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Ann Thorac Surg 1999;68:316-320
© 1999 The Society of Thoracic Surgeons
a Division of Thoracic Surgery, Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, Maryland, USA
b Division of Radiation Oncology, Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, Maryland, USA
c Division of Medical Oncology, Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, Maryland, USA
Address reprint requests to Dr Sonett, Division of Thoracic Surgery, University of Maryland Medical Center, 22 South Greene St, Rm N4W94, Baltimore, MD 21201
e-mail: jsonett{at}surgery2.umaryland.edu
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 1214, 1998.
| Abstract |
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Methods. We report safe pulmonary resection in 19 consecutive patients receiving neoadjuvant therapy that included greater than 59 Gy thoracic radiation. The mean thoracic radiation dose was 61.8 Gy (range 59.566.5) and mean age was 52 years (range 3672 years). Cell type was adenocarcinoma (6), squamous (7), and other non-small cell lung cancer (NSCLC) (6). Sixteen of 19 patients received concurrent chemotherapy. Median time from end of treatment to surgical resection was 89 days (range 22258 days). Surgical resection included 13 lobectomies and six pneumonectomies (four right, two left).
Results. A complete pathologic response was seen in 8 of 19 (42%) patients. Three patients required intraoperative transfusion of blood. Mean intensive care unit stay was 2.0 days (range 18 days), and mean length of stay (LOS) was 8.0 days (range 318 days). There were four postoperative complications; one bronchopulmonary fistula, one subarachnoid-pleural fistula, and 2 patients with prolonged atelectasis. There was no incidence of acute respiratory distress syndrome (ARDS) or operative mortality.
Conclusions. Pulmonary resection, including pneumonectomy, after chemotherapy and high-dose thoracic radiation may be performed safely with a low rate of intraoperative and postoperative complications.
| Introduction |
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50 Gy) (1 Gy = 100 rad) followed by surgery have been performed with acceptable treatment complications and encouraging long-term results [711]. Currently, a phase III randomized trial (Intergroup Trial 0139) comparing definitive radiation therapy (> 60 Gy) and chemotherapy versus radiation therapy to 45 GY and chemotherapy followed by surgery is in progress. Definitive-dose radiotherapy (> 60 Gy) and chemotherapy have been shown to have a survival advantage over chemotherapy alone in locally advanced non-small cell lung cancer treated nonoperatively [12, 13]. The use of curative intent radiation therapy (> 60 Gy) in a neoadjuvant setting, however, has been considered prohibitive in terms of surgical risk and has generally been considered a contraindication to surgery [14]. Ongoing clinical trials have enabled considerable experience to be gained in the surgical technique and postoperative care of patients undergoing pulmonary resection after neoadjuvant therapy. Advances in the delivery of external beam radiation have also improved the morbidity and collateral radiation effects of external beam radiation. Given these improvements in treatment techniques and therapeutic effects, our group began offering surgical resection to a select group of patients who were considered unresectable by standard techniques and were treated with definitive doses of radiotherapy (> 59 Gy). We retrospectively studied the results of consecutive patients undergoing lobectomy or pneumonectomy after receiving full-course radiotherapy with and without chemotherapy, and report the ability to safely resect these carefully evaluated and selected patients.
| Patients and methods |
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Surgical procedures included complete resection of the primary with complete mediastinal lymph node dissections, and anatomic lung resections. After the first pneumonectomy, all pneumonectomy stumps were stapled and bolstered with an intercostal muscle flap or pericardial fat pad. Harvest of the intercostal muscle flap was performed at the start of the case to avoid damage to the vascular bundle with rib spreading. The fifth or six rib would be resected, before the pleural space was violated. The rib resection was performed without bovie electrocautery so that the vascular bundle would not be damaged. The muscle and vascular bundle would be detached anteriorly by sharp dissection, and the intercostal vascular bundle on the remaining (sternal side) would be tied; however, to maintain maximal blood flow to the newly created flap, the end of the muscle flap was not tied until before use. The bundles would be wrapped in gauze with normal saline and protected throughout the resection. At the time of buttressing, the flap was tied off distally and secured to the bronchus with two or three absorbable sutures, being careful not to ligate the vascular bundle.
| Results |
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Four postoperative complications were noted. One late broncho-pleural fistula occurred 1 month after a pneumonectomy. This patient had a positive margin and did not receive a pedicled intercostal muscle flap. He was treated with an eloeser flap. One patient who underwent a Pancoast resection, developed syndrome of inappropriate antidiuretic hormone (SIADH), which resolved with medical therapy. Two patients required repeat bronchoscopy and extended respiratory treatments because of recurrent atelectasis.
Pathologic response to therapy was significant with 8 of 19 patients (42%) having a complete pathologic response with no microscopic evidence of viable tumor. No patient with clinical N0 disease had pathologic adenopathy at the time of resection. Of note, 5 of 6 patients who had preoperative pathologic documentation of mediastinal adenopathy had a complete pathologic response of their lymphadenopathy (Table 2).
Disease recurrence has been noted in 6 of the 19 patients. Four of these were distant and two were local. Sites of recurrence have been; brain (three), bone (two), lung (one), mediastinum (one), and liver (one). Eleven of the patients are alive with no evidence of disease, and 1 is alive with disease. Three have died with no evidence of disease, and 4 died of disease. Mean and median overall survival was 19 months; survival was calculated from the date of diagnosis. The survival range was from 5 to 59 months, and median survival has not yet been reached in 6 patients.
| Comment |
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Modern trials utilizing greater than 50-Gy radiation therapy in a neoadjuvant protocol are limited to three trials with a collective operative patient accrual of 60 patients. The first trial by Yashar and associates in 1992 reported 31 patients who were resected after concurrent chemotherapy with cisplatin and etoposide (VP16) with 55 Gy of thoracic radiation [21]. They reported a complete pathologic response in 28% of the patients and a low overall mortality of 5.6%. This included radical pneumonectomies in 27 of 31 patients. Fowler and associates in 1993 reported an excessively high morbidity and mortality in a prospective single institution phase II trial that was stopped early, due to a high complication and mortality rate [14]. In 16 operative patients who received concurrent 5-FU, cisplatin, and etopiside with 60-Gy thoracic radiation, an overall mortality rate of 23% was reported. In 1994, Deutsch and associates reported similar results in 16 patients who received concurrent carboplatin and VP 16 with 60-Gy radiation, reporting a 19% overall mortality and a 33% mortality for those undergoing pneumonectomy [22].
Our results, although encouraging, must be viewed with caution because of the small and disparate patient population. Our series does substantiate, however, the ability to perform an anatomic lobectomy safely with low morbidity and mortality after high-dose thoracic irradiation. Our results also indicate the ability to perform an anatomic pneumonectomy with low morbidity and mortality after high-dose thoracic radiation therapy, results that were similar to those published by Yashar and colleagues [21]. Safe resection after high-dose neoadjuvant therapy must be attributed, to a large extent, to careful patient selection. In our series, resection was only performed if, after quantitative ventilation perfusion (V/Q) scan and pulmonary function tests (PFTs), a postoperative predicted FEV1 of > 40% and diffusion lung carbon monoxide (DLCO) of > 40% would result. Additionally, all patients were kept intravascularly depleted and great care was taken to avoid intraoperative blood loss that would warrant fluid and blood resuscitation. These perioperative practices may help explain our low rate of postpneumonectomy pulmonary edema, the major cause of morbidity in previous series. Finally, all our patients were treated in an era of improved delivery of radiotherapy, thus decreasing collateral damage to the mediastinum and contralateral lung, factors that might have increased their perioperative morbidity and mortality after pneumonectomy.
The ability to safely deliver curative intent chemotherapy and radiation therapy in a neoadjuvant setting may have biologic and clinical advantages. Large prospective clinical trials by the Cancer and Leukemia Group B (CALGB) and South Western Oncology Group (SWOG) have demonstrated the ability to perform neoadjuvant therapy in a broad multi-institutional setting. These studies, even without high-dose radiotherapy, have demonstrated the ability to significantly downstage tumor burden preoperatively [7, 8]. Improved long-term survival in these patients appears to correlate with final pathologic stage; patients with a complete pathologic response have the best mean and long-term survival rates [7, 23]. Utilizing the best-proven medical therapy to produce the greatest degree of complete pathologic response preoperatively may further improve long-term outcomes. Our complete pathologic response rate of 42% is one of the highest reported to date and supports the theoretical advantage of utilizing the best medical therapy preoperatively.
The ability to utilize maximal medical and radiation therapy in a neoadjuvant protocol may as well have practical clinical benefit. In the future, patients with advanced local disease may be able to be treated uniformly, with maximal medical and radiation therapy, rather than being tracked early to operative versus nonoperative therapy. This may allow maximal therapy upfront, while still maintaining the ability to restage patients after induction therapy. Definitive pathologic restaging after neoadjuvant therapy may allow clinicians to better prognose the potential benefits of definitive resection.
Limitations of this study include the small and disparate patient population, the retrospective nature of the review, and single institution bias. Although all the patients received high-dose radiotherapy, the chemotherapy regimens and dose delivery in relation to the radiation therapy varied. However, 16 of the 19 (84%) patients did receive full, concurrent chemotherapy and radiotherapy. To address these deficiencies, we have developed a prospective protocol of concurrent chemotherapy and high-dose radiotherapy, with subsequent surgical resection for patients with advanced non-small cell cancer who decline or are not eligible for national group neoadjuvant trials.
Pulmonary resection after chemotherapy and high-dose radiotherapy (60 Gy) may be performed safely with minimal morbidity and mortality. Lobectomy and pneumonectomy with complete lymph node dissections can both be performed in these carefully selected patients. Postoperative predicted FEV1, DLCO, and patient functional status should all be assessed carefully before proceeding with resection. Limited fluid administration and vascularized bronchial stump coverage may help limit morbidity and mortality. The use of neoadjuvant therapy in the treatment of advanced-stage non-small cell lung cancer continues to be promising, but its overall effectiveness needs to be validated in ongoing multi-institutional prospective clinical trials.
| References |
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