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Superior Vena Cava Resection for Lung and Mediastinal Malignancies: A Single-Center Experience With 70 Cases
Lorenzo Spaggiari, MD, PhD, Francesco Leo, MD, PhD, Giulia Veronesi, MD, Piergiorgio Solli, MD, Domenico Galetta, MD, Brunilda Tatani, MD, Francesco Petrella, MD, and Davide Radice, PhD Divisions of Thoracic Surgery and Epidemiology and Biostatistics, European Institute of Oncology, and University of Milan School of Medicine, Milan, Italy
Background. The oncologic value of superior vena cava (SVC) resection for lung and mediastinal malignancies remains controversial. In this context, we have reviewed our experience in the treatment of locally advanced lung and mediastinal tumor invading the SVC system, analyzing postoperative outcome and long-term oncologic results. Methods. The clinical data of patients who underwent SVC resection were retrospectively analyzed to assess postoperative mortality, and overall and procedure-specific morbidity. Overall survival was calculated for mediastinal and lung tumor groups. Results. From 1998 to 2004, 70 consecutive patients (52 with lung cancer and 18 with mediastinal tumors) underwent SVC system resection. There were 25 replacements (36%) of the SVC system by prosthesis, whereas the remaining underwent partial resection. Major postoperative morbidity and mortality rates in lung cancer pa-
tients were 23% and 7.7%, respectively (50% and 5.6% in mediastinal tumors). In the lung cancer group, 5-year survival probability was 31%, and it was affected by mediastinal nodal status (5-year survival in N0 –N1 patients 52%, 21% in N2 patients, 0 in N3 patients). Median survival for mediastinal tumors was 49 months. Conclusions. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, only when pathologic N2 disease is excluded by preoperative mediastinoscopy.
S
provement of both technical devices and surgical experience have renewed the interest in the use of SVC resection. In the last 15 years, several series of SVC resections have been published, confirming feasibility and reporting long-term survival data (Table 1) [2–12]. With the aim of contributing to the existing experience on this topic, this study reviews our experience in resections for mediastinal and pulmonary neoplasms invading the SVC system, with particular attention to the results and pitfalls of this extended surgery.
uperior vena cava (SVC) system invasion by lung and mediastinal malignancies has long been considered a contraindication for surgical resection. However, during the 1970s and 1980s, experimental animal research and clinical case reports suggested the technical feasibility of such an extended surgery for mediastinal and pulmonary malignancies, resulting in long-term survival in some instances. The absence of suitable prosthetic material for SVC replacement, the technical incertitude concerning the effect of SVC clamping, the fear of graft thrombosis and infection after pulmonary resection, and finally, the dismal oncologic prognosis after initial SVC resection experiences have limited its diffusion as a surgical treatment. The poor prognosis of locally advanced lung cancer treated by radiotherapy (5-year survival 5%), or chemoradiotherapy (5-year survival 5% to 17%) [1], the imAccepted for publication July 27, 2006. Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 –Feb 1, 2006. Address correspondence to Dr Spaggiari, Department of Thoracic Surgery, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy; e-mail: [email protected].
© 2007 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2007;83:223–30) © 2007 by The Society of Thoracic Surgeons
Material and Methods The primary objective of this study was to analyze the mortality, morbidity, and long-term results of SVC resection, both in terms of survival and in the patency of the prosthetic replacement, when performed. Our Ethical Committee was informed of the study and did not require approval. All patients gave their informed consent for the study.
Database A specific database was designed for patients undergoing SVC resection and comprised four sections: demograph0003-4975/07/$32.00 doi:10.1016/j.athoracsur.2006.07.075
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Table 1. English-Language Literature Review (1990 –2005): Full Papers With More Than 6 Patients [2–12] Author, Year of Publication GENERAL THORACIC
Patients
Prosthetic Graft
Mortality
5-Year Survival
6 15 32 14 8 25 11 8 109 15 40
0 4 7 14 3 7 3 2 26 9 11
17% 7% 22% 7% NR 12% 0 NR 12% 14% 10%
NR 24% NR 31% NR 29% NR 25% 21% 57% (3 years) 24%
Piccione, 1990 Thomas, 1994 Tsuchiya, 1994 Dartevelle, 1997 Fukuse, 1997 Spaggiari, 2000a Spaggiari, 2000b Bernard, 2001 Spaggiari, 2004c Shargall, 2004 Suzuchy, 2005 a
Marie Lannelongue Hospital, Paris, experience.
b
European Institute of Oncology, Milan, experience.
c
Multicentric study.
NR ⫽ not reported.
ics (age, sex, history, presence of SVC syndrome signs, American Society of Anesthesiologists score, forced expiratory volume in 1 second [FEV1], and diffusion capacity of the lung for carbon monoxide [Dlco]); oncologic data (clinical and pathologic TNM, type and duration of induction treatment, response to chemotherapy when performed, bronchoscopy, positron emission tomography scan results); intraoperative data (access, duration of surgery, duration of SVC clamping, associated lung resection, intraoperative continuous hemodynamics monitoring data, amount of adminitered fluids, intraoperative adverse events); and postoperative and follow-up data (postoperative deaths, morbidity, postoperative radiotherapy, status of the patient at last follow-up, status of the disease, patency of SVC graft at the last computed tomography [CT] control).
the fourth intercostal space, or of the fifth intercostal space with the resection of the fifth cartilage. This approach was usually utilized in case of planned associated bronchoplastic or carinal resection, whereas in cases with right upper lobectomy, the hemiclamshell approach was preferred. In the case of mediastinal tumor, sternotomy or the hemiclamshell approach were used.
Intraoperative Management In the case of lung tumors, the surgical approach utilized was the standard muscle-sparing lateral thoracotomy in
Fig 1. Operative picture during partial superior vena cava resection for lung cancer. Reconstruction of the superior vena cava by a pericardial patch (Arrow).
Fig 2. Operative picture after complete resection of the superior vena cava and both brachiocephalic veins for mediastinal tumor; revascularization was done between the left brachiocephalic vein and superior vena cava using an autologous custom-made pericardial tube (arrow). Surgical approach: sternotomy; lung resection: right upper lobectomy.
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daily, after discontinuing low-molecular-weight heparin. Patients who underwent partial SVC resection without prosthetic replacement did not undergo anticoagulation therapy.
Follow-Up Patients with SVC resection were followed up at 1 month and every 4 months afterward. All of them received contrast chest CT scan before discharge and before each follow-up visit (coupled with upper abdomen CT scan). Information for the present study was obtained by directly contacting the patient or the referring physician. In case of absent information, a certificate was obtained from the anagraphic database of the patient’s city of birth.
Statistical Analysis Fig 3. Operative picture after complete superior vena cava resection with polytetrafluoroethylene (PTFE) graft replacement for lung cancer. Surgical approach: hemiclamshell; lung resection: upper bilobectomy; prosthesis: no. 14 ringed PTFE.
The type of SVC resection performed depended on the degree of venous involvement. When vessel involvement was limited (less than 50%), resection and direct repair was preferred, using basic techniques such as mechanical suture or continuous polypropylene suture on a vascular clamp. When the defect was too large, it was repaired by the use of a pericardial patch (Fig 1). When the SVC was not extensively infiltrated close to one of the BCV trunks (left or right), the entire venous trunk was removed without subsequent reconstruction, unless both BCV were infiltrated or the patient had a previously resected or ligated contralateral internal jugular vein; in that case, the BCV was reconstructed by prosthetic replacement (Fig 2). When SVC infiltration involved more than 50% of the circumference of the SVC, prosthetic replacement by cross-clamping technique was preferred (Fig 3). On an exceptional basis, when SVC infiltration involved the right side of the heart, the use of extracorporeal circulation was planned (Fig 4). During the first period of the study (1998 to 2002), SVC prosthetic replacement was performed by a polytetrafluoroethylene (PTFE) graft (Fig 3). Since 2003, all patients have received SVC replacement using a biological, custom-made bovine pericardial tube (Shelhigh NoReact Pericardial Patch [10 ⫻ 15]; Shelhigh, Millburn, New Jersey [Fig 5]). To compensate for the acute SVC syndrome and the expected drop in arterial pressure at SVC clamping due to the reduction in cardiac output, intraoperative fluid and vasoactive agents administration were managed to obtain a mean arterial pressure before clamping of 80 mm Hg. Intravenous sodium heparin (0.5 mg/mL) was used in all patients requiring SVC clamping. Postoperatively, in patients with PTFE prosthesis, anticoagulation therapy was continued using lowmolecular-weight heparin for 1 month and maintained afterward with oral anticoagulants. Patients with bovine pericardium prosthesis received ticlopidine, 150 mg
Postoperative mortality was defined as any death occurring during hospitalization or within 30 days after surgery. Morbidity and mortality were analyzed to assess whether age, preoperative FEV1, SVC prosthetic replacement, duration of SVC clamping time, preoperative chemotherapy, and type of lung resection had an impact on postoperative risk. Comparisons were performed using Student’s t test (paired values) for continuous variables and the Fisher’s exact test for categorical variables. Survival curves were obtained by the Kaplan-Meier method, and were compared between groups (lung cancer versus mediastinal tumors) using the log-rank test. Additionally, in the lung cancer group, survival was analyzed by age, preoperative chemotherapy, and mediastinal nodes status.
Fig 4. Operative picture after complete resection of superior vena cava and both brachiocephalic veins, and partial right atrium resection (arrow) for mediastinal tumor. Revascularization was performed between the right brachiocephalic vein and right atrium with no. 14 ringed polytetrafluoroethylene (PTFE) prosthesis. Surgical approach: sternotomy; lung resection: none; operation performed using extracorporeal circulation and cardiac arrest. Inset: The neoplastic thrombus completely occluding the superior vena cava, and partially occluding the upper part of the right atrium.
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Table 2. Patient Characteristics Number GENERAL THORACIC
Population Mediastinal tumors Type of SVC repair SVC prosthetic replacement SVC-BCV prosthesis Direct SVC repair Survival (dead/alive) 1 year 3 years 5 years Lung tumors Induction treatment Chemotherapy Radiochemotherapy Stage pT0 pT1 pT2 pT3 pT4 pN0 pN1 pN2 pN3 Stage I Stage II Stage III Type of SVC repair SVC prosthetic replacement SVC-BCV prosthesis Direct SVC repair Autologous pericardial patch Lung resection Pneumonectomy Tracheal sleeve pneumonectomy Lobectomy/bilobectomy Tracheal sleeve lobectomy Sleeve lobectomy Segmentectomy Survival (dead/alive) 1 year 3 years 5 years BCV ⫽ brachiocephalic vein;
70 18 6 3 9 4/11 7/8 8/3 52 33 7 3 1 8 9 31 8 18 21 5 3 13 36 13 3 32 4
cancer. Twenty-one patients (40%) underwent mediastinal investigation by mediastinoscopy before SVC surgery, and 40 (77%) received preoperative induction treatment (chemotherapy, n ⫽ 33; chemoradiation therapy, n ⫽ 7). The indication for SVC resection was the direct involvement of the vessel in all but 6 patients who underwent resection for bulky N2 disease after induction chemotherapy at the beginning of our experience. Twelve extended pneumonectomies (23%; 9 tracheal sleeve pneumonectomies), 7 tracheal sleeve lobectomies, 13 sleeve lobectomies, 4 bilobectomies, 14 lobectomies, and 2 segmentectomies were performed. In 18 patients, resection was performed for mediastinal malignancies; in 9 patients, it was performed for thymus tumors (thymoma, thymus carcinoma, carcinoid of the thymus), whereas the remaining patients were affected by miscellaneous rare mediastinal tumors (namely, primary sarcoma of the mediastinum, and so forth).
Superior Vena Cava Reconstruction In 25 cases (35.7%), extent of SVC infiltration required a prosthetic replacement. All prosthetic replacements were performed using the cross-clamping technique, except one in which extracorporeal circulation was used to remove an invasive thymoma invading SVC and right atrium with endoluminal neoplastic thrombus (Fig 4). Median cross-clamping time was 30 minutes. In the group of 13 patients who received SVC replacement for lung cancer, replacement was performed by a PTFE graft in 8 patients (median size, 14; range, 10 to 16); and since 2003 by a biological, custom-made bovine pericardial tube in 5 patients (size no. 20; Fig 5) [13]. In the group of mediastinal tumors, there were 6 complete SVC resections with prosthetic replacement, in 5 patients using a PTFE graft and 1 with a custom-made bovine pericardial tube. In 6 cases (8.5%; 3 cases in the lung cancer group and
3 9 18 7 13 2 14/38 23/12 14/7
SVC ⫽ superior vena cava.
Results Population From November 1998 to May 2004, 70 patients underwent SVC system resection for either lung or mediastinal malignancies. Clinical characteristics of the population are reported in Table 2. Fifty-two patients (42 male patients, median age 62,7 years) had SVC resection for nonsmall-cell lung
Fig 5. Operative picture after complete superior vena cava resection with custom-made bovine pericardial tube replacement for lung cancer. Surgical approach: anterolateral thoracotomy; lung resection: tracheal sleeve pneumonectomy; prosthesis: bovine pericardial prosthesis, no. 20.
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3 in the mediastinum group), tumor infiltration was at the brachiocephalic vein (BCV) junction, needing reconstruction of BCV and the upper portion of SVC. The BCV prosthetic replacement was performed in 5 cases by PTFE graft and in 1 case by autologous pericardial tube. In 41 cases, infiltration of SVC was peripheral and allowed direct repair by vascular stapler or tangential clamping and simple running suture. In 4 cases, direct repair was not possible, and the SVC was repaired by an autologous pericardial patch.
Morbidity and Mortality No intraoperative death was observed. One patient did not tolerate SVC cross-clamping, and the resection was performed by tangential clamping. In the lung cancer group, major postoperative complications developed in 23% of patients (n ⫽ 12). The postoperative mortality was 7.7% (n ⫽ 4). The causes of postoperative death were 2 cases of late bleeding after discharge but within 30 days, 1 case of adult respiratory distress syndrome, and 1 cardiac arrest without organic causes 7 days after the operation. The most frequent complications were pulmonary (7 of 12, 58%). In the mediastinal tumor group, major postoperative complications developed in 9 patients (50%), and the postoperative mortality was 5.5% (n ⫽ 1) due to adult respiratory distress syndrome. None of the demographic and intraoperative variables had a significant impact on morbidity and mortality. Moreover, postoperative morbidity and mortality was not negatively affected by preoperative chemotherapy in either group (Fisher’s exact test, p ⫽ 0.11).
Early and Late Thrombosis With a median follow-up of 32 months, 6 prosthetic thromboses were recorded (overall thrombosis rate 8.5%, prosthetic thrombosis rate 24%). Four thromboses occurred within 1 months after operation (early thrombosis). One of the 19 patients (4.5%) who had complete SVC prosthetic replacement experienced early postoperative graft thrombosis. Three of 6 patients who had both left BCV and partial SVC resection experienced early thrombosis of the PTFE graft. All patients were treated by anticoagulation. Two late thromboses (more than 1 month after surgery) were recorded in patients with mediastinal tumors 2 and 7 months after operation, respectively, and they were both medically treated (22%). No thrombosis was recorded in patients with bovine pericardium SVC prosthesis. The occurrence of thrombosis was not significantly related to any of the demographic and intraoperative variables considered. Nevertheless, in 4 of 6 cases (66.6%), a BCV reconstruction was associated.
Long-Term Survival In the lung cancer group, full-thickness infiltration of SVC (pT4) was confirmed pathologically in 31 patients (60%). Pathologic assessment of lymph node involvement showed N2 disease in 21 patients (40%), N1 disease in 18 patients, N0 disease in 8 patients, and N3 disease in 5 patients. Eighteen patients (35%) underwent adjuvant radiotherapy. Follow-up information was obtained in all
Fig 6. Survival curve (Kaplan-Meier method) of patients who underwent resection of the superior vena cava for nonsmall-cell lung cancer. The probability of survival at 5 years was 31%; the number of surviving patients at risk at 60 months was 21. Median survival was 16.2 months (95% confidence interval: 12.6 to 36.7).
the cases. Median survival was 16.2 months (95% confidence interval: 12.6 to 36.7), with a 5-year probability of survival of 31% (Fig 6). Mediastinal lymph nodes involvement affected survival, being 5-year survival 56% for N0 –N1 patients, 21% for N2 patients, and 0% for N3 patients (p ⫽ 0.056). No difference in terms of survival was found between patients who received preoperative chemotherapy and those who did not (log-rank test, p ⫽ 0.68). Median survival in the mediastinal tumours group was 49 months, with a 5-year probability of survival of 45%.
Comment Our series confirmed data from existing literature showing that resection of the SVC is a feasible additional procedure during resection of pulmonary or mediastinal tumors infiltrating the venous mediastinal axis, minimally increasing postoperative complications in experienced hands. Nevertheless, two questions regarding SVC surgery remain unaswered: what are the defining characteristics of an optimum candidate for SVC resection, and which SVC reconstruction technique provides the best results. Concerning the first question, the selection of candidates for SVC resection depends first and foremost on the underlying pathology. In the case of lung tumors infiltrating the mediastinum, SVC resection is often only part of a more extended procedure, such as pneumonectomy with or without carinal resection [10, 14]. In these cases, patients have to be fit enough to tolerate extended pneumonectomy, ideally no more than 70 years of age, classed American Society of Anesthesiologists score 1 or 2, with a predicted postoperative FEV1 of more than 40%, and finally, with no major cardiac comorbidity. Another important point is that SVC resection should never be considered in the case of urgent treatment of acute SVC syndrome. The dramatic hemodynamic changes occurring in such a situation create instability in
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the patient at SVC cross-clamping, making it impossible to perform a radical resection, thereby eliminating the utility of this type of surgery. Apart from general considerations, patient selection is mainly based on oncologic aspects. The best results in terms of survival are obtained in mediastinal tumors (median survival 49 months in our series). They represent a heterogeneous group of diseases, the most frequent being thymoma. Its position in the anterior mediastinum makes BCV and SVC infiltration a common feature of invasive thymoma; therefore, vascular resection becomes necessary to obtain a radical resection, and it is justified by the natural history of these tumors, which are locally aggressive but have a low risk of distant metastases. Superior vena cava resection may also be indicated in case of other mediastinal tumors such as nonseminomatous germ cell tumors after chemotherapy and the normalization of markers, when a significant residual mass is still present and presents risks of further degeneration or teratoma slow-growing syndrome. In lung cancer, our series confirmed an acceptable 5-year survival (31%) obtained by lung resection associated with SVC resection and did not confirm the adverse role of SVC grafting as compared with direct repair, as had been previously suggested [10, 13]. The most important prognostic factor, even in this subset of patients, remains mediastinal nodal status. In fact, in our series, 5-year survival is encouraging when there is no mediastinal involvement (52%), disappointing in the case of pathologic N2 disease (21%), and absent when N3 disease was occasionally discovered during the hemiclamshell approach. One of the practical consequences is that mediastinoscopy should be routinely performed in all the patients with suspected SVC infiltration, as the positron emission tomography scan is often ineffective because tumor fixation may mask mediastinal disease. Another important issue in the proper selection of surgical candidates is the role of neoadjuvant chemotherapy. Even in the absence of absolute evidence from the literature, we advocate its use in lung tumors with SVC infiltration for four main reasons. The first is the clinical observation that in a nonnegligible proportion of patients who undergo extended surgery (not only SVC resection), distant metastases develop a few months after operation that had not been evident at preoperative staging. The second reason is represented by the theoretical advantage of induction treatment (decreasing tumor size, increasing the likelihood of negative margin, sterilizing micrometastatic disease, defining tumor response to chemotherapy), which may facilitate operation and exclude patients with rapidly evolving disease from surgery. The third consideration is that a negative impact of induction chemotherapy on postoperative morbidity and mortality has not been clearly demonstrated. Finally, the benefits of chemotherapy in terms of survival have been demonstrated in early stage [14], stage IIIa [15, 16], and stage IV [17, 18]; therefore, why should T4 tumors infiltrating SVC represent an exception? The supposed survival advantage of induction chemotherapy was not evident in our series, being instead due to
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the bias of selection and to the limited dimension of the population. Only a prospective randomized trial could confirm the actual advantages provided by preoperative induction treatment. Unfortunately, its feasibility is limited by several factors, first of all the difficulty of precise clinical staging in tumors infiltrating the SVC. It is true that a percentage of patients classed as clinical T4 are “false T4” (about 40%) [19], which occurs when the pathologist does not confirm vessel infiltration. However, there is no possibility of avoiding the overtreatment of SVC resection in these patients because this assessment is sometimes impossible even intraoperatively. In any case, survival curves of “false T4” and “true T4” patients in the subset of N0 –N1 cases overlap (5-year survival 51.5% and 36.9%, respectively; log-rank test, p ⫽ 0.72). Morover, it is impossible to evaluate how many false T4 patients were actually true T4 before induction chemotherapy. Which SVC reconstruction technique provides the best results? It depends on the degree of SVC infiltration. Direct repair is the simplest reconstruction, but it is acceptable only when the caliber of the repaired SVC is 50% or more of the original one. When that is not the case, but SVC is not circumferentially resected, SVC can be cross-clamped and repaired by an autologous pericardial patch, which does not require long-term anticoagulation. When a circumferential SVC resection is performed, a prosthetic replacement should be performed immediately afterward. Historically, the gold standard of SVC prosthetic replacement was PTFE. The main problems of PTFE replacement are the need for long-term anticoagulation therapy and thrombosis. Few data are available on long-term patency of SVC prostheses. When considering all thrombotic events (early and late, SVC or BCV, or both), the rate of prosthetic thrombosis ranges between 22% [20] and 50% [21]. Apart from the technical factors (such as the need for BCV reconstruction or an excessive prosthetic length), it has to be kept in consideration that SVC is a venous high-flow/low-pressure conduit, emptied when negative pressure that has built in the right atrium is transmitted into its lumen. The PTFE does not respect this physiologic mechanism. Moreover, the fibrotic tissue covering its wall [20] further increases the risk of trombosis. Pericardium represents an ideal material for the reconstruction of the SVC. Unfortunately, the availability of autologous pericardium is almost always insufficient to construct an SVC prosthesis. The possibility of using heterologous (bovine) pericardium is tempting. This material is usually treated by glutaraldehyde to improve tissue stability and to reduce antigenicity [22]. Even if glutaraldehyde preservation has been proposed for the treatment of human pericardium in the reconstruction of SVC [23], it has been widely shown that it damages connective tissue, predisposing tissue to mineralization [24, 25]. A new anticalcification technique, the No React technique, has been developed by Biocor (Belo Horizonte, Brasil) for bovine pericardium, and it has been shown to significantly reduce inflammatory response and to improve fibroblast colonization [26]. Owing to the theoretically lower risk of thrombosis of bovine pericar-
dium treated by the No React technique, we used this material for SVC prosthetic replacement (Shelhigh NoReact Pericardial Patch, 10 ⫻ 15) since 2003 [27]. Preliminary long-term results available from this series are promising, since the 5 patients who received bovine pericardium SVC prosthesis, treated only by ticlopidine after discharge, have not developed any type of SVC or BCV thrombosis to date. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. Selection is the key to satisfactory results. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, but only when pathologic N2 disease is excluded by preoperative mediastinoscopy.
References 1. Ginsberg RJ, Vokes EE, Rosenzweig K. Non small cell lung cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer. Principles and practice of oncology. 6th ed. Philadelphia: Lippincott-Raven, 2001:925– 83. 2. Piccione W, Penfield Faber L, Warren WH. Superior vena cava reconstruction using autologous pericardium. Ann Thorac Surg 1990;50:417–9. 3. Thomas P, Magnan PE, Moulin G, Giudicelli R, Fuentes P. Extended operation for lung cancer invading the superior vena cava. Eur J Cardiothorac Surg 1994;8:177– 82. 4. Tsuchiya R, Asamura H, Kondo H, Goya T, Naruke T. Extended resection of the left atrium, great vessels, or both for lung cancer. Ann Thorac Surg 1994;57:960 –5. 5. Dartevelle PG. Extended operations for the treatment of lung cancer. Ann Thorac Surg 1997;63:12–9. 6. Fukuse T, Wada H, Hitomi S. Extended operation for non small cell lung cancer invading great vessels and left atrium. Eur J Cardiothorac Surg 1997;11:664 –9. 7. Spaggiari L, Regnard JF, Magdeleinat P, Jauffret B, Puyo P, Levasseur P. Extended resections for bronchogenic carcionoma invading the superior vena cava system. Ann Thorac Surg 2000;69:233– 6. 8. Spaggiari L, Pastorino U. Combined tracheal sleeve and superior vena cava resection for non small cell lung cancer Ann Thorac Surg 2000;70:1172–5. 9. Bernard A, Bouchot O, Hagry O, Favre JP. Risk analysis and long term survival in patients undergoing resection of T4 lung cancer. Eur J Cardiothorac Surg 2001;20:344 –9. 10. Spaggiari L, Magdeleinat P, Kondo H, et al. Results of superior vena cava resection for lung cancer. Analysis of prognostic factors. Lung Cancer 2004;44:339 – 46. 11. Shargall Y, de Perrot M, Keshavjee S, et al. 15 Years single center experience with surgical resection of the superior vena cava for non-small cell lung cancer. Lung Cancer 2004;45:357– 63.
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12. Suzuki K, Asamura H, Watanabe S, Tsuchiya R. Combined resection of superior vena cava for lung carcinoma: prognostic significance of patterns of superior vena cava invasion. Ann Thorac Surg 2005;78:1184 –9. 13. Spaggiari L, Thomas P, Magdeleinat P, et al. Superior vena cava resection with prosthetic replacement for non small cell lung cancer: long term results of a multicentric study. Eur J Cardiothorac Surg 2002;21:1080 – 6. 14. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non–small-cell lung cancer. N Engl J Med 2005;352:2589 –97. 15. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 1994;330:153– 8. 16. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 1994;86:673– 80. 17. Stephens RJ, Fairlamb N, Gower N, et al. The Big Lung Trial (BLT): determining the value of cisplatin-based chemotherapy for all patients with non-small cell lung cancer (NSCLC). Preliminary results in the supportive care setting. Proc Am Soc Clin Oncol 2002;21:38(abstract 1161). 18. The Elderly Lung Cancer Vinorelbine Italian Study Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999;91:66. 19. DiPerna CA, Wood DE. Surgical management of T3 and T4 lung cancer. Clin Cancer Res 2005;11(Suppl):5038s– 44s. 20. Dartevelle PG, Chapelier AR, Pastorino U, et al. Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal-pulmonary malignant tumors. J Thorac Cardiovasc Surg 1991;102:259 – 65. 21. Shintani Y, Ohta M, Minami M, et al. Long-term patency after replacement of the brachiocephalic veins combined with resection of mediastinal tumors. J Thorac Cardiovasc Surg 2005;129:809 –12. 22. Carpentier A, Lemaigre G, Robert L, et al. Biological factors affecting long-term results of valvular heterografts. J Thorac Cardiovasc Surg 1969;58:467– 83. 23. D’Andrilli A, Ibrahim M, Venuta F, De Giacomo T, Coloni GF, Rendina EA. Glutaraldehyde preserved autologous pericardium for patch reconstruction of the pulmonary artery and superior vena cava. Ann Thorac Surg 2005;80: 357– 8. 24. Bernacca GM, Dimitri WR, Fisher AC, Mackay TG, Wheatley DJ. Chemical modification of bovine pericardium and its effects on calcification in the rat subdermal model. Biomaterials 1992;13:345–52. 25. Schoen FJ, Tsao JW, Levy RJ. Calcification of bovine pericardium used in cardiac valve bioprostheses: implications for the mechanism of bioprosthetic tissue mineralization. Am J Pathol 1986;123:134 – 45. 26. Abolhoda A, Yu S, Oyarzun JR, McCormick JR, Bogden JD, Gabbay S. Calcification of bovine pericardium: glutaraldheyde versus no-react biomodification. Ann Thorac Surg 1996;62:169 –74. 27. Spaggiari L, Veronesi G, D’Aiuto M, Tosoni A. Superior vena cava reconstruction using heterologous pericardial tube after extended resection for lung cancer. Eur J Cardiothorac Surg 2004;26:649 –51.
DISCUSSION DR JESSICA S. DONINGTON (Stanford, CA): With the poor impact of N2 disease in these patients, after your induction therapy how do you restage these patients? Do you repeat a mediastinoscopy? Do you perform positron emission tomography on them? How do you deal with those patients?
DR SPAGGIARI: I think that before the extended surgery, if I find R2 lymph nodes positive, the patient is excluded from surgery, but often, mainly in patients with locally advanced disease, superior vena cava and carinal involvement, we can find some R4 lymph nodes. So, they do not represent a formal
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contraindication for surgery after induction chemotherapy, unless in case of bulky disease. Restaging is mainly based on CT scan and PET scan. I don’t use redo mediastinoscopy.
in these cases, loading the patient with fluid potentially may result in postpneumonectomy pulmonary edema. Please tell us how you manage these situations.
DR HON CHI SUEN (St. Louis, MO): I want to congratulate the authors for their substantial series of SVC resections and excellent results. Could you tell us more about the way you manage the patient physiologically when you clamp the superior vena cava? According to Dr Dartevelle, if you clamp the superior vena cava, there is a decrease in venous return and a decrease in the systemic blood pressure, and with an increase in the central venous pressure, there is a decrease in the cerebral perfusion pressure, and he recommends loading the patient up with fluid and starting inotropes to increase the systemic blood pressure. As you know, since we may need to perform pneumonectomies
DR SPAGGIARI: Thank you for the question. The crossclamping technique has been studied in France by the group of Philippe Dartevelle experimentally on animals, and they demonstrated that key issues for intraoperative management are a short clamping time (safe in experimental model up to 60 minutes), heparinization, fluids intake and the use of vasoactive agents to maintain an adequate mean arterial pressure. Pneumonectomy, when required, is performed at least 30 minutes after SVC replacement, therefore the anesthesist can progressively reduce fluid overload before closing the pulmonary artery.
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Background. The oncologic value of superior vena cava (SVC) resection for lung and mediastinal malignancies remains controversial. In this context, we have reviewed our experience in the treatment of locally advanced lung and mediastinal tumor invading the SVC system, analyzing postoperative outcome and long-term oncologic results. Methods. The clinical data of patients who underwent SVC resection were retrospectively analyzed to assess postoperative mortality, and overall and procedure-specific morbidity. Overall survival was calculated for mediastinal and lung tumor groups. Results. From 1998 to 2004, 70 consecutive patients (52 with lung cancer and 18 with mediastinal tumors) underwent SVC system resection. There were 25 replacements (36%) of the SVC system by prosthesis, whereas the remaining underwent partial resection. Major postoperative morbidity and mortality rates in lung cancer pa-
tients were 23% and 7.7%, respectively (50% and 5.6% in mediastinal tumors). In the lung cancer group, 5-year survival probability was 31%, and it was affected by mediastinal nodal status (5-year survival in N0 –N1 patients 52%, 21% in N2 patients, 0 in N3 patients). Median survival for mediastinal tumors was 49 months. Conclusions. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, only when pathologic N2 disease is excluded by preoperative mediastinoscopy.
S
provement of both technical devices and surgical experience have renewed the interest in the use of SVC resection. In the last 15 years, several series of SVC resections have been published, confirming feasibility and reporting long-term survival data (Table 1) [2–12]. With the aim of contributing to the existing experience on this topic, this study reviews our experience in resections for mediastinal and pulmonary neoplasms invading the SVC system, with particular attention to the results and pitfalls of this extended surgery.
uperior vena cava (SVC) system invasion by lung and mediastinal malignancies has long been considered a contraindication for surgical resection. However, during the 1970s and 1980s, experimental animal research and clinical case reports suggested the technical feasibility of such an extended surgery for mediastinal and pulmonary malignancies, resulting in long-term survival in some instances. The absence of suitable prosthetic material for SVC replacement, the technical incertitude concerning the effect of SVC clamping, the fear of graft thrombosis and infection after pulmonary resection, and finally, the dismal oncologic prognosis after initial SVC resection experiences have limited its diffusion as a surgical treatment. The poor prognosis of locally advanced lung cancer treated by radiotherapy (5-year survival 5%), or chemoradiotherapy (5-year survival 5% to 17%) [1], the imAccepted for publication July 27, 2006. Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30 –Feb 1, 2006. Address correspondence to Dr Spaggiari, Department of Thoracic Surgery, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy; e-mail: [email protected].
© 2007 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2007;83:223–30) © 2007 by The Society of Thoracic Surgeons
Material and Methods The primary objective of this study was to analyze the mortality, morbidity, and long-term results of SVC resection, both in terms of survival and in the patency of the prosthetic replacement, when performed. Our Ethical Committee was informed of the study and did not require approval. All patients gave their informed consent for the study.
Database A specific database was designed for patients undergoing SVC resection and comprised four sections: demograph0003-4975/07/$32.00 doi:10.1016/j.athoracsur.2006.07.075
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Table 1. English-Language Literature Review (1990 –2005): Full Papers With More Than 6 Patients [2–12] Author, Year of Publication GENERAL THORACIC
Patients
Prosthetic Graft
Mortality
5-Year Survival
6 15 32 14 8 25 11 8 109 15 40
0 4 7 14 3 7 3 2 26 9 11
17% 7% 22% 7% NR 12% 0 NR 12% 14% 10%
NR 24% NR 31% NR 29% NR 25% 21% 57% (3 years) 24%
Piccione, 1990 Thomas, 1994 Tsuchiya, 1994 Dartevelle, 1997 Fukuse, 1997 Spaggiari, 2000a Spaggiari, 2000b Bernard, 2001 Spaggiari, 2004c Shargall, 2004 Suzuchy, 2005 a
Marie Lannelongue Hospital, Paris, experience.
b
European Institute of Oncology, Milan, experience.
c
Multicentric study.
NR ⫽ not reported.
ics (age, sex, history, presence of SVC syndrome signs, American Society of Anesthesiologists score, forced expiratory volume in 1 second [FEV1], and diffusion capacity of the lung for carbon monoxide [Dlco]); oncologic data (clinical and pathologic TNM, type and duration of induction treatment, response to chemotherapy when performed, bronchoscopy, positron emission tomography scan results); intraoperative data (access, duration of surgery, duration of SVC clamping, associated lung resection, intraoperative continuous hemodynamics monitoring data, amount of adminitered fluids, intraoperative adverse events); and postoperative and follow-up data (postoperative deaths, morbidity, postoperative radiotherapy, status of the patient at last follow-up, status of the disease, patency of SVC graft at the last computed tomography [CT] control).
the fourth intercostal space, or of the fifth intercostal space with the resection of the fifth cartilage. This approach was usually utilized in case of planned associated bronchoplastic or carinal resection, whereas in cases with right upper lobectomy, the hemiclamshell approach was preferred. In the case of mediastinal tumor, sternotomy or the hemiclamshell approach were used.
Intraoperative Management In the case of lung tumors, the surgical approach utilized was the standard muscle-sparing lateral thoracotomy in
Fig 1. Operative picture during partial superior vena cava resection for lung cancer. Reconstruction of the superior vena cava by a pericardial patch (Arrow).
Fig 2. Operative picture after complete resection of the superior vena cava and both brachiocephalic veins for mediastinal tumor; revascularization was done between the left brachiocephalic vein and superior vena cava using an autologous custom-made pericardial tube (arrow). Surgical approach: sternotomy; lung resection: right upper lobectomy.
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daily, after discontinuing low-molecular-weight heparin. Patients who underwent partial SVC resection without prosthetic replacement did not undergo anticoagulation therapy.
Follow-Up Patients with SVC resection were followed up at 1 month and every 4 months afterward. All of them received contrast chest CT scan before discharge and before each follow-up visit (coupled with upper abdomen CT scan). Information for the present study was obtained by directly contacting the patient or the referring physician. In case of absent information, a certificate was obtained from the anagraphic database of the patient’s city of birth.
Statistical Analysis Fig 3. Operative picture after complete superior vena cava resection with polytetrafluoroethylene (PTFE) graft replacement for lung cancer. Surgical approach: hemiclamshell; lung resection: upper bilobectomy; prosthesis: no. 14 ringed PTFE.
The type of SVC resection performed depended on the degree of venous involvement. When vessel involvement was limited (less than 50%), resection and direct repair was preferred, using basic techniques such as mechanical suture or continuous polypropylene suture on a vascular clamp. When the defect was too large, it was repaired by the use of a pericardial patch (Fig 1). When the SVC was not extensively infiltrated close to one of the BCV trunks (left or right), the entire venous trunk was removed without subsequent reconstruction, unless both BCV were infiltrated or the patient had a previously resected or ligated contralateral internal jugular vein; in that case, the BCV was reconstructed by prosthetic replacement (Fig 2). When SVC infiltration involved more than 50% of the circumference of the SVC, prosthetic replacement by cross-clamping technique was preferred (Fig 3). On an exceptional basis, when SVC infiltration involved the right side of the heart, the use of extracorporeal circulation was planned (Fig 4). During the first period of the study (1998 to 2002), SVC prosthetic replacement was performed by a polytetrafluoroethylene (PTFE) graft (Fig 3). Since 2003, all patients have received SVC replacement using a biological, custom-made bovine pericardial tube (Shelhigh NoReact Pericardial Patch [10 ⫻ 15]; Shelhigh, Millburn, New Jersey [Fig 5]). To compensate for the acute SVC syndrome and the expected drop in arterial pressure at SVC clamping due to the reduction in cardiac output, intraoperative fluid and vasoactive agents administration were managed to obtain a mean arterial pressure before clamping of 80 mm Hg. Intravenous sodium heparin (0.5 mg/mL) was used in all patients requiring SVC clamping. Postoperatively, in patients with PTFE prosthesis, anticoagulation therapy was continued using lowmolecular-weight heparin for 1 month and maintained afterward with oral anticoagulants. Patients with bovine pericardium prosthesis received ticlopidine, 150 mg
Postoperative mortality was defined as any death occurring during hospitalization or within 30 days after surgery. Morbidity and mortality were analyzed to assess whether age, preoperative FEV1, SVC prosthetic replacement, duration of SVC clamping time, preoperative chemotherapy, and type of lung resection had an impact on postoperative risk. Comparisons were performed using Student’s t test (paired values) for continuous variables and the Fisher’s exact test for categorical variables. Survival curves were obtained by the Kaplan-Meier method, and were compared between groups (lung cancer versus mediastinal tumors) using the log-rank test. Additionally, in the lung cancer group, survival was analyzed by age, preoperative chemotherapy, and mediastinal nodes status.
Fig 4. Operative picture after complete resection of superior vena cava and both brachiocephalic veins, and partial right atrium resection (arrow) for mediastinal tumor. Revascularization was performed between the right brachiocephalic vein and right atrium with no. 14 ringed polytetrafluoroethylene (PTFE) prosthesis. Surgical approach: sternotomy; lung resection: none; operation performed using extracorporeal circulation and cardiac arrest. Inset: The neoplastic thrombus completely occluding the superior vena cava, and partially occluding the upper part of the right atrium.
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Table 2. Patient Characteristics Number GENERAL THORACIC
Population Mediastinal tumors Type of SVC repair SVC prosthetic replacement SVC-BCV prosthesis Direct SVC repair Survival (dead/alive) 1 year 3 years 5 years Lung tumors Induction treatment Chemotherapy Radiochemotherapy Stage pT0 pT1 pT2 pT3 pT4 pN0 pN1 pN2 pN3 Stage I Stage II Stage III Type of SVC repair SVC prosthetic replacement SVC-BCV prosthesis Direct SVC repair Autologous pericardial patch Lung resection Pneumonectomy Tracheal sleeve pneumonectomy Lobectomy/bilobectomy Tracheal sleeve lobectomy Sleeve lobectomy Segmentectomy Survival (dead/alive) 1 year 3 years 5 years BCV ⫽ brachiocephalic vein;
70 18 6 3 9 4/11 7/8 8/3 52 33 7 3 1 8 9 31 8 18 21 5 3 13 36 13 3 32 4
cancer. Twenty-one patients (40%) underwent mediastinal investigation by mediastinoscopy before SVC surgery, and 40 (77%) received preoperative induction treatment (chemotherapy, n ⫽ 33; chemoradiation therapy, n ⫽ 7). The indication for SVC resection was the direct involvement of the vessel in all but 6 patients who underwent resection for bulky N2 disease after induction chemotherapy at the beginning of our experience. Twelve extended pneumonectomies (23%; 9 tracheal sleeve pneumonectomies), 7 tracheal sleeve lobectomies, 13 sleeve lobectomies, 4 bilobectomies, 14 lobectomies, and 2 segmentectomies were performed. In 18 patients, resection was performed for mediastinal malignancies; in 9 patients, it was performed for thymus tumors (thymoma, thymus carcinoma, carcinoid of the thymus), whereas the remaining patients were affected by miscellaneous rare mediastinal tumors (namely, primary sarcoma of the mediastinum, and so forth).
Superior Vena Cava Reconstruction In 25 cases (35.7%), extent of SVC infiltration required a prosthetic replacement. All prosthetic replacements were performed using the cross-clamping technique, except one in which extracorporeal circulation was used to remove an invasive thymoma invading SVC and right atrium with endoluminal neoplastic thrombus (Fig 4). Median cross-clamping time was 30 minutes. In the group of 13 patients who received SVC replacement for lung cancer, replacement was performed by a PTFE graft in 8 patients (median size, 14; range, 10 to 16); and since 2003 by a biological, custom-made bovine pericardial tube in 5 patients (size no. 20; Fig 5) [13]. In the group of mediastinal tumors, there were 6 complete SVC resections with prosthetic replacement, in 5 patients using a PTFE graft and 1 with a custom-made bovine pericardial tube. In 6 cases (8.5%; 3 cases in the lung cancer group and
3 9 18 7 13 2 14/38 23/12 14/7
SVC ⫽ superior vena cava.
Results Population From November 1998 to May 2004, 70 patients underwent SVC system resection for either lung or mediastinal malignancies. Clinical characteristics of the population are reported in Table 2. Fifty-two patients (42 male patients, median age 62,7 years) had SVC resection for nonsmall-cell lung
Fig 5. Operative picture after complete superior vena cava resection with custom-made bovine pericardial tube replacement for lung cancer. Surgical approach: anterolateral thoracotomy; lung resection: tracheal sleeve pneumonectomy; prosthesis: bovine pericardial prosthesis, no. 20.
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3 in the mediastinum group), tumor infiltration was at the brachiocephalic vein (BCV) junction, needing reconstruction of BCV and the upper portion of SVC. The BCV prosthetic replacement was performed in 5 cases by PTFE graft and in 1 case by autologous pericardial tube. In 41 cases, infiltration of SVC was peripheral and allowed direct repair by vascular stapler or tangential clamping and simple running suture. In 4 cases, direct repair was not possible, and the SVC was repaired by an autologous pericardial patch.
Morbidity and Mortality No intraoperative death was observed. One patient did not tolerate SVC cross-clamping, and the resection was performed by tangential clamping. In the lung cancer group, major postoperative complications developed in 23% of patients (n ⫽ 12). The postoperative mortality was 7.7% (n ⫽ 4). The causes of postoperative death were 2 cases of late bleeding after discharge but within 30 days, 1 case of adult respiratory distress syndrome, and 1 cardiac arrest without organic causes 7 days after the operation. The most frequent complications were pulmonary (7 of 12, 58%). In the mediastinal tumor group, major postoperative complications developed in 9 patients (50%), and the postoperative mortality was 5.5% (n ⫽ 1) due to adult respiratory distress syndrome. None of the demographic and intraoperative variables had a significant impact on morbidity and mortality. Moreover, postoperative morbidity and mortality was not negatively affected by preoperative chemotherapy in either group (Fisher’s exact test, p ⫽ 0.11).
Early and Late Thrombosis With a median follow-up of 32 months, 6 prosthetic thromboses were recorded (overall thrombosis rate 8.5%, prosthetic thrombosis rate 24%). Four thromboses occurred within 1 months after operation (early thrombosis). One of the 19 patients (4.5%) who had complete SVC prosthetic replacement experienced early postoperative graft thrombosis. Three of 6 patients who had both left BCV and partial SVC resection experienced early thrombosis of the PTFE graft. All patients were treated by anticoagulation. Two late thromboses (more than 1 month after surgery) were recorded in patients with mediastinal tumors 2 and 7 months after operation, respectively, and they were both medically treated (22%). No thrombosis was recorded in patients with bovine pericardium SVC prosthesis. The occurrence of thrombosis was not significantly related to any of the demographic and intraoperative variables considered. Nevertheless, in 4 of 6 cases (66.6%), a BCV reconstruction was associated.
Long-Term Survival In the lung cancer group, full-thickness infiltration of SVC (pT4) was confirmed pathologically in 31 patients (60%). Pathologic assessment of lymph node involvement showed N2 disease in 21 patients (40%), N1 disease in 18 patients, N0 disease in 8 patients, and N3 disease in 5 patients. Eighteen patients (35%) underwent adjuvant radiotherapy. Follow-up information was obtained in all
Fig 6. Survival curve (Kaplan-Meier method) of patients who underwent resection of the superior vena cava for nonsmall-cell lung cancer. The probability of survival at 5 years was 31%; the number of surviving patients at risk at 60 months was 21. Median survival was 16.2 months (95% confidence interval: 12.6 to 36.7).
the cases. Median survival was 16.2 months (95% confidence interval: 12.6 to 36.7), with a 5-year probability of survival of 31% (Fig 6). Mediastinal lymph nodes involvement affected survival, being 5-year survival 56% for N0 –N1 patients, 21% for N2 patients, and 0% for N3 patients (p ⫽ 0.056). No difference in terms of survival was found between patients who received preoperative chemotherapy and those who did not (log-rank test, p ⫽ 0.68). Median survival in the mediastinal tumours group was 49 months, with a 5-year probability of survival of 45%.
Comment Our series confirmed data from existing literature showing that resection of the SVC is a feasible additional procedure during resection of pulmonary or mediastinal tumors infiltrating the venous mediastinal axis, minimally increasing postoperative complications in experienced hands. Nevertheless, two questions regarding SVC surgery remain unaswered: what are the defining characteristics of an optimum candidate for SVC resection, and which SVC reconstruction technique provides the best results. Concerning the first question, the selection of candidates for SVC resection depends first and foremost on the underlying pathology. In the case of lung tumors infiltrating the mediastinum, SVC resection is often only part of a more extended procedure, such as pneumonectomy with or without carinal resection [10, 14]. In these cases, patients have to be fit enough to tolerate extended pneumonectomy, ideally no more than 70 years of age, classed American Society of Anesthesiologists score 1 or 2, with a predicted postoperative FEV1 of more than 40%, and finally, with no major cardiac comorbidity. Another important point is that SVC resection should never be considered in the case of urgent treatment of acute SVC syndrome. The dramatic hemodynamic changes occurring in such a situation create instability in
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the patient at SVC cross-clamping, making it impossible to perform a radical resection, thereby eliminating the utility of this type of surgery. Apart from general considerations, patient selection is mainly based on oncologic aspects. The best results in terms of survival are obtained in mediastinal tumors (median survival 49 months in our series). They represent a heterogeneous group of diseases, the most frequent being thymoma. Its position in the anterior mediastinum makes BCV and SVC infiltration a common feature of invasive thymoma; therefore, vascular resection becomes necessary to obtain a radical resection, and it is justified by the natural history of these tumors, which are locally aggressive but have a low risk of distant metastases. Superior vena cava resection may also be indicated in case of other mediastinal tumors such as nonseminomatous germ cell tumors after chemotherapy and the normalization of markers, when a significant residual mass is still present and presents risks of further degeneration or teratoma slow-growing syndrome. In lung cancer, our series confirmed an acceptable 5-year survival (31%) obtained by lung resection associated with SVC resection and did not confirm the adverse role of SVC grafting as compared with direct repair, as had been previously suggested [10, 13]. The most important prognostic factor, even in this subset of patients, remains mediastinal nodal status. In fact, in our series, 5-year survival is encouraging when there is no mediastinal involvement (52%), disappointing in the case of pathologic N2 disease (21%), and absent when N3 disease was occasionally discovered during the hemiclamshell approach. One of the practical consequences is that mediastinoscopy should be routinely performed in all the patients with suspected SVC infiltration, as the positron emission tomography scan is often ineffective because tumor fixation may mask mediastinal disease. Another important issue in the proper selection of surgical candidates is the role of neoadjuvant chemotherapy. Even in the absence of absolute evidence from the literature, we advocate its use in lung tumors with SVC infiltration for four main reasons. The first is the clinical observation that in a nonnegligible proportion of patients who undergo extended surgery (not only SVC resection), distant metastases develop a few months after operation that had not been evident at preoperative staging. The second reason is represented by the theoretical advantage of induction treatment (decreasing tumor size, increasing the likelihood of negative margin, sterilizing micrometastatic disease, defining tumor response to chemotherapy), which may facilitate operation and exclude patients with rapidly evolving disease from surgery. The third consideration is that a negative impact of induction chemotherapy on postoperative morbidity and mortality has not been clearly demonstrated. Finally, the benefits of chemotherapy in terms of survival have been demonstrated in early stage [14], stage IIIa [15, 16], and stage IV [17, 18]; therefore, why should T4 tumors infiltrating SVC represent an exception? The supposed survival advantage of induction chemotherapy was not evident in our series, being instead due to
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the bias of selection and to the limited dimension of the population. Only a prospective randomized trial could confirm the actual advantages provided by preoperative induction treatment. Unfortunately, its feasibility is limited by several factors, first of all the difficulty of precise clinical staging in tumors infiltrating the SVC. It is true that a percentage of patients classed as clinical T4 are “false T4” (about 40%) [19], which occurs when the pathologist does not confirm vessel infiltration. However, there is no possibility of avoiding the overtreatment of SVC resection in these patients because this assessment is sometimes impossible even intraoperatively. In any case, survival curves of “false T4” and “true T4” patients in the subset of N0 –N1 cases overlap (5-year survival 51.5% and 36.9%, respectively; log-rank test, p ⫽ 0.72). Morover, it is impossible to evaluate how many false T4 patients were actually true T4 before induction chemotherapy. Which SVC reconstruction technique provides the best results? It depends on the degree of SVC infiltration. Direct repair is the simplest reconstruction, but it is acceptable only when the caliber of the repaired SVC is 50% or more of the original one. When that is not the case, but SVC is not circumferentially resected, SVC can be cross-clamped and repaired by an autologous pericardial patch, which does not require long-term anticoagulation. When a circumferential SVC resection is performed, a prosthetic replacement should be performed immediately afterward. Historically, the gold standard of SVC prosthetic replacement was PTFE. The main problems of PTFE replacement are the need for long-term anticoagulation therapy and thrombosis. Few data are available on long-term patency of SVC prostheses. When considering all thrombotic events (early and late, SVC or BCV, or both), the rate of prosthetic thrombosis ranges between 22% [20] and 50% [21]. Apart from the technical factors (such as the need for BCV reconstruction or an excessive prosthetic length), it has to be kept in consideration that SVC is a venous high-flow/low-pressure conduit, emptied when negative pressure that has built in the right atrium is transmitted into its lumen. The PTFE does not respect this physiologic mechanism. Moreover, the fibrotic tissue covering its wall [20] further increases the risk of trombosis. Pericardium represents an ideal material for the reconstruction of the SVC. Unfortunately, the availability of autologous pericardium is almost always insufficient to construct an SVC prosthesis. The possibility of using heterologous (bovine) pericardium is tempting. This material is usually treated by glutaraldehyde to improve tissue stability and to reduce antigenicity [22]. Even if glutaraldehyde preservation has been proposed for the treatment of human pericardium in the reconstruction of SVC [23], it has been widely shown that it damages connective tissue, predisposing tissue to mineralization [24, 25]. A new anticalcification technique, the No React technique, has been developed by Biocor (Belo Horizonte, Brasil) for bovine pericardium, and it has been shown to significantly reduce inflammatory response and to improve fibroblast colonization [26]. Owing to the theoretically lower risk of thrombosis of bovine pericar-
dium treated by the No React technique, we used this material for SVC prosthetic replacement (Shelhigh NoReact Pericardial Patch, 10 ⫻ 15) since 2003 [27]. Preliminary long-term results available from this series are promising, since the 5 patients who received bovine pericardium SVC prosthesis, treated only by ticlopidine after discharge, have not developed any type of SVC or BCV thrombosis to date. In conclusion, SVC resection may achieve permanent cure in patients who would have been defined as inoperable 10 years ago. Selection is the key to satisfactory results. In the case of mediastinal tumors, the need for SVC resection alone should not be considered a contraindication for surgery when prosthetic replacement is feasible. In the case of lung tumors, infiltration of SVC can achieve satisfactory long-term results after neoadjuvant chemotherapy, but only when pathologic N2 disease is excluded by preoperative mediastinoscopy.
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DISCUSSION DR JESSICA S. DONINGTON (Stanford, CA): With the poor impact of N2 disease in these patients, after your induction therapy how do you restage these patients? Do you repeat a mediastinoscopy? Do you perform positron emission tomography on them? How do you deal with those patients?
DR SPAGGIARI: I think that before the extended surgery, if I find R2 lymph nodes positive, the patient is excluded from surgery, but often, mainly in patients with locally advanced disease, superior vena cava and carinal involvement, we can find some R4 lymph nodes. So, they do not represent a formal
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contraindication for surgery after induction chemotherapy, unless in case of bulky disease. Restaging is mainly based on CT scan and PET scan. I don’t use redo mediastinoscopy.
in these cases, loading the patient with fluid potentially may result in postpneumonectomy pulmonary edema. Please tell us how you manage these situations.
DR HON CHI SUEN (St. Louis, MO): I want to congratulate the authors for their substantial series of SVC resections and excellent results. Could you tell us more about the way you manage the patient physiologically when you clamp the superior vena cava? According to Dr Dartevelle, if you clamp the superior vena cava, there is a decrease in venous return and a decrease in the systemic blood pressure, and with an increase in the central venous pressure, there is a decrease in the cerebral perfusion pressure, and he recommends loading the patient up with fluid and starting inotropes to increase the systemic blood pressure. As you know, since we may need to perform pneumonectomies
DR SPAGGIARI: Thank you for the question. The crossclamping technique has been studied in France by the group of Philippe Dartevelle experimentally on animals, and they demonstrated that key issues for intraoperative management are a short clamping time (safe in experimental model up to 60 minutes), heparinization, fluids intake and the use of vasoactive agents to maintain an adequate mean arterial pressure. Pneumonectomy, when required, is performed at least 30 minutes after SVC replacement, therefore the anesthesist can progressively reduce fluid overload before closing the pulmonary artery.
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