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Journal of Clinical Oncology, Vol 22, No 21 (November 1), 2004: pp. 4351-4356 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.188 Role of Lung Transplantation in the Treatment of Bronchogenic Carcinomas for Patients With End-Stage Pulmonary DiseaseFrom the Toronto Lung Transplant Program, University of Toronto, Ontario, Canada Address reprint requests to Shaf Keshavjee, MD, Director, Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth St, EN 10-224, Toronto, Ontario, Canada M5G 2C4; e-mail: shaf.keshavjee{at}uhn.on.ca
PURPOSE: To determine the role of lung transplantation in the treatment of patients presenting with bronchogenic carcinoma and end-stage lung disease. METHODS: An international survey was conducted to determine the outcome of patients with bronchogenic carcinoma in the explanted lung at the time of transplantation. A group of 69 patients was collected from 33 centers. RESULTS: Twenty-six patients underwent 29 lung transplantations for advanced multifocal bronchioloalveolar carcinoma (BAC) as the primary indication for transplantation, and 13 developed a recurrence, with an overall 5-year actuarial survival of 39%. Incidental bronchogenic carcinomas classified as stage I (n = 22), II (n = 12), and III (n = 2), or as incidental multifocal BAC (n = 7), were found in the explanted lung of the remaining 43 patients. The 5-year actuarial survival was 51% in patients with stage I carcinomas, and was significantly better than for patients with stage II and III carcinomas (survival of 14%) or with incidental multifocal BAC (survival of 23%). Time from transplantation to recurrence and from recurrence to death was significantly longer in patients with multifocal BAC than in patients with other types of bronchogenic carcinoma. In addition, the site of recurrence was limited to the transplanted lung in 88% of the patients with multifocal BAC, whereas it was always widespread in patients with other types of bronchogenic carcinoma. CONCLUSION: This study demonstrates that long-term survival can be achieved after lung transplantation in patients with stage I bronchogenic carcinoma or with advanced multifocal BAC.
Lung transplantation has enjoyed increasing success during the last two decades. It has evolved from an experimental endeavor to the mainstay of therapy for many end-stage lung diseases. The Registry of the International Society for Heart and Lung Transplantation (ISHLT) reported in 2003 that almost 15,000 lung transplantations have been performed worldwide and that more than 1,500 lung transplantations are performed annually.1 Bronchogenic carcinoma is one of the most common forms of cancer worldwide and remains the leading cause of cancer-related deaths in Europe and North America.2 Because of the theoretical risk of rapid cancer dissemination with post-transplant immunosuppression, bronchogenic carcinoma has been considered a strict contraindication to lung transplantation.3 Bronchioloalveolar carcinoma (BAC) represents a unique and small subgroup of bronchogenic carcinoma that is characterized by the proliferation of well-differentiated tumor cells along the walls of alveoli with preservation of the underlying lung architecture. It can present as a localized discrete lesion or with a diffuse multifocal pattern involving one or both lungs. Pulmonary recurrence without systemic dissemination is often observed after lung resection for multifocal BAC, and survival beyond 2 years is uncommon.4,5 Death usually occurs as a result of pulmonary failure secondary to tumor replacement of the functioning lung.4–6 Despite case reports and small case series on lung transplantation for multifocal BAC, the role of lung transplantation in the treatment of patients with bronchogenic carcinoma and end-stage lung disease remains unknown.7–10 We therefore conducted an international survey to determine the outcome of patients presenting with bronchogenic carcinoma in the explanted lung at the time of transplantation. The goal of this study was to assess the world experience and to determine whether lung transplantation might have a role in the treatment of selected patients with bronchogenic carcinoma and end-stage lung disease. For a case to be included in the study, bronchogenic carcinoma had to be either incidentally discovered in the explanted lung at the time of transplantation or be known before the transplantation procedure, but in all cases, the tumor had to be completely removed at the time of transplantation.
In August 2002, a questionnaire was sent to 150 programs affiliated with the ISHLT registry, and by March 2003, 67 centers had responded (Appendix). Of a total of 8,000 lung transplantations performed at these centers, 69 patients were reported to have a bronchogenic carcinoma in the explanted lung (incidence, 0.9%). The large majority of centers reported having no patient with lung cancer (n = 34), 19 centers reported one patient, seven reported two patients, three reported three patients, and one center each reported to have five, six, seven, and nine patients. Four recipients presenting with malignant disease other than bronchogenic carcinoma were excluded from the study. One patient had a mucosa-associated lymphoid tissue lymphoma in the explanted lung, one was transplanted for an angiosarcoma, and two underwent transplantation for metastatic disease limited to the lung (chondrosarcoma and uterine leiomyoma). Data are expressed as mean ± SEM, or as median and range. The t test was used to calculate differences between continuous variables. Survival and recurrence-free survival were calculated with the use of the Kaplan-Meier method, and survival curves were compared using the log-rank test. The threshold of significance was set at P < .05. The Graphpad software package (Graphpad Software Inc, San Diego, CA) was used for all statistical analyses.
The indication for lung transplantation was end-stage lung disease secondary to advanced multifocal BAC in 26 patients (Table 1). The time on the waiting list ranged from 3 days to 14 months, with a median of 3 months. Preoperative investigations included computed tomography scan of the chest (n = 26) and abdomen (n = 22), bone scan (n = 21), brain imaging (n = 16), mediastinoscopy (n = 15), and positron emission tomography scan (n = 5). Four (44%) of the nine patients undergoing single lung (n = 8) or heart–single lung transplantation (n = 1) because of previous contralateral pneumonectomy died postoperatively, whereas none of the remaining 17 patients undergoing bilateral lung (n = 16) or heart–bilateral lung transplantation (n = 1) died postoperatively (P = .003). The primary cause of death in these four patients was primary graft failure (n = 2), right ventricular failure (n = 1), and cardiogenic shock (n = 1).
Among the 22 patients who survived the operation, 13 (59%) developed recurrence between 5 and 49 months (median, 12 months) after transplantation, and nine of them died between 11 and 82 months (median, 22 months) after transplantation (Table 1). The majority of recurrences were located in the transplanted lung only (n = 11), and most patients died from respiratory failure (n = 7). No significant difference was observed with regards to age, sex, previous surgery for BAC, type of transplantation, or use of cardiopulmonary bypass between patients presenting with or without recurrence. The proportion of nonsmokers, however, was significantly higher in the group of patients presenting with recurrence than in the group of patients without recurrence (92% v 44%, respectively; P = .01). Three patients presented with N2 disease in the group with recurrence, whereas none of them had metastatic nodal disease in the group without recurrence (P = .1). Three patients underwent re-transplantation for recurrent BAC (one single lung, one bilateral lung, and one heart-lung transplantation); one died postoperatively, one died of recurrence after 21 months, and one is alive without recurrence almost 7 years after retransplantation. The overall actuarial 5- and 10-year survival rates for the 26 patients were 39% and 31%, respectively (Fig 1). The 5-year recurrence-free survival was 35%. The survival rate was similar to the overall survival reported by the ISHLT registry in 13,453 patients undergoing lung transplantation, with a 5-year survival of 45% and a 10-year survival of 23%.1
The indication for lung transplantation in the remaining 43 patients was mainly emphysema and idiopathic pulmonary fibrosis (Table 2). The time on the waiting list ranged from 2 days to 36 months (median, 8 months). Tumors ranged from 0.3 to 3.5 cm (median, 1.5 cm) and were characterized as T1N0 (n = 19), T2N0 (n = 3), T1N1 or T2N1 (n = 12), and T1N2 or T2N2 (n = 2) according to the TNM system classification. Two patients presented with a tumor larger than 3 cm, whereas the remaining T2 lesions were due to invasion of the visceral pleura. Two patients presented with bilateral squamous cell carcinoma without any lymph node metastases, and were considered as two primary stage I tumors. Multifocal BAC confined to one (n = 6) or both lungs (n = 1) was detected in seven patients and was considered as incidental multifocal BAC (in contrast to advanced multifocal BAC described in the Introduction).
The 5-year and 10-year survival for patients with stage I (T1-2N0) disease were significantly better than for patients with stage II (T1-2N1) and stage III (T1-2N2) or with incidental multifocal BAC (Fig 2). After a median follow-up of 30 months (range, 3 to 120 months), 14 (64%) of the 22 patients with stage I carcinoma were alive without recurrence. Only five patients with stage I disease developed recurrences, and all died within 12 months of transplantation (median, 8 months).
Among the 14 patients with stage II or III carcinomas, nine (64%) died from recurrence after a median of 8 months (range, 4 to 16 months), two are alive without recurrence after 20 and 98 months, and three died without recurrence after 3, 9, and 10 months. Among the seven patients with incidental multifocal BAC, three died from recurrence; one is alive with recurrence in the transplanted lung; two are alive without recurrence 9 and 49 months after transplantation, respectively; and one died without recurrence 2 months postoperatively. Multifocal BAC seems to behave differently than other types of bronchogenic carcinoma. Patients with multifocal BAC presented with delayed recurrence and slow-growing tumors when compared to recurrence from other types of bronchogenic carcinomas (Fig 3). Furthermore, the site of recurrence was limited to the transplanted lung in 88% of the patients with multifocal BAC, whereas it was always widespread in patients with other types of bronchogenic carcinoma.
This survey of the international experience with lung transplantation for patients with bronchogenic carcinoma in the explanted lung demonstrates three important findings: (1) few patients with stage I bronchogenic carcinoma develop recurrences, (2) most patients with stage II and III bronchogenic carcinoma develop recurrences and die within 1 year of transplant because of widespread metastasis, and (3) most patients with multifocal BAC develop recurrences, but recurrence is usually limited to the transplanted lung and is slow growing despite the immunosuppressive therapy. Patients with stage I bronchogenic carcinoma achieved a 5-year survival of 51% with only five of 22 patients developing recurrence. In contrast, the large majority of patients diagnosed with more advanced stage bronchogenic carcinoma (ie, stage II and III) developed recurrent disease and died within 1 year of surgery. Only two patients with stage II disease were alive without recurrence more than 18 months after the transplant procedure; both of these patients had presented with a single metastatic lymph node located within the lung parenchyma. A similar experience has been reported in the liver transplant population. Indeed, several studies have shown that selected patients presenting with early stage hepatocellular carcinoma can be cured with liver transplantation.11,12 In contrast, rapid recurrence and subsequent death was observed in patients with more advanced stages defined by the size and the number of tumors in the liver.11 Hence, the tumor stage appears to be directly related to the rate of recurrence after both liver and lung transplantation, and patients with early stage disease appears to have a good prognosis despite immunosuppression. We identified 26 patients who underwent 29 lung transplantations for advanced multifocal BAC. All these patients had diffuse pulmonary involvement precluding any other type of surgical resection than lung transplantation. Tumor recurrence developed in 13 patients surviving the transplant procedure. Interestingly, in contrast to other bronchogenic carcinomas, the recurrence was limited to the transplanted lung in most patients and was slow growing despite immunosuppresion. Similar findings were observed in the seven patients with incidentally discovered multifocal BAC in the explanted lung at the time of transplantation. Hence, lung transplantation for multifocal BAC is unlikely curative, even if incidentally discovered in the explanted lung. However, a 5-year survival of 39% appears relatively good considering that there is currently no alternative therapy available for this group of patients. Since the outcome is similar to lung transplantation for other end-stage lung disease and considering that there is currently no other therapy available for these patients, we consider that lung transplantation remains a valuable option for selected patients with respiratory failure secondary to advanced multifocal BAC. These patients should be thoroughly staged with chest and abdominal computed tomography, brain magnetic resonance imaging, bone scan, and possibly positron emission tomography scan repeated every 3 months while on the waiting list. Some authors have also recommended mediastinoscopy at the time of transplantation with a plan for a back up recipient if metastatic disease was found in the mediastinal lymph nodes on frozen section.8 Further researches are warranted to determine the mechanisms of recurrence of multifocal BAC. Garver et al10 suggested that recurrent tumor cells were more likely originating from the recipient than from the donor, and recent work demonstrated that the host inflammatory response had a negative impact on outcome by promoting the proliferation of BAC cells.13,14 In the future, better understanding of the exact nature of BAC and its interaction with immunosuppressive regimen may help to improve the outcome of these patients. In conclusion, only a few patients undergoing lung transplantation for end-stage pulmonary disease and presenting with a stage I bronchogenic carcinoma in the explanted lung developed recurrence after lung transplantation. In contrast, patients undergoing lung transplantation for end-stage pulmonary disease and presenting with stage II or III bronchogenic carcinoma in the explanted lung usually died rapidly after transplantation, with widespread recurrence. Although rarely curative, lung transplantation remains a valuable procedure for patients with impending respiratory failure secondary to advanced multifocal BAC.
Australia: Alfred Hospital, Prahran, St Vincent's Hospital, Sydney. Austria: University of Vienna, University Hospital, Innsbruck. Belgium: Hopital Erasme, Brussels, Centre Hospitalier, Liege, University Hospital, Leuven. Canada: Toronto General Hospital, University of Alberta, Edmonton, University of BC, Vancouver. Denmark: University of Copenhagen. England: Northern Hospital, Sheffield. France: Hopital Xavier-Bichat, Paris, Hopital Marie-Lannelongue, Paris, Hopital Foch, Paris, Hopital Louis Pradel, Lyon, Hopital Ste Marguerite, Marseille. Germany: Goethe Universitat, Frankfurt, Paulinen Krankenhaus, Berlin, University Hospital, Homburg/Saar, University of Munich, University of Hannover. Italy: Policlinico S Matteo, Pavia, La Sapienza, Roma. Japon: Tohoku University, Sendai. Netherland: University Hospital Groningen. New Zealand: Green Lane Hospital, Auckland. Norway: University Hospital, Oslo. Spain: University Hospital, Madrid, University Hospital, Valencia. Sweden: University Hospital, Lund, Sahlgrenska Hospital, Goteborg. Switzerland: University Hospital, Zurich, University Hospital, Geneva. United-States: Johns Hopkins, Maryland, University of Alabama, Birmingham, Brigham and Women's Hospital, Boston, University of Columbia, New York, Henry Ford Hospital, Detroit, Duke University, North Carolina, University of Florida, Gainesville, Loyola University, Illinois, University of Minnesota, Minneapolis, Vanderbilt University, Tennessee, Ochsner Medical Center, Louisiana, University of Pennsylvania, Philadelphia, University of Texas, San Antonio, Emory Hospital, Georgia, Stanford University, California, University of Washington, Seattle, Children's Hospital, Boston, Massachusetts General Hospital, Boston, University of North Carolina, Chapel Hill, Washington University, St Louis, University of Virginia, Charlottesville, University Hospital of Cleveland, Ohio, University of Texas, Dallas, Baylor College of Medicine, Texas, Children's Hospital of Wisconsin, Milwaukee, Medical College of Wisconsin, Milwaukee, Ohio State University, Ohio, Oregon University, Portland, Mayo Clinic, Minnesota, University of California, San Diego, University of California, Davis, University of Arizona, Tucson.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Trulock EP, Edwards LB, Taylor DO, et al: The registry of the international society for heart and lung transplantation: Twentieth official adult lung and heart-lung transplant report-2003. J Heart Lung Transplant 22:625-635, 2003[CrossRef][Medline]
2. Spiro SG, Porter JC: Lung cancer–where are we today? Current advances in staging and nonsurgical treatment. Am J Respir Crit Care Med 166:1166-1196, 2002 3. Maurer JR, Frost AE, Estenne M, et al: International guidelines for the selection of lung transplant candidates. J Heart Lung Transplant 17:703-709, 1998[Medline]
4. Okubo K, Mark EJ, Flieder D, et al: Bronchoalveolar carcinoma: Clinical, radiologic, and pathologic factors and survival. J Thorac Cardiovasc Surg 118:702-709, 1999
5. Hsu CP, Chen CY, Hsu NY: Bronchioloalveolar carcinoma. J Thorac Cardiovasc Surg 110:374-381, 1995 6. Greco RJ, Steiner RM, Goldman S, et al: Bronchoalveolar cell carcinoma of the lung. Ann Thorac Surg 41:652-656, 1986[Abstract]
7. Etienne B, Bertocchi M, Gamondes JP, et al: Successful double-lung transplantation for bronchioalveolar carcinoma. Chest 112:1423-1424, 1997 8. de Perrot M, Fischer S, Waddell TK, et al: Management of lung transplant recipients with bronchogenic carcinoma in the native lung. J Heart Lung Transplant 22:87-89, 2003[Medline] 9. Paloyan EB, Swinnen LJ, Montoya A, et al: Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs. Transplantation 69:2446-2448, 2000[CrossRef][Medline]
10. Garver RI Jr., Zorn GL, Wu X, et al: Recurrence of bronchioloalveolar carcinoma in transplanted lungs. N Engl J Med 340:1071-1074, 1999 11. Bismuth H, Chiche L, Adam R, et al: Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 218:145-151, 1993[Medline]
12. Yoo HY, Patt CH, Geschwind JF, et al: The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time. J Clin Oncol 21:4329-4335, 2003 13. Bellocq A, Antoine M, Flahault A, et al: Neutrophil alveolitis in bronchioloalveolar carcinoma: Induction by tumor-derived interleukin-8 and relation to clinical outcome. Am J Pathol 152:83-92, 1998[Abstract] 14. Wislez M, Phillipe C, Antoine M, et al: Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor infiltrating inflammatory cells. Inflamm Res 53:4-12, 2004[CrossRef][Medline] Submitted December 30, 2003; accepted August 9, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
