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a St. Joseph Cancer Institute, Towson, University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland
b Thoracic Oncology Program, University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland
c Columbia Presbyterian Medical Center, New York, New York
d Valley Hospital, Ridgewood, New Jersey
e National Institutes of Health, Bethesda, Maryland
Accepted for publication August 27, 2009.
* Address correspondence to Dr Krasna, The Cancer Institute, St. Joseph Medical Center, 7501 Osler Dr, Suite 104, Towson, MD 21204 (Email: markkrasna{at}catholichealth.net).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006
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Abstract |
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Methods: Clinical records of patients with non-small cell lung cancer who underwent pneumonectomy at our institution between 1995 and 2005 after preoperative concurrent chemoradiation were reviewed retrospectively.
Results: Twenty-nine patients underwent pneumonectomy after preoperative concurrent chemoradiation. Of the 21 men and 8 women who were treated, 1 had stage IIB (T3N0M0) and the remainder had stage IIIA or IIIB non-small cell lung cancer. Mean patient age at surgery was 53.4 years. There were 15 right pneumonectomies, of which 2 were for pancoast tumors. All patients received concurrent preoperative chemoradiation. Mean total radiation dose was 61.1 Gy. All patients went on to have complete (R0) resection by pneumonectomy. Pathologic complete response was found in 16 patients (55.2%). All patients were discharged alive from the hospital after pneumonectomy. Median hospital length of stay was 5 days (mean 8.6). Ninety-day mortality after surgery was 3.4% (n = 1). Recurrences have been found in 11 patients (38%), including brain metastases (n = 6), bone metastases (n = 4), liver metastases (n = 2), and cervical lymph node metastases (n = 2). One patient had a contralateral new primary lung cancer develop 70 months after undergoing pneumonectomy. Estimated 5-year disease-free survival is 48%. Median survival time has not been reached.
Conclusions: Pneumonectomy can be performed safely after preoperative concurrent chemoradiation, even with high-dose radiation. The frequency of disease recurrence in the brain underscores the need to evaluate the role of prophylactic cranial radiation in non-small cell lung cancer.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The use of neoadjuvant chemoradiotherapy can present challenges in the perioperative management of patients undergoing lung resection for non-small cell lung cancer [5, 6]. Preoperative chemoradiotherapy may reduce pulmonary function, and can result in significant fibrosis around key anatomic structures, making dissection difficult and hazardous. Neoadjuvant chemoradiation may increase patient susceptibility to fluid overload and pulmonary edema, and may also impair the ability of bronchial stumps to heal. Concerns about postoperative complications have led to the use of lower doses (30 to 45 Gy) of radiation in the neoadjuvant setting in many institutions [7]. The surgical challenges in managing locally advanced non-small cell lung cancer are greatest, however, in the case of patients requiring pneumonectomy after chemoradiation, with some authors warning that pneumonectomies—especially on the right side—should be avoided after chemoradiation [8].
Our group has previously reported on the feasibility and safety of performing major lung resection in patients who have received preoperative chemotherapy and high-dose radiotherapy [9, 10]. We supplement our previous reports with a specific retrospective analysis of the feasibility of pneumonectomy after preoperative chemotherapy and high-dose radiation.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Patient Selection
Patients included in this review met the following criteria: histologic diagnosis of non-small cell lung cancer, locally advanced disease potentially amenable to curative resection, and were physiologically fit to tolerate trimodality therapy. Locally advanced disease included tumors associated with involvement of mediastinal lymph nodes (N2 or N3), T3 tumors with any nodal involvement, and T4 tumors excluding malignant pleural effusion. Patients were considered for trimodality therapy only if they were free of major comorbidity and had a good performance status, DLCO/VA of at least 40% predicted, and an estimated postpneumonectomy forced expiratory volume in 1 second (FEV1) 40% of predicted.
Preoperative Chemotherapy
Platinum-based chemotherapy was administered concurrently with radiotherapy. This typically involved weekly chemotherapy. Some patients received one or two cycles of full-dose, or "induction," chemotherapy before commencing concurrent neoadjuvant chemoradiotherapy. Chemotherapy regimens varied based upon patient referral patterns.
Preoperative Radiotherapy
Radiation treatment was based upon three-dimensional computed tomography (CT) planning tailored to minimize toxicity to nearby structures including the esophagus and spinal cord. Three-dimensional conformal radiation therapy was administered to the primary tumor and mediastinum, followed by a small-field boost to the primary tumor. Most patients were treated with once-daily fractions, 5 days a week. A few patients received twice-daily hyperfractionated radiotherapy on a prior protocol.
Surgical Approach
Approximately 4 weeks after completion of neoadjuvant chemoradiation, patients were restaged radiologically. Patients with radiologic evidence of disease progression during neoadjuvant therapy were treated nonoperatively. In the absence of any evidence of disease progression, patients underwent open lung resection with en-bloc chest wall resection as appropriate. Intrapericardial dissection was used liberally for central tumors invading the pericardium or mediastinal pleura, or when hilar surgical dissection planes were made indistinct by preoperative radiation. All visible, surgically accessible hilar and mediastinal lymph nodes were removed and submitted for histologic evaluation along with the pneumonectomy specimen. Bronchial stumps were generally covered with pedicled muscle flaps mobilized at the time of chest opening. Either serratus anterior or intercostal muscle flaps were used. Intraoperative fluid administration was kept to a minimum, and patients were routinely extubated at the end of the procedure. There were no inoperable trimodality resection patients during this period. No patient had progression of disease. Patients who had a positive mediastinal lymph node sample after chemoradiation were not referred for resection.
Histologic Evaluation
Resections were considered R0 when there was no evidence of viable tumor at the resection margins. Resections were considered R1 if microscopic residual tumor was identified at the resection margins. After neoadjuvant chemoradiation, pathologic complete response (p-CR) was defined as an absence of viable tumor in the resection specimen. Mediastinal clearance was defined as downstaging of patients with initial N2 or N3 disease to N0 or N1 disease.
Patient Follow-Up
All patients discharged from the hospital after undergoing pneumonectomy received regular outpatient follow-up. Initial followup visits typically took place 2 to 4 weeks postoperatively. Thereafter, patients were seen in follow-up every three to six months for the first 2 to 3 years, and every 6 to 12 months thereafter. Follow-up assessments included CT scans of the chest and upper abdomen, often with brain magnetic resonance imaging or CT.
Statistical Analysis
Data were entered on an Excel spreadsheet (Microsoft, Redmond, WA). Statistical analysis was performed using STATA-SE, version 9.1 (StataCorp, College Station, TX). Survival rates were calculated using the Kaplan-Meier method. In calculations of recurrence-free survival, patients who died without developing recurrence were censored. Survival times are reported from the time of surgical resection. The follow-up period for this study was until January 2006 or time of death.
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Results |
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All patients received platinum-based chemotherapy. All but 6 patients received their chemotherapy at our center. Regimens included cisplatin/paclitaxel, carboplatin/paclitaxel, carboplatin/paclitaxel/bortezomib, cisplatin/vinorelbine, carboplatin/vinorelbine, and cisplatin/etoposide. One patient received carboplatin alone. All patients but 1 (who received only 37.5 Gy) received chemotherapy concurrently with radiotherapy. Chemotherapy given concurrently with radiotherapy was administered weekly in lowered doses. Some patients also received additional standard doses of chemotherapy either before or after concurrent chemoradiotherapy. Time elapsed from completion of preoperative chemotherapy until surgery ranged between 28 and 97 days (mean 62.7).
All but 7 patients received their radiotherapy at our center. Two patients received less than 50 Gy preoperatively (37.5 Gy and 45 Gy). Two patients received 50.4 Gy preoperatively. The remainder of the patients received between 59.4 Gy and 69.6 Gy. The mean total dose of preoperative radiation was 61.1 Gy. Time elapsed from completion of radiation until surgery ranged between 23 and 155 days (mean 67.1). Two patients underwent surgery within less than 42 days of completing radiotherapy.
There were 15 right pneumonectomies, of which 2 involved the superior sulcus (pancoast tumors) and another 4 of which involved en-bloc chest wall resections. One of the right Pancoast resections represented a completion pneumonectomy in a patient who had previously undergone ipsilateral lobectomy. Of the 14 left pneumonectomies, there were no superior sulcus lesions but 2 required en-bloc chest wall resections. Intrapericardial dissection was required in 7 of the left pneumonectomies and 8 of the right pneumonectomies (Table 1). All but 3 patients had muscle flap reinforcement of their bronchial stump. In 1 patient, a pleural flap was used for right mainstem bronchial stump reinforcement. Two right pneumonectomies (the first and third in the series) were performed without bronchial stump reinforcement. Four right pneumonectomies were performed with serratus muscle flap reinforcement of the bronchial stump. All of the remaining pneumonectomies were performed with intercostal muscle bundle bronchial stump reinforcement (Table 2).
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Of the 11 patients who had recurrence of their malignancy, 3 were alive at the end of the study period. One underwent gamma knife ablation of a brain metastasis and had no evidence of disease more than 31 months after his recurrence. Another underwent resection of a scalp metastasis and a small bowel metastasis and had no evidence of disease more than 15 months after his first recurrence. One patient who remained free from recurrence of his original lung cancer had a new primary left lung cancer 70 months after undergoing right pneumonectomy. Among all patients in this series, recurrence-free survival was 48% at 5 years (Fig 2). Overall survival was 35% at 5 years (Fig 3).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The Southwest Oncology Group phase II trial 8805 evaluated the feasibility of trimodality therapy of stage III non-small cell lung cancer [2]. Induction therapy consisted of two cycles cisplatin and etoposide with concurrent 45 Gy chest radiotherapy. Additional chemoradiation was administered if unresectable disease was encountered at surgery or if positive margins or nodes were found. Mortality in the postoperative period was 9% overall, 16% for patients undergoing pneumonectomy. Three-year survival rates were 27% for stage IIIA and 24% for stage IIIB. Importantly, the strongest predictor of long-term survival was the absence of tumor in the mediastinal nodes at surgery. Three-year survival was 44% for node-negative patients as compared with 18% for patients with residual nodal disease [14].
A retrospective review of 103 patients from Brigham and Womens' Hospital who underwent lung resection for N2 non-small cell lung cancer after neoadjuvant therapy also demonstrated the importance of lymph node stage at the time of resection [15]. Five-year survival after surgery was significantly improved in patients whose nodal disease was eradicated after neoadjuvant therapy versus patients with persistent nodal disease (36% versus 9%). The authors observed that patients who are not downstaged by neoadjuvant therapy do not appear to benefit from surgical resection.
The North American Intergroup Trial 0139 compared chemoradiation versus chemoradiation followed by surgery in patients with stage IIIA (pN2) non-small cell lung cancer [16]. Chemotherapy with cisplatin/etoposide was administered concurrently with radiotherapy. Patients randomly assigned to undergo surgical resection received 45 Gy whereas patients in the nonsurgical arm of the study received 61Gy. Patients who received trimodality therapy with chemoradiation followed by surgery are enjoying significantly better 5-year progression-free survival as compared with patients who received chemoradiation without surgery (22.4% versus 11.1%). A trend toward better overall 5-year survival with trimodality therapy (27.2% versus 20.3%) has not reached statistical significance. As in earlier studies, the finding of mediastinal nodal clearance at the time of lung resection (ie, after neoadjuvant chemoradiation) was associated with improved overall 5-year survival (41% versus 24%). Pneumonectomy after chemoradiation was associated with high rates of morbidity and mortality whereas lobectomy was associated with better overall and disease-free survival.
Neoadjuvant therapy should be aimed at maximizing the likelihood of achieving nodal clearance. Restaging of the lymph nodes after neoadjuvant therapy is important to avoid performing lung resections that are not likely to improve outcome [17]. This can be achieved by repeat positron emission tomography/CT transbronchial needle biopsy mediastinoscopy, repeat mediastinoscopy, or recently using esophageal ultrasound and transbronchial ultrasound together with needle aspiration. An attempt at pathologic restaging should be pursued as this is the single most important determinant of survival after chemoradiation. In an effort to improve the clearance rate of nodal disease with neoadjuvant chemoradiotherapy, higher doses (greater than 50 Gy) of radiation have been used. Published reports of high-dose radiation as a component of concurrent neoadjuvant chemoradiotherapy have described doses ranging from 50.4 Gy to 70.2 Gy [10, 18–20]. In these series, the rates of nodal clearance have ranged from 65% to 82.5%, and the rates of complete pathologic response have ranged from 27% to 45%. There has in fact been a correlation between higher mediastinal radiation and rate of nodal clearance, but no prospective study has been done to date.
Pneumonectomy after neoadjuvant therapy has been associated with relatively high mortality. A relatively early series of 13 patients [5] reported a mortality of 43%. More recently, in a series of 12 patients from the University of Alabama [20], mortality was 16.7%. A European series of 69 patients [21] reported 7.2% mortality. In a French series of 100 patients [22], mortality was 12%. A series of 97 pneumonectomies performed after neoadjuvant therapy at Memorial Sloan Kettering Cancer Center [8] resulted in a mortality rate of 11.3%, with a startling discrepancy in mortality between left pneumonectomies (0%) and right pneumonectomies (23.9%). Some of the patients reported in these series received neoadjuvant chemoradiotherapy, whereas others received only neoadjuvant chemotherapy without radiotherapy. The great majority of reported patients who received neoadjuvant radiotherapy received only 45 Gy or less.
The literature is replete with warnings about the relatively high mortality of pneumonectomy after neoadjuvant therapy [5, 7, 8, 22]. In the case of right pneumonectomy, some authors warn of high operative mortality even in the absence of neoadjuvant therapy [23]. This is troubling given that the frequency with which pneumonectomy is required for complete resection is increased in stage III non-small cell lung cancer. The progression-free survival advantage enjoyed by patients undergoing resection in the Intergroup trial makes the pursuit of a safe post–neoadjuvant pneumonectomy an important goal. Moreover, the importance of nodal clearance—as evident from the available data—makes high-dose radiotherapy an attractive component of concurrent neoadjuvant chemoradiotherapy.
In this limited, single-institution series, we have demonstrated the feasibility of safely performing pneumonectomy after neoadjuvant chemotherapy and concurrent high-dose radiotherapy. There are many possible reasons for the relatively low mortality in this series. One of the key factors is likely to be patient selection and preoperative management. Meticulous three-dimensional planning of radiation fields should be aimed at maximizing the dose delivered to the region of interest while minimizing damage to surrounding tissues. During neoadjuvant chemoradiation, radiation esophagitis should be managed aggressively with analgesics and high-calorie nutritional supplements. Excessive radiation-induced skin burns are a potential risk factor for healing complications. There was no difference in the preresection regimen with regard to outcomes in this series. Many of these patients were on phase 1 and 2 clinical trials evaluating different chemotherapy regimens. There was no correlation with extent of N2 disease. These patients included single station as well as multiple station disease, and macrospcopic as well as microscopic-only lymph node involvement.
Judicious intraoperative use of intravenous fluids is helpful in preventing pulmonary edema. Anatomic planes may become indistinct, making dissection especially difficult and hazardous. Excellent exposure is mandatory, and liberal use of intrapericardial dissection may allow easier dissection due to relatively intact tissue planes. The mainstem bronchus should be dissected proximally up to the carina, taking care to avoid devascularization of the bronchial stump. The bronchus should be divided nearly flush with the carina, preferably using a 4.8-mm stapler. Thorough reinforcement of the bronchial stump with a vascularized muscle flap is most important. Fluid restriction and aggressive repletion of potassium and magnesium can help prevent pulmonary edema and supraventricular dysrhythmias.
Strong consideration should be given to adjuvant chemotherapy in full doses to decrease the likelihood of distant recurrence. It has been our practice to use prophylactic cranial irradiation in an attempt to decrease the risk of cancer recurrence in the brain. Regular lifelong follow-up is maintained to recognize disease recurrence as early as possible and to screen for new second primary lung cancers.
We maintain that, in carefully selected patients with stage III non-small cell lung cancer, pneumonectomy can be performed safely after neoadjuvant chemotherapy and high-dose radiotherapy. The recently closed Radiation Therapy Oncology Group phase II Trial 0229 used concurrent neoadjuvant chemotherapy with weekly carboplatin/paclitaxel chemotherapy and 61.2 Gy administered in daily fractions [24]. We support the importance of this research effort in helping to establish the efficacy of pneumonectomy after neoadjuvant chemotherapy. In view of the relative frequency of brain metastases seen in most series, we also support the recently closed Radiation Therapy Oncology Group phase III Trial 0214, which examines the potential benefits of prophylactic cranial irradiation in patients with non-small cell lung cancer [25]. It is only through aggressive multidisciplinary efforts that the prognosis of patients with locally advanced non-small cell lung cancer can be expected to improve.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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DR GAMLIEL: As this is not an "intent-to-treat" analysis, I can't give you exact figures about the toxicity of the neoadjuvant therapy. Although a majority of the patients were treated at our institution, not all were. The focus of this study is to evaluate the morbidity and mortality associated with the surgical aspect of the therapy.
DR JOHN R. ROBERTS (Nashville, TN): I think your results are great and I appreciate your presentation. One of the options to doing a pneumonectomy is doing a sleeve resection, either the airway or the artery, and it would strike me that high-dose radiotherapy might make that difficult. Do you have any information about the number of your folks who underwent sleeve resection, since those groups are often comparable with respect to their tumor location and stage.
DR GAMLIEL: I don't have that data at my disposal at this time. I can tell you that sleeve resection after high-dose radiotherapy in our institution is less common than pneumonectomy. It is performed, however, with the same attention to detail and the same sort of coverage of the anastomosis with an intercostal muscle bundle.
DR ARA VAPORCIYAN (Houston, TX): I enjoyed your presentation. Especially with the data coming out of Albain's study, it's important that we look at this group. I have one question. In comparing your results to that study, and you may have mentioned it, were all of these patients documented to have N2 disease before going on study or was there only a portion of the group that had truly documented N2 disease?
DR GAMLIEL: Unfortunately this is a retrospective study, not a prospective study. Some of these patients only came to our institution after having received neoadjuvant chemoradiotherapy. A number of patients in this group were staged only radiologically at the onset of their neoadjuvant therapy and were treated as if they had mediastinal lymph node involvement without histologic confirmation.
DR MARK I. BLOCK (Hollywood, FL): Very nice presentation and I enjoyed it and congratulate you on your results. You introduced your presentation with well-known data that we're all familiar with about downstaging the mediastinum improving survival. My question relates to the biological significance of that and therefore your choice of therapies. I tend to view mediastinal lymph nodes more as surrogates of systemic disease, so when someone is downstaged, that means that the chemotherapy is more effective at treating their systemic disease. So I wonder what the relevance is of downstaging the mediastinum with a local therapy like radiation. It seems to me that that would only be valuable if you view mediastinal nodes as a source of metastatic disease, not as a marker of metastatic disease. So I wonder whether you're going to achieve any long-term benefit by radiating your mediastinal nodes into oblivion as opposed to finding those patients who really respond to the chemotherapy and therefore have better control of their systemic disease. Your results show that lack of control of systemic disease is the major problem. Are you in favor of using patients who are only downstaged with chemotherapy as candidates for surgery rather than those who need the additional boost of radiation therapy? I would appreciate your thoughts on the role of mediastinal disease as a source versus a marker of systemic disease.
DR GAMLIEL: With data from observational studies, as opposed to mechanistic studies, it is not possible to determine why things are as they are. The data, particularly from the Intergroup trial, quite clearly show that progression-free survival is enhanced by the addition of surgical resection. The purpose of this talk is really to demonstrate that pneumonectomy should not necessarily be regarded differently from other forms of lung resection as a valid component of trimodality therapy. Why radiation therapy to the primary tumor and mediastinum results in improved survival, I can't say based upon data from clinical studies. What I will submit to you is that the data are fairly convincing and that—particularly in recent years—we have been recommending adjuvant chemotherapy for these patients as well. I don't know that it is currently possible to demonstrate specifically how or why radiation therapy impacts survival.
DR SCOTT J. SWANSON (New York, NY): I appreciated all the data that you showed. Do you have any details on the cause of death for those people who did not die of cancer? It seemed like there were a good number of deaths unrelated to cancer. Were the deaths attributable to a respiratory cause? Do you think the induction therapy had any relationship to the noncancerous deaths?
DR GAMLIEL: Unfortunately I do not have that information. The patients in this series returned for regular follow-up visits with us. Those who were found to be free of any evidence of recurrent or metastatic disease then returned to their normal day-to-day activities. Typically, we would learn after the fact when they died of some noncancer-related cause.
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Acknowledgments |
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References |
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M. J. Krasna Reply to the Editor J. Thorac. Cardiovasc. Surg., March 1, 2010; 139(3): 807 - 807. [Full Text] [PDF]
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