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Ann Thorac Surg 2006;82:227-231
© 2006 The Society of Thoracic Surgeons

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Original article: General thoracic

Pneumonectomy After High-Dose Radiation and Concurrent Chemotherapy for Nonsmall Cell Lung Cancer

^a Department of Cardiothoracic Surgery, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
^b Department of Radiation Oncology, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
^c Department of Radiation Oncology, Brown University, Providence, Rhode Island

Accepted for publication February 27, 2006.

^_* Address correspondence to Dr Daly, Boston Medical Center, Robinson B-402, 88 E Concord St, Boston, MA 02118 (Email: benedict.daly{at}bmc.org).

Presented at the Poster Session of the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: Pneumonectomy after high-dose radiotherapy and concurrent chemotherapy has been associated with high operative mortality. Therefore, most induction protocols limit radiation to 5,000 cGy or less. Additionally, the safety of right pneumonectomy after induction therapy has been questioned. The feasibility of pneumonectomy after high-dose radiotherapy and concurrent chemotherapy is reviewed.

METHODS: From 1990 to 2005, 30 patients with locally advanced nonsmall-cell lung cancer underwent pneumonectomy after 5,940 cGy of radiation and two cycles of etoposide and cisplatin. To minimize postpneumonectomy pulmonary edema, patients were treated with a protocol that included fluid restriction and 48 hours of mechanical ventilation. Morbidity, mortality, and survival were examined.

RESULTS: There were 18 right and 12 left pneumonectomies. Death occurred in 4 patients (13.3%) but in only 1 (5.6%) after right pneumonectomy. Causes of death included aspiration, bronchopleural fistula, pneumonia, and massive pulmonary embolus. Major morbidity occurred in 5 (pnemonia in 2 and aspiration in 3). Median hospital stay was 9 days (range, 2 to 45), and intensive care unit stay was 2 days (range, 2 to 35). Median overall survival was 22 months with a 5-year survival of 33%. Patients surviving operation had a median survival of 33 months and a 5-year survival of 38%.

CONCLUSIONS: The mortality rate after pneumonectomy after high-dose radiation and concurrent chemotherapy is relatively high but results in significant survival. The mortality rate is not increased after right-sided operations. Pneumonectomy should continue to be offered to patients with advanced locoregional disease after induction high-dose radiotherapy and concurrent chemotherapy when a complete resection cannot be carried out with a lesser procedure.

	Introduction

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For patients with locally advanced lung cancer, improved operability and resectability has been observed after induction protocols utilizing concurrent chemoradiotherapy [1–4]. Most induction protocols, however, limit the radiation dose to 5,000 cGy or less because of the technical difficulty and operative mortality associated with higher doses. That has been particularly true when pneumonectomy has been carried out [5, 6]. In fact, the safety of pneumonectomy, especially right pneumonectomy, after induction therapy has been questioned [7, 8]. On the other hand, tumor and nodal downstaging has been associated with improved survival, suggesting that in patients with locally advanced nonsmall-cell lung cancer, local control imparts a survival advantage [1, 9]. The role of surgical intervention after radiation and chemotherapy is open to question, with comparable results achieved in a randomized trial of concurrent high-dose radiotherapy (HDRT) of 6,100 cGy and chemotherapy versus concurrent chemoradiotherapy (4,500 cGy) followed by surgery [10]. Whether high-dose radiation and concurrent chemotherapy followed by surgery will result in even better local control and hence survival is not known, and whether pneumonectomy can be safely carried out in this setting remains to be determined.

In 1997, we reported our initial results utilizing an induction protocol employing HDRT (5,940 cGy) with concurrent platinum-based chemotherapy [11]. In this series, 42 patients were treated and 33 were resected. Nine patients underwent pneumonectomy, and there were no operative deaths. The University of Maryland in their initial report in 1999 reported similar results [12]. In 2004, they reported their experience in 40 patients undergoing resection after high-dose radiation and concurrent chemotherapy [13]. There were 40 patients in that series, with 11 pneumonectomies and no deaths. These results suggest that this aggressive approach may be feasible. This report updates our experience in 30 patients requiring pneumonectomy for locally advanced disease after HDRT and concurrent chemotherapy, summarizes the literature to date, and offers strategies to improve results.

	Patients and Methods

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In 1987, we began utilizing induction HDRT with concurrent chemotherapy for locally advanced potentially operable nonsmall-cell lung cancer as our standard of care. At the time we initiated this practice, T3N0 tumors were considered stage IIIA. Because of our favorable results in this group of patients, we continued the practice of including them in this aggressive protocol. Patients with stage IIIB tumors were considered if they were thought to be potentially resectable if tumor regression occurred. Patients with tumor involvement of the carina were excluded. Between 1987 and January of 2005, 143 patients were entered into this protocol. Sixteen of these patients had solitary cerebral metastases and were excluded from further analysis.

Tumor staging consisted of a computed tomography (CT) scan of the chest, bone scan, and either a contrast-enhanced CT or magnetic resonance imaging of the brain. Invasive lymph node staging of the mediastinum was carried out when possible in all patients with enlarged hilar or mediastinal lymph nodes on chest CT scan and in patients with central tumors. Lymph nodes were considered enlarged if they were 1 cm or greater in short axis, 1.5 cm in long axis, or if the tumor obliterated a mediastinal nodal compartment. Twenty-six of the 30 patients in this series underwent mediastinoscopy. Four patients did not undergo invasive staging. All 4 had left-sided T3 or T4 tumors involving the aorticopulmonary window. Three were central. The one peripheral tumor had massive lymph node involvement involving the takeoff of the left main pulmonary artery, confirmed at subsequent resection. Currently, all patients with locally advanced tumors undergo positron emission tomography CT scans and invasive staging. All patients had pulmonary function tests performed, including a lung diffusing capacity for carbon monoxide (DLCO). The DLCO alone was not used as an exclusion criterion. Patients with a forced expiratory volume in 1 second (FEV₁) of less than 2 L underwent a quantitative ventilation perfusion scan. Patients with a predicted postresection FEV₁ of less than 1 L were excluded. All patients 50 years of age and older underwent an imaged cardiac stress test, and patients with significant irremediable ischemia were also excluded. When a patient's performance status was at odds with the results of the cardiopulmonary testing, an exercise pulmonary function study was performed; and patients with maximum oxygen consumption (VO₂max) of 12 mL · kg–¹ · min–¹ or less were excluded. The exact number of patients seen and considered medically inoperable is not known. Only patients considered potentially operable anatomically and physiologically and in whom invasive staging was, therefore, carried out were followed.

Patients received a total dose of 5,940 cGy to all tumor, including involved mediastinal lymph nodes. The complete extent of the target volume (defined as the area of the primary tumor and its direct extension into chest wall or mediastinum and the involved regional lymph nodes) is encompassed with a 2-cm margin of noninvolved tissue. Initial fields were treated using equally weighted anterior and posterior fields. Spinal cord doses were kept below 4,500 cGy utilizing single or multiple oblique fields. More recently, radiation planning and delivery has been accomplished by three-dimensional conformal techniques maintaining similar dose parameters to the target volume. Radiation is delivered 5 days a week in 180 cGy fractions for 33 treatments. Patients receive two cycles of chemotherapy. On days 1 and 21 of radiation, patients receive cisplatin 60 mg/m², and on days 1 to 3 and 21 to 23, patients receive etoposide 100 mg/m². Four weeks after the last dose of radiation, patients are restaged with a CT scan of the chest, bone scan, and brain CT or magnetic resonance imaging. Patients with disease progression are not considered surgical candidates. Residual N2 disease, however, was not considered a contraindication to resection. Postoperatively, patients receive 4 additional cycles of chemotherapy. Initially, all patients received cisplatin and etoposide. We then changed the protocol so that patients with residual tumor received carboplatinum (AUC6) and taxol 150 mg/m² instead. Currently, almost all patients receive carboplatinum and taxol postoperatively. In patients having a lobectomy, treatment usually begins 4 weeks after resection. In patients undergoing pneumonectomy, postoperative therapy usually does not begin for 6 weeks.

One hundred and three of the 127 patients with locally advanced tumors undergoing induction therapy (81%) were resected. Complete mediastinal lymph node dissections were carried out. For both left-sided and right-sided tumors, a complete subcarinal lymph node dissection was carried out. Any lymph nodes in the inferior pulmonary ligament were also removed. For right-sided tumors, a right paratracheal lymph node dissection was carried out, removing all lymph from the takeoff of the innominate artery to the right mainstem bronchus below the azygos vein. For left-sided tumors, all lymph nodes in the aorticopulmonary window and adjacent to the left mainstem bronchus were removed. Sixty-six patients underwent a lobectomy, 30 a pneumonectomy, and 7 a lesser resection. The bronchial stump and pulmonary artery and whenever possible the pulmonary veins were covered with the pericardial fat pad, which was mobilized superiorly along with the thymus.

Patients remained intubated on the ventilator for 48 hours with 5 cm positive end-expiratory pressure to maintain positive pressure in the lung to reduce the risk of postoperative pulmonary edema. Many patients were weaned to continuous positive airway pressure within 24 hours. Fluids were restricted to 50 to 75 mL/h, and urine outputs of 20 mL/h were tolerated. Any excessive shift of the mediastinum was corrected. No patient undergoing a pneumonectomy or lesser procedure had pulmonary edema. Every attempt was made to extubate the patient at 48 hours after operation. Morbidity and mortality and response to treatment were documented. Patients were seen in follow-up every 3 months for 2 years, every 6 months for 3 years, and every year thereafter. At follow-up, a history, physical examination, and standard posterior-anterior chest roentgenography were carried out. Positive findings were pursued further as indicated. Follow-up is complete for all patients.

Patients undergoing a pneumonectomy were analyzed further and are the subject of this report. Cause of death and sites of recurrence were recorded. Survival was calculated using the Kaplan-Meier method. Differences in survival were calculated using the log-rank method using SSPS version 10.1 software (SSPS, Chicago, Illinois) A difference of p less than 0.05 was considered significant.

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Twenty-six of the 30 patients undergoing pneumonectomy had central tumors. Fifteen underwent a right pneumonectomy and 11 a left pneumonectomy. Four had peripheral tumors, and 3 of these had a right pneumonectomy and 1 a left pneumonectomy. All of these patients had extensive hilar (1 patient) or mediastinal nodal disease (3 patients). Their median age was 54 years (range, 38 to 74). The mean pretreatment FEV₁ was 2.48 ± 0.73 L. Seventeen patients had squamous cell carcinoma, 8 adenocarcinoma, 4 large cell carcinomas, and 1 adenosquamous cell carcinoma. The preoperative stage of their tumors and response to induction therapy is shown in Table 1. Of the 12 patients presenting with N0 disease, 7 had a complete pathologic response. On the other hand, only 1 of 6 patients with N1 disease and 2 of 11 patients with N2 disease had a complete pathologic response. Three of the 6 patients with N1 disease became node negative. Five of 11 patients with N2 disease were downstaged, 4 of them to N0. Seven patients had T4 tumors. Five patients had tumor extension to the main pulmonary artery, 1 tumor involved the left atrium, and in 1 patient there was both extensive mediastinal infiltration and a satellite nodule. Four patients died in the hospital. One patient died after a right pneumonectomy. He had aspiration early postoperatively that precipitated a perioperative myocardial infarction, failure, and death. Three patients died after a left pneumonectomy. One died of postoperative pneumonia, 1 owing to a bronchopleural fistula followed by adult respiratory distress syndrome, and a third of a massive pulmonary embolus to the opposite lung on the second postoperative day despite leg compression boots and subcutaneous heparin. During this same period, only 1 patient (1 of 73) undergoing a lobectomy or lesser procedure after induction HDRT and concurrent chemotherapy died. Five patients experienced a major complication that prolonged their hospital course. Pneumonia developed in these 5 patients, 3 cases as a result of aspiration of gastric contents. The median hospital stay was 9 days (range, 2 to 45), and the median intensive care unit stay was 2 days (range, 2 to 35).

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curve showing the long-term survival of patients who recovered from pneumonectomy surgery. The number of patients at risk was 21 at 12 months, 14 at 24 months, 11 at 36 months, 10 at 48 months, 5 at 60 months, and 3 at 96 months.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

Although our initial report included 9 pneumonectomies with no deaths, our experience with induction HDRT and concurrent chemotherapy is now more than 100 cases with 30 pneumonectomies. The relatively high number of pneumonectomies in our series reflects the advanced locoregional nature of the tumor in these patients and our aggressive approach to treatment. All but 4 of our patients had central tumors. Most patients with peripheral tumors were resectable by lobectomy.

There were 4 deaths. Only 1 of 15 patients died after a right pneumonectomy. This patient died as a result of aspiration. Three of 11 patients died after left pneumonectomy, 1 from pneumonia, 1 from a bronchopleural fistula, and 1 from a massive pulmonary embolus. Five patients experienced major complications, and 3 of these were due to aspiration. This complication is preventable, and we focus attention on preventing it. Gastric residuals are measured before removing nasogastric tubes, and oral feeding is often delayed. We do not believe that the numbers of deaths or the complications are specific to the side of operation. Our results compare with those reported by Martin and colleagues [7] from the Memorial Sloan-Kettering Cancer Center who reported 11 deaths in 97 patients undergoing pneumonectomy after induction therapy. Preoperative radiation was administered to only 18.1% of the patients in their entire series of 297 patients, and the median dose was 5,000 cGy. Nonetheless, their mortality rate after right pneumonectomy was 23.9% (6 of 46), and they concluded right pneumonectomy should be avoided. In the smaller series of pneumonectomies (11) reported by Sonett and colleagues [13], there were no deaths after pneumonectomy. In the series by Cerfolio and colleagues [15], however, the operative mortality was 17% (2 of 12), and 20% (1 of 5) after left pneumonectomy. They, too, concluded radiation should be avoided in patients undergoing pneumonectomy [15]. The overall combined operative mortality of the series reported since 1994 is 12% (6 of 50).

The two dreaded complications associated with mortality, namely, pulmonary edema and bronchopleural fistula, can be avoided by attention to detail. The risk of pulmonary edema associated with pneumonectomy is increased by the impact of radiation on the nonoperated lung and the sclerosis of the mediastinal lymphatics associated with radiation and lymph node dissection. We have utilized fluid restriction and positive pressure ventilation to prevent third-spacing of fluid within the pulmonary interstitium in the period after surgery. Sonett and colleagues [13] have preferred a protocol that emphasizes fluid restriction and aggressive diuresis. Despite these differences in approach, the ultimate objective is to prevent fluid accumulation in the remaining lung that is difficult to remove. Bronchopleural fistula used to be a dreaded complication after pneumonectomy, particularly after radiation. However, vascularized flaps of pericardial fat, intercostal muscle or serratus anterior muscle have largely been successful in preventing this complication. In the series by Sonett and colleagues [13], 1 patient had a bronchopleural fistual after pneumonectomy but did not have coverage of the bronchial stump, and 1 patient had postpneumonectomy pulmonary edema after a large fluid load but survived. Neither of these complications was observed in the series by Cerfolio and colleagues [15] in the HDRT group. One of the deaths in the latter series, however, was secondary to aspiration.

Long-term survival after pneumonectomy in our series was only 33% compared with 44% after lobectomy. For those surviving operation, it was 38%. Eight patients, however, had T3N0 tumors, and 4 patients had T4N0 tumors. Significant tumor downstaging occurred. Thirty-seven percent of all patients had a complete pathologic response, and 55% of the patients with N2 disease had nodal downstaging (Table 1). We could not, however, correlate these with survival. That may be related to the small numbers of patients in the pneumonectomy group. Only 8 of the 17 late deaths were secondary to lung cancer. Four of the late deaths were related to pulmonary disease. It is impossible to determine if the induction therapy, particularly the radiation, had a long-term effect in these patients. The death from acute myelogenous leukemia, however, was likely secondary to the induction chemotherapy. No one factor accounted for differences in survival.

There is no question that pneumonectomy after induction therapy carries significant risk. That is especially true when radiation is included in the induction protocol, and the relative risk increases with the dose. Cord tolerance (4,500 cGy) necessitates delivering some radiation to the opposite lung when nodal disease is present, even when newer conformal techniques are utilized. However, there is an apparent survival benefit to utilizing HDRT and concurrent chemotherapy to treat patients with advanced local regional disease. The addition of surgery after these protocols suggests a survival advantage: 46.2% at 5 years in the series reported by Sonett and colleagues [13] and 38% in the series by Cerfolio and colleagues [15], which only included patients with N2 disease. Even in this series limited to our pneumonectomy experience, the survival at 5 years was 33%. By comparison, the 3-year survival after high-dose radiation and concurrent chemotherapy without surgery as definitive treatment for stage IIIA-N2 disease in Intergroup Trial 0139 was only 33% [10].

Although pneumonectomy carries a significant operative risk that impacts overall long-term survival, we believe the survival benefit demonstrated in these studies justifies its continued evaluation as an acceptable procedure for patients with advanced locoregional nonsmall-cell lung cancer. Further evaluation of this aggressive protocol will best be carried out in prospective clinical trials. However, the risk will likely be affected by the experience of the operating surgeon and the experience of the center where it is being carried out and may only prove reasonable at centers treating large numbers of patients with nonsmall-cell lung cancer. The Radiation Therapy Oncology Group R0229 is a current limited institution phase 2 trial examining the safety and efficacy of this approach.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
This study was supported by the Edmund C. Lynch, Jr, Cancer Fund at Boston Medical Center.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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