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a University of Pittsburgh, Pittsburgh, Pennsylvania
b St. Catharines General Hospital, St. Catharines, Ontario, Canada
c Ottawa Hospital–General Campus, Ottawa, Ontario, Canada
Accepted for publication June 10, 2009.
* Address correspondence to Dr Landreneau, Shadyside Medical Bldg, 5200 Centre Ave, Suite 715, Pittsburgh, PA 15232 (Email: landreneaurj{at}upmc.edu).
Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.
| Dr d'Amato discloses that he has a financial relationship with Oncotech Inc; Dr Ferson with Axcan Pharma Inc; Dr Luketich with Oncotech Inc and Axcan Pharma Inc.
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Abstract |
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Methods: A review of 315 nonsmall-cell lung cancer patients (196 male [62%]) undergoing pneumonectomy over a 15-year period was undertaken. Patients were well matched for clinical variables other than receiving induction chemotherapy. Complications and operative mortality were analyzed for associations with laterality and induction chemotherapy.
Results: Median age was 64 years, (range, 25 to 82). Age was predictive of mortality in 13 of 86 patients (15%) more than 70 years old, compared with 16 of 229 patients (7%) less than 70 years old (hazard ratio = 1.77, p = 0.046). Overall operative mortality was 9.2% (29 of 315). There were 115 left-sided (37%) and 200 right-sided (63%) pneumonectomies. Sixty-eight patients (22% [left = 31, right = 37]) received induction chemotherapy. Surgery alone was performed in 247 patients. Mortality among patients undergoing induction chemotherapy was 21% (odds ratio = 4.01; p = 0.0007). After induction chemotherapy, postoperative bronchopleural fistula associated with respiratory failure was predictive of operative mortality (hazard ratio = 148, p = 0.0001). Left-side pneumonectomy did appear to a have a greater incidence of postoperative arrhythmia.
Conclusions: Morbidity and mortality after pneumonectomy is substantial. Patients greater than 70 years old appear to be at increased risk. Induction chemotherapy also increases the risk of operative mortality after pneumonectomy. Patients should be advised of this increased operative risk, and the multidisciplinary team must consider this when pneumonectomy appears necessary after induction therapy for locally advanced nonsmall-cell lung cancer.
Pneumonectomy has been associated with increased operative risk in the setting of multimodality (neoadjuvant/adjuvant) therapy [1–4]. In the most recently reported prospective randomized trial (Southwest Oncology Group [SWOG] 9900), a 17% mortality rate was noted in patients undergoing pneumonectomy after platinum-based induction chemotherapy [5–7]. Such observations have led some authors to question the safety and efficacy of pneumonectomy in the setting of locoregionally advanced nonsmall-cell lung cancer (NSCLC). Although long-term survival is likely better in many patients with NSCLC who undergo induction chemotherapy followed by surgery [8, 9], the requirement for pneumonectomy heightens the risk of early morbidity and mortality in these patients [4]. Right-sided resections have also been demonstrated to carry a higher morbidity and mortality than left pneumonectomy does, serving to further exaggerate the surgical risk in the setting of neoadjuvant chemotherapy [10, 11].
Prospective studies published to date include only a minority of patients undergoing pneumonectomy, from which an increased perioperative risk has been extrapolated. In the current study, the combined experience from two institutions regarding early mortality with pneumonectomy after neoadjuvant chemotherapy for locally advanced disease is reported. Variables associated with increased perioperative risk are identified, with particular attention to the impact of induction therapy on outcomes after pneumonectomy.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionReferences |
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Data fields abstracted included age, sex, date of surgery, laterality, neoadjuvant therapy, agents administered, use of radiation therapy and pulmonary function studies including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusion capacity of the lung for carbon monoxide (DLCO). Pulmonary function data were compared as percent predicted values in the comparative analyses.
Pneumonectomy was performed on all patients after obtaining informed consent. Specific operative details were performed according to the individual surgeon's preference. General anesthesia with narcotic supplementation and epidural analgesia, when available, were used as standard therapy. Single-lung ventilation was routinely performed through either a double-lumen endotracheal tube or an endobronchial blocker, or by contralateral main-stem bronchus intubation. Fiberoptic bronchoscopy was routinely performed to evaluate resectability and to confirm endotracheal tube placement. Open thoracotomy was performed in all cases utilizing posterolateral, anterior (extended Chamberlain), or muscle-sparing vertical axillary incisions. Bronchial and vascular structures were routinely ligated and divided with the aid of mechanical staplers. After pneumonectomy, bronchial stump reinforcement was performed according to surgeon preference utilizing an intercostal muscle flap, azygous vein, pericardial fat pad, or autologous pericardium. No data elements regarding the frequency or type bronchial closure or reenforcement were collected in this review.
Outcome measures for early morbidity and mortality included the following: operative mortality defined as death from any cause within 30 days of surgery, including hospital death; atrial arrhythmias requiring pharmacologic rate control or DC cardioversion; myocardial infarction, defined as new electrocardiographic changes, elevation of creatine kinase-MB fractions, or wall motion abnormalities on transthoracic echocardiogram; and other cardiac complications documented in the patient's medical record. Bronchopleural fistula was defined as bronchial stump disruption with associated air leak diagnosed at the time of bronchoscopy or surgery that requireed specific intervention (chest tube, operation, or other procedure). Empyema was defined by aspiration of purulent or infected fluid from the pneumonectomy space. Pneumonia was defined as new pulmonary infiltrates associated with leukocytosis or culture-positive sputum. Respiratory failure was identified and defined by either documentation of reintubation, placement of tracheostomy, or more than 4 ventilator days after pneumonectomy.
Complications were analyzed for associations with laterality and neoadjuvant chemotherapy. Categorical variables were analyzed by Fisher's exact test; and the continuous variables age, FEV1, FVC, and DLCO were analyzed by two-sided t test. As 33 of 68 patients undergoing induction therapy received both chemotherapy and radiation, the Wilcoxon Mann-Whitney U test was used to reject the null hypothesis that complications were associated with chemoradiotherapy or chemotherapy alone. In a preliminary analysis, no significant differences were identified between these groups; therefore, patients receiving either chemotherapy or chemoradiotherapy were combined and compared with pneumonectomy patients having surgery alone for all subsequent calculations. Statistical analyses were performed using GraphPad InStat version 3.0a for Macintosh (GraphPad Software, San Diego, CA).
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Results |
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The occurrence of respiratory failure itself was highly predictive of operative mortality (hazard ratio = 148, p = 0.0001) for the entire cohort, irrespective of laterality or neoadjuvant chemotherapy. Reintubation for respiratory failure was required in 12 of 315 patients (3.8%), representing 3 of 155 left pneumonectomy patients (1.9%), none of whom received induction therapy, versus 9 of 200 right pneumonectomy patients (4.5%), with 2 of 37 (5.4%) in the neoadjuvant therapy group. Tracheostomy was required in 3 of 315 pneumonectomy patients: 2 right (1 with induction) and 1 left (without induction therapy). The incidence of operative mortality associated with either BPF/empyema or pneumonia by univariate analysis was not significantly different.
There was no significant age difference between induction therapy and surgery groups. Nevertheless, for the overall patient cohort, age itself was also moderately predictive of early death. Age was predictive of operative mortality in 13 of 86 (15%) patients aged more than 70 years compared with 16 of 229 patients (7%) less than 70 years old (hazard ratio = 1.77, p = 0.046).
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Comment |
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The current posture toward the risk of pneumonectomy in the setting of neoadjuvant therapy has been significantly influenced by the findings of two recent (as yet unpublished) prospective, randomized trials. In the North American Intergroup trial 0139, Albain and associates [2] demonstrated no significant survival benefit for patients undergoing surgical resection after neoadjuvant chemotherapy compared with definitive chemoradiation alone (approximate 5-year survival: 27% versus 20%, respectively; p = 0.24) for stage IIIA NSCLC. Although neoadjuvant therapy followed by lobectomy was associated with improved survival compared with chemoradiation alone (36% versus 18%; p = 0.002), a similar improvement in survival was not seen in the case of pneumonectomy (22% versus 24%; p = nonsignificant). This difference was thought to be due predominantly to the significantly higher mortality seen in the pneumonectomy cohort (14 of 54; 25.9%). The preliminary results of the SWOG S9900 trial presented at the same meeting similarly demonstrated a high mortality rate (4 of 24; 16.7%) among patients undergoing pneumonectomy after induction therapy [6]. These studies have generated much concern and skepticism internationally regarding the utility of pneumonectomy after neoadjuvant therapy. Drawing definitive conclusions from these subset analyses, however, may be premature.
In contrast, Mansour and colleagues [15] reported results from 298 patients over a 6-year period that showed a 30-day mortality of only 6.7% for patients after induction therapy versus 5.5% for patients after surgery alone. No differences were noted in the incidence of empyema, bronchopleural fistula, or adult respiratory distress syndrome, suggesting that induction chemotherapy did not adversely affect outcome after pneumonectomy. In another series of 118 patients undergoing pneumonectomy after induction therapy, Alifano and associates [16] reported a mortality rate of 5.9% (7 of 118). Gudbjartsson and associates [17] presented a series of 35 patients undergoing pneumonectomy after neoadjuvant chemoradiation without operative mortality. The results of the present study, comprising a comparatively large cohort of patients undergoing pneumonectomy after induction therapy, contrast with the findings of the above European studies and lend further support to the unpublished findings of the Intergroup 0139 and SWOG S9900 trials. These conflicting results underscore the need for dedicated prospective, randomized data to better delineate the risks and benefits of pneumonectomy after neoadjuvant therapy.
Sonett and colleagues [18] examined a series of 40 patients including 11 pneumonectomies (7 right, 4 left), illustrating a high pathologic response rate with high-dose (more than 59 Gy) radiotherapy and concurrent chemotherapy, and reported no postoperative deaths. These results were in contrast to results [19] that showed an increase in complication rate occurring in patients receiving radiotherapy with more than 45 Gy. Our series noted no differences in chemotherapy and chemoradiotherapy with regard to complications; however, induction therapy of any kind was associated with high mortality (21%).
In one of the first studies examining the effect of induction therapy that included only 7 pneumonectomies, an unacceptable morbidity and mortality was documented—including 3 deaths [20]. In another case-controlled study of 42 pneumonectomy patients after induction therapy, there was no apparent difference in mortality with regard to the extent of surgical resection [21]. A large retrospective multi-institutional French study reported results of 3,888 surgeries from 51 thoracic surgery centers [22]. Age, high clinical risk score, and performance of right pneumonectomy were associated with early death. It was noted that preoperative chemotherapy did not increase either mortality or major complication rates. In our report from two North American centers, the data illustrate that although overall complication rates are similar, operative mortality for pneumonectomy is increased in the setting of induction therapy. The mortality rate of patients undergoing pneumonectomy without induction therapy was 6.1%, which compares favorably with accepted modern-day mortality rates for pneumonectomy. The overall rate of 9.2% in this series appears to be driven by the unexpectedly high rate of mortality noted for patients receiving induction therapy (21%).
Several reports illustrate a higher postoperative mortality with right pneumonectomy after induction therapy [1, 2, 10, 11]. In a series of 97 patients, Martin and associates [10] reported a 23.9% mortality after right pneumonectomy. Morbidity and mortality were also highly associated with increased blood loss and low preoperative FEV1. In a single-institution study, Darling and coworkers [11] reported a series of 187 patients comparing right versus left pneumonectomy with and without induction therapy. The risk of death was higher with right pneumonectomy and was associated with an increase incidence of BPF. A meta-analysis demonstrated increased risk of morbidity and mortality with right-sided resections irrespective of the use of induction therapy [11]. In a multi-institutional phase III study of induction therapy that included 54 pneumonectomy patients, Albain and coworkers [1, 2] reported a 25.9% mortality after pneumonectomy after induction therapy and a 37.9% mortality after right-sided resections. The incidence of bronchopleural fistulas was not reported.
In contradistinction, Alexiou and colleagues [23] reported a series of 206 pneumonectomy patients, and documented an operative mortality of only 6.8%. Age and the development of BPF were found to be independent predictors of mortality. In patients with right pneumonectomy, irrespective of induction therapy, morbidity appeared to be higher among patients who have BPF.
Our findings are also consistent a United Kingdom series of 206 pneumonectomy patients, wherein the overall operative mortality was 6.8%, yet the development of BPF and advanced age were independent predictors of mortality [23].
Increasing age appears to be associated with an increased risk of pulmonary complications in the setting of pneumonectomy. Leo and colleagues [24] reported an overall mortality rate of 5% for 202 consecutive pneumonectomies for lung cancer. Univariate analysis revealed that pulmonary complications were higher among patients aged more than 70 years, among patients with a low diffusion capacity, and among elderly patients after induction therapy. Factors associated with age-related diseases were identified as significant risk factors by Dyszkiewicz and associates [25] in a case-controlled report of 42 patients more than 70 years old having undergone pneumonectomy compared with 48 patients with lesser resections. The highest mortality rate was noted for pneumonectomy patients with chronic obstructive pulmonary disease, hypertension, need for reexploration, and high blood-urea nitrogen. These data are consistent with our findings that age greater than 70 years appears to be an independent predictor of early mortality.
Limitations of our study include that it is a retrospective review of patient outcomes over more than a decade, and unrealized differences related to the pulmonary toxicity of various preoperative induction therapy regimens may have contributed to respiratory embarrassment and the high rate of early mortality. There was some improvement in early mortality over time, suggesting that increasing surgical experience, better patient selection, or improvements in the delivery of the induction regimens themselves may have an impact on perioperative morbidity and mortality. Another limitation of the current study is that we do not have complete information on all patients undergoing induction therapy on an intent-to-treat basis; this study includes only those patients deemed fit for surgery. We do not know how many patients received "induction therapy" but ultimately progressed, showed no acceptable response, or deteriorated physiologically to a point where surgery could not be performed. The results of the current analysis must be interpreted with this in mind. Irrespective of these limitations, this study does represent a large cohort of patients with locally advanced lung cancer and may contribute to our understanding of potential, and perhaps preventable, morbidity in pneumonectomy patients after induction therapy.
In conclusion, an increased risk of early mortality is noted with pneumonectomy performed in the setting of induction therapy. Patients more than 70 years old appear to be at increased risk. Mortality did not appear to be associated with operative laterality in this cohort of patients. Mortality is most often related to respiratory complications and advanced age. Therefore, we believe that outside the setting of a clinical trial, patients with locally advanced NSCLC should be evaluated by a multidisciplinary team that includes the thoracic surgeon and that caution should be exercised when considering pneumonectomy. Patient selection based on age, laterality, and comorbidities should be carefully considered. When feasible, parenchymal-sparing procedures (e.g., sleeve resection) should also be utilized, and routine bronchial stump reinforcement may help to reduce the incidence of BPF. In the event that pneumonectomy is performed, best clinical practices including judicious perioperative fluid administration, avoidance of barotrauma during single-lung ventilation, aggressive postoperative pulmonary hygiene, head-of-bed elevation, and avoidance of aspiration are prudent measures that may reduce respiratory complications in otherwise suitable patients. Although pneumonectomy may be suitable for carefully selected patients, a well-controlled, protocol-driven clinical trial appears warranted to firmly establish the role of pneumonectomy in the treatment of locally advanced lung cancer after induction therapy.
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Discussion |
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I have to admit that I'm troubled. There are excellent data that were presented at this meeting several years ago from Montreal, from Poland, from my partner, and from Dr Gamliel, documenting risk of postinduction pneumonectomy, with mortalities below 6%. There are obviously also data in the literature, especially from their most recent randomized trial with chemotherapy and radiation, of a high risk of pneumonectomy, as high as 25% in that study. However, there are several single-institution studies, and yours is a compilation of single-institution studies, particularly from Alabama, BU, and Maryland, with combined mortalities after chemotherapy and radiation with pneumonectomy that were way under 10% and that didn't show the difference in mortality between the right and the left side. Obviously, this is a retrospective review. It was multi-institutional and it's done in excellent institutions. How do you account for the difference, especially since only a minority of the patients received chemotherapy alone and not chemotherapy and radiation? It seems surprising that the mortality is that high, and I wonder if you could explain it. If you look at your overall mortality of 9% during that period, how would you explain the difference there from the recent papers from France, Montreal, and Poland?
DR D'AMATO: Those are excellent comments and perhaps many of them difficult for me to completely answer for you.
The study period for this report is over 15 years. Some data that I did not show were an improvement in survival rate over time, which may be related to improved intensive care unit care and improved patient management. There are likely surgical factors, which may include whether or not bronchial stump coverage, et cetera, was performed routinely on patients. Chemotherapeutic agents, as we reported, did vary. We only had information on 52 of the 68 who did receive chemotherapy, and the exact numbers of regimens, doses, or cycles were not always listed and available for review. For statistical analysis, no data were available on how well they had tolerated neoadjuvant therapy. So I think to answer the question as to the relatively high overall mortality of 9% or so, I think that relates to the surgical factors, plus critical care factors. The mortality of 6% in the surgery-only arm is probably quite in line with many centers in North America, which is somewhere between 5% and 7%.
The perils of a retrospective review over this long period may limit its usefulness in some way, but I think it adds important information that may lend itself for a repeat meta-analysis and support the need for prospective studies.
DR DAVID A. WALLER (Leicester, UK): Could you comment on your operative strategy? Is it true that you were operating to remove the disease that was there before induction chemotherapy and is that why you have such a high pneumonectomy rate? And could you comment on the alternative strategy, which is what I think we use in most European centers, to achieve microscopically-negative resection margins with the use of intraoperative frozen section, and therefore have a lower rate of pneumonectomy after induction therapy and possibly a higher use of bronchoplastic surgery.
DR D'AMATO: We did not evaluate that in a retrospective review. This was all based on surgeon preference. The multiple authors are the surgeons who contributed to the series and they all had their own preference.
DR WALLER: Could you comment on your current strategy? Is your current strategy to remove the disease that was there before induction therapy or to evaluate the situation de novo after induction therapy and maybe limit the size of resection just to obtain microscopically-clear resection margins? What's your current strategy?
DR D'AMATO: My current personal strategy is to remove all disease that is found, and I do send frozen sections at the time of surgery. If a bronchoplasty can be performed, I'll perform it.
DR ARA A. VAPORCIYAN (Houston, TX): I enjoyed the presentation, and having tried to tackle the problem with pneumonectomies and morbidity, it's a difficult question to answer.
One question I have, though, for you is your statistical analysis. Was a multivariable analysis entertained for trying to tease apart some of the issues that you discovered, like the differences in your mortality with the chemotherapy group?
DR D'AMATO: We did not. As I mentioned, only 52 of the 68 had chemotherapy data available. We didn't have any good information on toxicities as these related to specific agents. Also, the interval between chemotherapy and surgery was not always reported.
DR DAVID H. HARPOLE (Durham, NC): This is a very nice attempt at connecting data points so we can learn more about this difficult group of patients.
I just want to make a comment. We originally felt that the risk of mortality from pneumonectomies after induction therapy, as is the same with bronchoplastic procedures, is going to be due to bronchial dehiscences. Therefore, when we do these, most of us do some sort of bronchial vascularized pedicle coverage. In fact, that's not what the mortality is due to. Most of the large series have shown that the mortality is actually due to some sort of adult respiratory distress syndrome (ARDS) picture. Doctor Jean Deslauriers taught us to use balanced suction so that we got rid of the hydrostatic issues in the contralateral lung, and that seems to have reduced the ARDS. But in our hands at Duke, and I know at other centers, it's frankly chemotherapy-dependent. We have seen a lot more of the ARDS after taxanes than we have versus Navelbine and so forth. So one of the issues here is when you have lots of different chemotherapeutics in your patient population, it's a very heterogeneous group. And I don't have a good answer on what we do about treating this lung toxicity in the contralateral lung when we're forcing a lot more blood flow through there when you've done your pneumonectomy, except to say that we try to keep the FiO2 down as low as we can in the operating room when we're doing the operation. Do you have any pearls of wisdom to elucidate on factors that you all have tried to decrease your mortality from this devastating day 2, day 3 ARDS, where they go from room air to 100% and death in about 36 hours?
DR D'AMATO: I think that some of the available literature would suggest that judicial use of perioperative fluids, early diuresis, low as possible FiO2s, balanced suction for the first day, I think these maneuvers may be helpful. I get concerned about the airway pressure imparted by the anesthesia circuit in the operating room on the contralateral lung during single-lung ventilation. I think the jury is still out on what impact any one of these factors has on surgical outcome; however, respiratory complications with bronchopleural fistula and respiratory failure were the highest predictor of things that we may perhaps modify in addition to ongoing efforts to prevent pneumonia or iatrogenic lung injury.
DR TIMOTHY M. ANDERSON (Boston, MA): The discussion thus far seems focused on looking at perioperative and postoperative care. I would argue that preoperative evaluation could be even more important. Have you looked specifically at pulmonary exercise testing, determining how the cardiorespiratory tree works under stress conditions? Have you practiced obtaining preoperative echocardiograms looking for elevated pulmonary artery pressures, which would be a fairly accurate predictor of mortality?
DR D'AMATO: We currently do that in all of our patients. Much of this series would have had too few numbers to analyze. These are all very valid points, and looking at resting pulmonary artery pressures to identify those patients with pulmonary hypertension preoperatively is important and may help to avoid unnecessary postoperative morbidity.
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