard ratio of 0.59 (95% CI = 0.43-0.80; P < .001) compared with pemetrexed and 0.30 (95% CI = 0.21-0.43; P < .001) compared with docetaxel. The response rate to crizotinib (66%) was significantly higher than both pemetrexed (29%) and docetaxel (9%) (P < .001). The median overall survival was 20.3 months with crizotinib and 22.8 months with chemotherapy, resulting in a nonsignificant hazard ratio for death with crizotinib of 1.02 (95% CI = 0.68-1.54; P = .54). Adverse events that were at least 5% higher for chemotherapy compared with crizotinib were fatigue, alopecia, dyspnea, and rash. Adverse events that were at least 5% higher with crizotinib compared with chemotherapy were vision disorder, nausea, vomiting, diarrhea, constipation, edema, dizziness, upper respiratory infection, and elevated liver aminotransferase levels. Of note, 2% of patients receiving chemotherapy experienced grade 3 or 4 elevated aminotransferase levels compared with 16% of patients receiving crizotinib, with 1 patient dying of liver failure. Based on patient survey data, patients with crizotinib demonstrated a significantly improved global quality of life as well as significant improvement in median time to deterioration regarding cough, dyspnea, or chest pain. The authors conclude that in patients with ALK-positive NSCLC crizotinib therapy increased tumor response rates, prolonged progression-free survival, and improved quality of life when compared with standard chemotherapy. They note that the higher rate of adverse events in the crizotinib group was likely in part due to the longer median treatment duration with crizotinib compared with chemotherapy (31 weeks vs 12 weeks). Also, patients who crossed over from standard chemotherapy to crizotinib after demonstrating progressive disease introduced confounding into the overall survival analysis. This study was supported by the maker of crizotinib, Pfizer.5
Surveillance After Trimodality Treatment of Esophageal Cancer Esophageal cancer is a devastating disease with an almost equivalent annual incidence and death rate of around 16 000 people per year. In the United States, adenocarcinoma is the most common type. Patients with locoregional disease are frequently treated with trimodality therapy consisting of chemoradiation followed by esophagectomy. Surveillance
is frequently continued afterwards; however, the protocols are not standardized and guidelines are mostly based on expert opinion. The goal of surveillance is to identify patients with locoregional recurrence without metastatic disease who may benefit from salvage chemoradiation or surgery. The effectiveness of this management has only been evaluated by a limited number of single-center, retrospective reviews. Sudo and colleagues6 at the MD Anderson Cancer Center performed a retrospective review of prospectively collected data of 518 patients. All patients had undergone trimodality therapy and been followed with the standardized, conservative surveillance program at that institution. The authors’ primary goal was to assess outcomes for those patients who received salvage therapy after recurrence as well as type and timing of recurrences. This was the largest cohort of patients published on the subject to date. Patients analyzed in this data set had been diagnosed with localized esophageal adenocarcinoma and treated with trimodality therapy consisting of radiotherapy and chemotherapy with a fluoropyrimidine and either a platinum or taxane compound followed by esophagectomy. The surveillance protocol was a PET-CT and blood tests every 3 months for a year, then 6 months for 2 years, followed by yearly for at least 5 years. Also endoscopy was performed every 6 months for 18 months followed by yearly. For the 518 patients, the overall median follow-up time was 29 months and 55 months for those still alive. Of the 518 patients, 215 relapsed with 188 having distant, metastatic disease and 27 with locoregional disease only. Eleven of these patients had recurrence only in the esophageal lumen of which 8 were diagnosed by PET-CT. Sixtythree percent of locoregional recurrences (17 patients) occurred within 2 years and 89% (24 patients) occurred within 3 years. These 27 patients were 5% of the total 518 patients undergoing surveillance who could have potentially benefited from salvage therapy. Of these 27 patients, 12 were eligible for chemoradiation salvage therapy, 4 received surgical reoperation, and 11 were treated palliatively. Of the 12 patients treated with chemoradiation, 5 survived more than 2 years. Of the 4 treated with surgical resection, 3 survived more than 2 years. All patients treated surgically had significant perioperative morbidity, and all developed distant metastases. The median overall survival of the 27 patients with locoregional disease was 17 months. The median survival of those treated palliatively was 5 months. The authors provide a nice discussion on the utility of surveillance after trimodality therapy for esophageal adenocarcinoma. Per the institution’s protocol described above, the patients would have undergone numerous
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
28
Seminars in Cardiothoracic and Vascular Anesthesia 18(1)
PET-CT scans and endoscopies, which are both costly and uncomfortable. This surveillance went out to at least 5 years, but they noted that 89% of recurrences were identified within 3 years. They suggest that endoscopy may only be needed when imaging findings are concerning given costs and risks associated with the procedure and that most recurrences were identified with PET-CT. Overall only 5% of the 518 patients were identified with locoregional disease. Of these 27 patients, 16 were eligible for some type of salvage therapy and only 8 survived more than 2 years (1.5% of 518 patients). With so few patients benefiting from such extensive surveillance and treatment, the authors question the utility of the aggressive management. However, they recognize that there are few studies available to develop evidence-based surveillance guidelines.6
esophagectomy. The perioperative results of this study are comparable to others, albeit they are all small, single-center case series. This is a very exciting new field of thoracic surgery, which has plenty of room for advancement. It will be interesting to see data comparing it to traditional operations as this novel technique continues to become more refined and more prevalent.7
Conclusion The field of thoracic surgery continues to evolve and advance. Advancement with novel surgical techniques as well as chemotherapeutics continues to improve. The volume of quality research continues to increase and will only serve to improve the patient care provided to this population. Declaration of Conflicting Interests
Robotic Esophagectomy Robotic-assisted surgery is becoming increasingly more prevalent in many areas of surgery. This has also been true most recently in esophageal operations. Most of the current literature report feasibility and effectiveness in singlecenter early experience with the technique. Many articles report some type of hybrid approach. The report by Sarkaria and colleagues7 at Memorial Sloan-Kettering are included here as they report on a novel technique using robotic techniques for both the thoracic and abdominal portions of the procedure and demonstrate their experience with 21 consecutive patients over a 1-year period during 2011. The technical details of both the thoracic and abdominal portions of the procedure are well documented in the article but are beyond the scope of this review. Of note this is the first report of a series of patients undergoing totally robotic-assisted minimally invasive esophagectomy. Two surgeons primarily performed all procedures. The cohort of patients was mostly male and had a median age of 62 years old. The median operative time, including repositioning, was 556 minutes, which decreased to 414 minutes for the last 5 cases. Ten of the 21 required conversion to laparoscopic assist and 5 of those eventually required conversion to an open operation. However, none of the last 5 patients required conversion to open operations. Five of the patients experienced grade III or greater complications, and 1 patient died on postoperative day 70 due to respiratory failure after anastomotic leak. The median number of lymph nodes sampled was 20 (range 10-49). Seventeen patients achieved an R0 resection. Four patients obtained an R1 resection, but one of those was a radial margin of a patient who did not undergo neoadjuvant therapy. This is the first report of a series of patients undergoing completely robotic-assisted minimally invasive
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Swanson SJ, Miller DL, McKenna RJ, et al. Comparing robot-assisted thoracic surgical lobectomy with conventional video-assisted thoracic surgical lobectomy and wedge resection: results from a multihospital database (Premier) [published online November 7, 2013]. J Thorac Cardiovasc Surg. doi:10.1016/j.jtcvs.2013.09.046. 2. Cornwell LD, Bakaeen FG, Lan CKW, et al. Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy for preoperative nodal staging of lung cancer in a veteran population. JAMA Surg. 2013;148:1024-1029. 3. Smith CB, Swanson SJ, Mhango G, Wisnivesky JP. Survival after segmentectomy and wedge resection in stage I nonsmall-cell lung cancer. J Thorac Oncol. 2013;8:73-78. 4. Liu SV, Subramaniam D, Cyriac GC, Abdul-Khalek FJ, Giaccone G. Emerging protein kinase inhibitors for nonsmall cell lung cancer [published online December 20, 2013]. Expert Opin Emerg Drugs. doi:10.1517/14728214.2 014.873403. 5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394. 6. Sudo K, Taketa T, Correa AM, et al. Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies. J Clin Oncol. 2013;31:4306-4310. 7. Sarkaria IS, Rizk NP, Finley DJ, et al. Combined thoracoscopic and laparoscopic robotic-assisted minimally invasive esophagectomy using a four-arm platform: experience, technique and cautions during early procedure development. Eur J Cardiothorac Surg. 2013;43:e107-e115.
Downloaded from scv.sagepub.com at University of Alabama at Birmingham on May 11, 2014
