Outcomes for Lung Transplantation for Lung Cancer in the United Network for Organ Sharing Registry

Outcomes for Lung Transplantation for Lung Cancer in the United Network for Organ Sharing Registry

Section of Thoracic Surgery and Department of Epidemiology, Yale University School of Public Health, New Haven, Connecticut; Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama; Thoracic Oncology Program, Department of Surgery, University of California San Francisco, San Francisco, California; Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio; and Division of Cardiothoracic Transplantation, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Background. Advanced bronchoalveolar carcinoma (BAC) carries a poor prognosis, with median survival of approximately 1 year. More extended survivals have been reported after lung transplantation for BAC; however, fewer than 50 patients have been reported. To compare outcomes of lung transplantation for advanced BAC, we studied this population in a compulsory, prospectively maintained database. Methods. The United Network for Organ Sharing (UNOS) database was queried for patients undergoing lung transplant from 1987 to 2010 for the diagnosis of BAC or cancer. Pathology reports of explanted specimens were reviewed. Results. Twenty-nine patients underwent lung transplantation for BAC, representing 0.13% of the 21,553 lung transplants during the study period. BAC patients had better forced expiratory volume in 1 second percent

predicted (60% vs 35%, p < 0.0001) and received more double-lung transplants (79% vs 54%, p ⴝ 0.006). Pure BAC was present in only 52% of the explants, whereas 41% had some degree of invasive tumor, and 7% had pure adenocarcinoma. The BAC and general lung transplantation cohorts had similar 30-day mortality (10% vs 7%, p ⴝ 0.44) and 5-year survival (57% vs 50%, p ⴝ 0.66). Conclusions. Survival after lung transplantation for BAC appears to be consistent with that of lung transplantation for other diagnoses and is better than that reported with chemotherapy. Further study is warranted to identify the subgroup of patients with lung cancer who will have a maximum survival advantage after lung transplantation.

B

tions in the BAC cohort than other NSCLC subtypes, the use of epidermal growth factor receptor-tyrosine kinase inhibitors has not translated into dramatic improvements in the outcome for these patients [6 –9]. The perception that advanced BAC is a potentially lethal but lung-limited malignancy has motivated some centers to explore the use of lung transplantation for advanced BAC [10, 11]. Thus far, fewer than 50 lung transplants for advanced BAC have been reported. Recurrent BAC is common in the transplanted lungs: 75% shown by Zorn and colleagues [12] and 59% shown by de Perrot and colleagues [13]. However, the overall survival (median ⬎ 35 months) has compared well with other studies of medically managed advanced BAC [6 –9]. More recently, the prevalence and clinical importance of varying degrees of stromal invasion in the BAC population have led to the abandonment of the BAC terminology; instead, the categories of adenocarcinoma in situ with lepidic growth pattern and varying degrees of invasive adenocarcinoma have emerged [14, 15]. Although the change in nomenclature by itself is not justification for a treatment change, the recognition of invasive cancer

ronchoalveolar carcinoma (BAC) has been recognized as a distinct subtype of non-small cell lung cancer (NSCLC) with unique pathologic and clinical attributes since being described in 1960 [1]. The predominant histopathologic feature is lepidic growth along the alveolar walls without invasion into the stroma [2]. Clinically, BAC has tended to present at earlier stages, with lower rates of nodal or extrathoracic metastases and a better survival than other NSCLC subtypes [3, 4]. However, BAC has a greater propensity to recur or metastasize within the lung, at times advancing to a point beyond that which is amenable to surgical resection [5]. This so-called advanced (diffuse, pneumonic, or multifocal) BAC is associated with poor prognosis, with median survivals of approximately 1 year [5]. Despite higher frequencies of epidermal growth factor receptor muta-

Accepted for publication April 16, 2012. Presented at the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 –Feb 1, 2012. Address correspondence to Dr Boffa, 330 Cedar St, BB205, New Haven, CT 06520-8062; e-mail: [email protected].

© 2012 by The Society of Thoracic Surgeons Published by Elsevier Inc

(Ann Thorac Surg 2012;94:935– 41) © 2012 by The Society of Thoracic Surgeons

0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2012.04.069

GENERAL THORACIC

Usman Ahmad, MD, Zuoheng Wang, PhD, Ayesha S. Bryant, MSPH, MD, Anthony W. Kim, MD, MS, Jasleen Kukreja, MD, MPH, David P. Mason, MD, Christian A. Bermudez, MD, Frank C. Detterbeck, MD, and Daniel J. Boffa, MD

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in this population does raise questions about the likelihood of the disease remaining “lung-limited” and therefore challenges the rationale for lung transplantation in this setting. To assess outcomes of lung transplantation for BAC and to determine the prevalence and importance of invasive cancer in this cohort, we queried the prospectively maintained compulsory database of the United Network for Organ Sharing (UNOS).

Patients and Methods GENERAL THORACIC

This study was approved by UNOS, the Health Resources and Services Administration, and the Yale University Human Investigation Committee.

Patients The UNOS is a not-for-profit organization federally contracted to “gather, maintain and analyze data for the purpose of measuring and improving medical outcomes” (www.unos.org). This compulsory database has recorded elements of every transplant in the United States since 1986 for the Organ Procurement and Transplant Networks (OPTN). The vital status is checked against the Social Security Administration death master file. This publicly available database was searched for patients undergoing lung transplantation with the primary diagnosis of BAC or cancer between 1987 and 2010. This did not include patients with incidentally discovered malignancies in the explanted lungs. The median follow-up was 620 days for the BAC/cancer group and 874 days for the general group who received an allograft for a reason other than BAC or cancer.

Pathology

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Table 1. Demographic and Preoperative Characteristics Variablea Age, years Male BMI, kg/m2 Race Caucasian African American Asian Hispanic Other

BAC (n ⫽ 29)

General (n ⫽ 21,524)

p Value

48 ⫾ 11 52 24 ⫾ 4

49 ⫾ 15 53 24 ⫾ 7

0.690 0.904 0.846

86 7 7 0 0

87 7 1 2 3

0.882 0.978 0.001 0.394 0.392

a Continuous data are shown as the mean ⫾ standard deviation and categoric data as percentage.

BAC ⫽ bronchoalveolar carcinoma;

BMI ⫽ body mass index.

Results Demographic and Pretransplant Characteristics Of the 21,553 lung transplants in the United States between October 1987 and December 2010, 29 patients received lung transplants for the primary diagnosis of BAC, representing 0.13% of the lung transplant population. The age, race, sex, and body mass index (BMI) distributions were similar between the BAC and general transplantation groups (Table 1). The BAC patients did appear to have greater preoperative pulmonary reserve, as estimated by forced expiratory volume in 1 second percentage of predicted (60% vs 35%, p ⬍ 0.0001), and spent shorter amount of time on the waiting list (162 ⫾ 264 vs 316 ⫾ 401 days, p ⫽ 0.004).

Perioperative Variables

Individual pathology reports from the explanted lungs were located at each participating hospital using the UNOS-specific identifier, stripped of all protected health information, and sent to the study team coded only by the UNOS identifier. The pathologic information was merged with the remainder of the deidentified UNOS data based on the UNOS identifier. Of the 29 explant pathology reports, 27 (93%) were available for review. All histopathologic determinations with respect to the tumor subtype, invasion, and stage of the malignancy were taken as recorded by the submitting pathologist.

There were significant differences in the operative and perioperative characteristics between the two groups. The BAC group was more likely to undergo double-lung transplantation (79%) than the general group (54%, p ⫽ 0.006; Table 2). The pathology reports for the 6 patients who received single-lung transplants indicated that a previous contralateral pneumonectomy had been performed. The mean ischemia time was longer in the BAC/cancer group (5.6 vs 4.8 hours, p ⫽ 0.014), but the perioperative mortality rate and length of stay were similar (Table 2).

Statistics

Analysis of Final Pathology

The calculated means ⫾ one standard deviation are listed for continuous variables and were compared using the two-sample t test. Proportions are represented as number (%), and were compared using the normal approximation test for proportions. Survival curves were calculated using the Kaplan-Meier method. Univariate comparison of survival between groups was performed using a Cox proportional hazard model. Statistical analysis was performed using R 2.10.1 software (The R Project for Statistical Computing http://www.r-project.org/). Differences were considered significant at a p value of less than 0.05.

Pathology results of explanted specimens were available for 27 of 29 of the cohort (93%). Double-lung transplantation was done in 79% of BAC patients. All explants (unilateral and bilateral) were noted to have multilobar tumor involvement. Only 14 (52%) tumors were of pure BAC histology, and 11 (41%) had foci of invasion or other features consistent with adenocarcinoma on a predominant background of BAC histology. Two patients (7%) had predominant adenocarcinoma (Table 3). Mucin production was noted in 11 tumors (41%). Papillary and acinar features were noted in 15% and 19% of the invasive tumors, respectively.

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General (n ⫽ 21,524)

p Value

60 61 1151 ⫾ 726 162 ⫾ 264

35 49 798 ⫾ 489 316 ⫾ 401

⬍0.0001 0.002 0.107 0.004

21 79 5.6 ⫾ 1.5

46 54 4.8 ⫾ 1.8

0.006 0.006 0.014

23 ⫾ 29 10

24.5 ⫾ 30 7

0.827 0.436

a Continuous data are shown as the mean ⫾ standard deviation and categoric data as percentage.

BAC ⫽ bronchoalveolar carcinoma; FEV1, ⫽ forced expiratory volume in 1 second; FVC ⫽ forced vital capacity.

Hilar lymph nodes were assessed in all explant specimens, and mediastinal nodes were reported for 20 patients (74%), with an average of 7 N1 and 2 N2 nodes assessed per explanted lung. Metastatic carcinoma was present in 5 hilar (18.5%) and 4 mediastinal (14.8%) lymph nodes. Complete tumor resection with negative margins was achieved in 93%. Epidermal growth factor receptor and k-ras mutation analyses results were available for 2 patients (both negative).

Long-Term Survival Graft survival was similar for BAC/cancer and general transplant cohorts: 44% and 47% at 5 years and 19% and 24% at 10 years, respectively (p ⫽ 0.252). Overall survival was also similar at 5 (57% vs 50%) and at 10 years (25% vs

Prob bability of overaall survival

BAC (n ⫽ 29)

Variablea Preoperative FEV1, % predicted FVC, % predicted 6-min walk test, feet Time on waiting list, days Transplantation Single-lung Double-lung Ischemia time, hours Length of stay, days 30-day mortality

1.0

BAC General

0.8 0.6 0.4

0.2

0.0 0

2

4

Pure ADC No. (%)

14 (52)

11 (41)

2 (7)

5 (36) 0 0

5 (46) 5 (46) 3 (27)

1 (50) 0 1 (50)

6 2

10 3

3 ⬍1

0 1 (7)

4 (37) 2 (18)

1 (50) 1 (50)

Patients Histology Mucinous Acinar Papillary LN assessed per lung, No. N1 N2 Positive nodesa N1 N2 a

10

The cause of death was unknown in 41% of the BAC and 47% of general cohort patients. In the BAC group, 3 deaths were attributed to BAC and 2 deaths to lung cancer (17%), (Table 4). Malignancy was listed as the primary cause of death in 4% of the general lung transplant population, with 2 deaths attributed to BAC and 10

Invasive Non-invasive

HR = 2.24 p=0 203 0.203

0.8

0.6 0.4

02 0.2 0.0

Proportion of patients with LNs positive for metastatic carcinoma.

ADC ⫽ adenocarcinoma; lymph node.

8

Cause of Death

Pro obability of overrall survival

BAC ⫹ ADC No. (%)

6

27%) in the BAC/cancer and general groups, respectively (p ⫽ 0.665; Fig 1). Interestingly, the presence of invasive tumor (pure adenocarcinoma excluded; Fig 2) or lymph node metastases (Fig 3) did not preclude the possibility of long-term survival. Presence of invasive cancer, however, was associated with a trend toward decreased survival.

1.0 Pure BAC No. (%)

Years

Fig 1. Overall survival is shown for the bronchoalveolar carcinoma (BAC)/cancer cohort (dashed line; n ⫽ 29) compared with the general lung transplantation cohort (solid line; n ⫽ 21,524). (HR ⫽ hazard ratio.)

Table 3. Review of Final Pathology Variables

HR = 1.11 p = 0.665 0 665

BAC ⫽ bronchoalveolar carcinoma;

LN ⫽

0

2

4

Years

6

8

10

Fig 2. Overall survival is shown for bronchoalveolar carcinoma/ cancer patients with invasive (dashed line; n ⫽ 13) or noninvasive (solid line; n ⫽ 14) tumors. (HR ⫽ hazard ratio.)

GENERAL THORACIC

Table 2. Preoperative and Transplantation Variables

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Pro obability of overrall survival

1.0

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LN metastases No LN metastases

Table 5. Lung Transplantation for Diffuse BAC (Invasive Adenocarcinoma Excluded)

HR = 1.12 p = 0.886

First Author

No.

Recurrence

Survival

0.6

Geltner [16] Etienne [17] Paloyan [10]

1 1 2

0 (2 yrs) 0 (5.5 yrs) 50%a

0.4

Garver [18]b De Perrot [19]

7 3

57% 33%

0.2

Zorn [12]

8

75%

1 alive at 2 yrs 1 alive at 5.5 yrs 1 dead at 16 mos 1 alive at 4 yrs Not stated 1 dead at 35 mos 2 alive at 12 and 13 mos 5 dead (median, 38 mos) 3 alive (median, 87 mos)

0.8

0.0 0

2

4

Years

6

8

10

Fig 3. Overall survival is shown for bronchoalveolar carcinoma/ cancer patients in the presence (dashed line; n ⫽ 7), or absence (solid line; n ⫽ 20) of lymph node (LN) metastases. (HR ⫽ hazard ratio.)

to lung cancer combined, representing 0.05%. The solicitation of data relating to cause of death from the individual transplanting centers was, unfortunately, beyond the purview of the limited permission granted by UNOS.

Comment The concept of solid-organ transplantation for cancer is based on the assumptions that the malignancy is confined to the explanted organ and that survival with other medical or surgical therapies is unlikely. When considering lung transplantation for BAC (or adenocarcinoma in situ), it is unclear whether historical BAC data are sufficient to make these assumptions. Further complicating this discussion is the recognition of the spectrum of invasive disease under the former BAC terminology, with each subgroup potentially having a distinct propensity to be “organ limited” or refractory to nontransplant treatment strategies. Our review of the UNOS database and individual pathology reports was done in hopes of establishing outcomes associated with Table 4. Causes of Deatha Cause Cancer/BAC Infectious Graft failure Cardiovascular Other Not reported

BAC/Cancer, % (n ⫽ 29)

General, % (n ⫽ 21,524)

p Value

17 10 14 7 14 41

4 12 11 3 22 47

0.004 0.781 0.663 0.209 0.246 0.528

a Listed as the primary cause of death, 1 patient in the cancer group listed cancer as a tertiary cause contributing to more immediate causes of death.

BAC ⫽ bronchoalveolar carcinoma.

a

b Patient underwent retransplantation and without recurrence. Explant pathology is not described in detail, but described as bronchoalveolar carcinoma.

transplantation in this setting as well as to better characterize this population and their disease to inform future considerations of this highly selective practice. The overall survival after lung transplant for BAC was similar to that of the general transplant population, with approximately half the patients alive at 5 years. These results are similar to the findings of de Perrot and colleagues [13], who surveyed the contributors to the International Society for Heart and Lung Transplantation Registry. Although less than half of the 150 programs surveyed responded, 26 BAC patients (29 transplants) were noted to have received lung allografts. Recurrent BAC developed in 59% of patients overall, with a 5-year survival of 39%. Several smaller institutional series have shown a reasonable survival but high BAC recurrence. The major findings of the previously published reports of lung transplantation for BAC are summarized in Table 5. A subset of BAC patients with advanced diffuse tumor are known to have a high mortality rate associated with their disease. Several chemotherapy trials have shown median survival of about 1 year. More recently, newer targeted drug trials have reported minimal improvement in median survival (Table 6) [20, 21]. The review of the pathology reports suggested that all of the patients in the current series would have been considered “advanced” because of diffuse multilobar bilateral involvement. Therefore, a reasonable estimation of medical outcomes in this setting can be taken from published studies, which appear far inferior to those found in the current study after lung transplant, with a median survival of 5 years. We realize the significant limitations to this comparison, including the lack of available clinical staging information in this highly selected cohort. A direct comparison of chemotherapy and lung transplantation in comparable stage patients is needed before any conclusion can be reached. This study also revealed the relative high prevalence of invasive carcinoma in this cohort with BAC who underwent transplantation. However, durable survival was possible despite varying degrees of stromal invasion.

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First Author/Trial

No.

Stage

No.

Median Survival (mos)

Study Type

Drug

Breathnach [5]

28

Case series

Case series

58

4 24 7 51

15.2

SWOG 9714 [20]

IIIB IV IIIB IV NS IIIB IV I-IIIA IIIB-IV IIIB/IV IIIB/IV

12

Phase II

Paclitaxel

8.6 13

Phase II Phase II

Paclitaxel Gefitinib

13.2

Phase II

Gefitinib

13.6 13

Phase II Phase II

Bortezomib Cetuximab

EORTC 08956 [21] SWOG S0126 [6]

19 136

IFCT 0401 [7]

88

NCI 7003 [8] ECOG 1504 [9]

42 68

9 127 15 73

ECOG ⫽ Eastern Cooperative Oncology Group; EORTC ⫽ European Organisation for Research and Treatment of Cancer; IFCT ⫽ Intergroupe Francophone de Cancerologie Thoracique; NCI ⫽ National Cancer Institute (California Cancer Consortium Phase II study); NS ⫽ not specified; SWOG ⫽ Southwest Oncology Group.

Similarly, lymph node metastases did not preclude survival. The results of this review suggest that the clinicians were able to select patients who had diffuse pulmonary cancer of a type with a low propensity for distant metastasis. This selection was likely made primarily on clinical grounds. The utility of a lung biopsy is highly questionable at best. Whether invasion was or was not noted in the explanted lungs does not appear to have been important. Indeed, with our current understanding and classification, it is unlikely that any of these patients with disease diffuse enough to consider transplantation would be classified as not having invasion; at best, they might have a lepidic predominant (invasive) adenocarcinoma. Our analysis is limited by the need to rely only on what was listed in the pathology report. It would be quite interesting to review the pathology slides in light of our current understanding and classification system; however, this was beyond the scope of this project. How then, can we refine the selection of patients based on this review? It certainly stands to reason that exclusion of distant disease by positron-emission tomography scans and brain magnetic resonance imaging should be required. It is difficult to argue on the basis of the data reported here that mediastinoscopy should be required, but given that surgical resection for patients with N2postivie lung cancer is generally thought to be contraindicated, it seems hard to defend lung transplantation in this setting. Our opinion is that any suspicious N2 nodes should be defined by mediastinoscopy, and we would also recommend that some form of invasive mediastinal staging be done in all patients before considering as extensive an undertaking (with a limited resource) as lung transplant. We think this is prudent, given the incidence of N2 disease in these patients, even though survival of the (incidentally discovered) N2-positive patients was surprisingly reasonable. Finally, all cases should be discussed at a multidisciplinary tumor board. Lung transplantation for BAC poses equally challenging questions with respect to organ usage because more patients are currently awaiting lung transplant than or-

gans are available (http://optn.transplant.hrsa.gov/ latestData/rptData.asp). The effect of widespread adoption of lung transplant for lung cancer is unknown, but Egan and Detterbeck [22] estimated the prevalence of advanced BAC that would potentially be eligible for lung transplant to be more than 2,000 patients each year in the United States, which exceeds the 1,700 lung transplants done for noncancerous diagnoses. In conclusion, lung transplant for lung-limited, predominantly lepidic growth patterned adenocarcinoma with varying degrees of invasion is a reasonable option for patients in whom medical or surgical therapies have failed to control their disease. Confirmation of the superiority of transplant-associated outcomes over medical therapy in this setting should be confirmed with a prospective trial. A formal consensus guideline to define patient eligibility that is sensitive to the competing demands on the limited organ pool would be helpful before large-scale expansion of this practice.

We acknowledge Drs Abbas E. Abbas, James M. Tuchek, Scott B. Johnson, Hari R. Mallidi, Michael Savitt, Matthew G. Hartwig, and Dan M. Meyer for their help with the collection of pathology information.

References 1. Liebow AA. Bronchiolo-alveolar carcinoma. Adv Intern Med 1960;10:329 –58. 2. Travis WD, Garg K, Franklin WA, et al. Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria. J Thorac Oncol 2006;1: S13–9. 3. Grover FL, Piantadosi S. Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung—The Lung Cancer Study Group experience. Ann Surg 1989;209: 779 –90. 4. Ebright MI, Zakowski MF, Martin J, et al. Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. Ann Thorac Surg 2002;74:1640 – 6.

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Table 6. Chemotherapy for Advanced Bronchoalveolar Carcinoma With/Without Adenocarcinoma

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5. Breathnach OS, Ishibe N, Williams J, Linnoila RI, Caporaso N, Johnson BE. Clinical features of patients with stage IIIB and IV bronchioloalveolar carcinoma of the lung. Cancer 1999;86:1165–73. 6. West HL, Franklin WA, McCoy J, et al. Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126. J Clin Oncol 2006;24:1807–13. 7. Cadranel J, Quoix E, Baudrin L, et al. IFCT-0401 Trial Group. IFCT-0401 Trial: a phase II study of gefitinib administered as first-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype. J Thorac Oncol 2009;4: 1126 –35. 8. Ramalingam SS, Davies AM, Longmate J, et al. Bortezomib for patients with advanced-stage bronchioloalveolar carcinoma: a California Cancer Consortium Phase II study (NCI 7003). J Thorac Oncol 2011;6:1741–5. 9. Ramalingam SS, Lee JW, Belani CP, et al. Cetuximab for the treatment of advanced bronchioloalveolar carcinoma (BAC): an Eastern Cooperative Oncology Group phase II study (ECOG 1504). J Clin Oncol 2011;29:1709 –14. 10. Paloyan EB, Swinnen LJ, Montoya A, Lonchyna V, Sullivan HJ, Garrity E. Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs. Transplantation 2000;69:2446 – 8. 11. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant report—2010. J Heart Lung Transplant 2010;29:1104 –18. 12. Zorn GL Jr, McGiffin DC, Young KR Jr, Alexander CB, Weill D, Kirklin JK. Pulmonary transplantation for advanced bronchioloalveolar carcinoma. J Thorac Cardiovasc Surg 2003; 125:45– 8. 13. de Perrot M, Chernenko S, Waddell TK, et al. Role of lung transplantation in the treatment of bronchogenic carcinomas

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for patients with end-stage pulmonary disease. J Clin Oncol 2004;22:4351– 6. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244 – 85. Yoshizawa A, Motoi N, Riely GJ, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 2011;24:653– 64. Geltner C, Jamnig H, Bucher B, et al. Lung transplantation for bronchiolo-alveolar lung carcinoma. Lung Cancer 2002; 37(Suppl 1):S27. Etienne B, Bertocchi M, Gamondes JP, Wiesendanger T, Brune J, Mornex JF. Successful double-lung transplantation for bronchioalveolar carcinoma. Chest 1997;112:1423– 4. Garver RI Jr, Zorn GL, Wu X, McGiffin DC, Young KR Jr, Pinkard NB. Recurrence of bronchioloalveolar carcinoma in transplanted lungs. N Engl J Med 1999;340:1071– 4. 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 2003;22:87–9. West HL, Crowley JJ, Vance RB, et al; Southwest Oncology Group. Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study. Ann Oncol 2005;16: 1076 – 80. Scagliotti GV, Smit E, Bosquee L, et al; European Organisation for Research and Treatment of Cancer (EORTC) Lung Cancer Group (LCG). A phase II study of paclitaxel in advanced bronchioloalveolar carcinoma (EORTC trial 08956). Lung Cancer 2005;50:91– 6. Egan TM, Detterbeck FC. The ABCs of LTX for BAC. J Thorac Cardiovasc Surg 2003;125:20 –2.

DISCUSSION DR SETH FORCE (Atlanta, GA): That was an excellent discussion. I think this topic comes up a lot, especially at our tumor conference, and one of the problems that you alluded to is that you can have a good 5-year survival in the patients who don’t die and who don’t recur. And you probably went through a lot of the manuscripts that have been published in their small series while you were preparing for this talk, and you would see that there is a significant recurrence rate and death rate in every individual study. And so my comment and question is: When you were preparing for this talk, did you get a general feel of what the true recurrence rates were after transplantation? I know it is not in the United Network of Organ Sharing (UNOS) database, but it is easy to get and the manuscripts are already published and it is not a lot of papers. DR AHMAD: Thank you. That is an interesting question. Depending on whom you read in the various series, the recurrence rates are up to 40% to 50%. And some of these patients were retransplanted after recurrence. DR FORCE: And that seems to be one of the big problems. I think the other issue a lot of us have is staring at a patient with cancer on our wait list while we are waiting for an organ. What are your thoughts on that? If you had a patient who had bronchoalveolar carcinoma (BAC) and they were on your wait list for 4 weeks, 8 weeks, what would you do to evaluate them periodically to make sure they weren’t metastasizing?

DR AHMAD: I think the patients who could potentially be considered for lung transplantation, who have advanced BAC, are the ones who are, number one, not candidates for anatomic resection; and number two, don’t have any evidence of extrapulmonary or nodal disease. I think serial radiologic scanning would be the one thing to monitor in these patients every few months. However, I should say that we don’t do lung transplants at Yale and this is UNOS data. But we do refer frequently patients for lung transplantations, and tumor board discussion is our routine as well. DR JOSHUA SONETT (New York, NY): We all discuss this all the time, since most of us that transplant lungs are thoracic cancer surgeons too. We certainly put our cancer hat on and we want to offer them the transplant. But the less than 50% 5-year survival is not what we are gunning for these days. And I think, putting on the transplant hat, it is maybe not as an efficient use of an organ for somebody that may have a 5- or 10-year survival. So there is that, which you acknowledged in your discussion. I don’t know what the right argument is, especially on the personal level, it is hard. Two, I do worry about the UNOS database to extrapolating these kind of data. As was referred to by Seth, you said 14% recurrence, but some of the best papers show 40% to 50% recurrence, and they are using genetic analysis to prove these. That they are only saying 14% recurrence of cancer I think probably underreports what is going on. And the UNOS reporting is, although it sounds very good, those little subtle categories like cancer, not cancer, cancer recurrence, for busy coordinators,

may not be as accurate as we would like. So I’d just be a little bit wary of the data you got to work with, even though you worked with it perfectly. DR AHMAD: Thank you for your comments. I think that is true for the data. That is just a limitation of starting a database, I absolutely agree. DR DAVID MASON (Cleveland, OH): That was a nice talk. I think you supplemented the UNOS data nicely with the pathology. I know that we sent you some pathology as well. One question I’d want to ask and elicit responses from the audience as well is, what do you think the selection criteria should be, what workup should we do in considering the patient with BAC for transplantation, what are those things that should be done, and who is the best candidate? DR AHMAD: I think, as I mentioned earlier, the patients who could potentially be considered for lung transplantation are the ones who would not be candidates for anatomic resection and who don’t have any evidence of extrathoracic disease on their computed tomography or positron-emission tomography scans, and I think all of these patients who’d undergo preoperative mediastinoscopy (MEDs). Now, I don’t have data to show how many of them in this database underwent pre-op MEDs, just because some of these patients were worked-up at their institutions before they went to the transplant centers, but I think that’s certainly a necessity. And I would be hesitant to say that if somebody has an N2 disease, we can go ahead and transplant them, although the survival curves don’t seem different, but I think we are limited by the number of patients that we are looking at here. DR JAY K. BHAMA (Pittsburgh, PA): I wanted to start by congratulating you on a very nice study, really one of the first of its kind to describe a palliative option for these patients. At University of Pittsburgh Medical Center we also have had an experience with lung transplant for BAC in several patients over the years. The results really do mirror what you found in this study of the UNOS database. The survival of our BAC patients also has mirrored survival for patients with other diagnoses. However, they did have a very high recurrence rate. Interestingly, some of those patients have been followed up and even considered for retransplantation, and most continue to maintain a good quality of life, despite recurrence. Regarding organ allocation, most of the patients are younger patients; I really think that this is something we should be considering as an option for them; to give them, as you said, 5 years of extra life. We recently had a patient who we wanted to list for transplant, a young lady with young kids, and one of the big limitations was that even though we were willing to offer her

AHMAD ET AL LUNG TRANSPLANTATION FOR BAC

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a transplant, her insurance company would not approve her for transplantation. Many insurance companies look at it as an experimental procedure at this point. I think having this type of data and getting this data into the literature is exceedingly important to help open this option up for other patients. DR MASON: And if I could just make a comment. In terms of working-up the patient from my own perspective, one is, I think the patient needs a surgical lung biopsy that confirms that it is as pure, if you want to call it, BAC, or by its new terminology of adenocarcinoma in situ, as possible. So I think they need a surgical biopsy. I think they need a mediastinal staging procedure, whether that is endobronchial ultrasound or mediastinoscopy. I would think that everyone should have failed chemotherapy. Some people get a remarkable response to chemotherapy. So I think it should be left as a final option, particularly with new targeted therapies, investigational therapies, and vaccine trials for BAC, I think that there are a lot of potential other options before you get to transplantation. And finally, one thing that I don’t think you can get from the data is what their quality of life was before transplantation. I think it should be reserved for those really poor quality-of-life patients as opposed to the patient who has multiple radiologic findings and clearly has incurable disease but is getting along with a reasonable quality of life. So from my perspective, I think that they needed to fulfill all their transplantation criteria with regards to low quality of life, poor performance status, and high oxygen requirements. In addition, you need to be as certain as possible that it is pure BAC, and in addition, that they do not have any mediastinal spread which would go against it being pure. DR AHMAD: I completely agree. Although I think BAC is a spectrum of disease. And despite the fact that half of these patients had invasive cancer, it doesn’t seem that that changed their survival a lot. And about 10% of the patients had nodal metastases, which, if these were truly invasive adenocarcinomas, it is kind of rare for adenocarcinoma. So it seems that BAC is a different entity, although we haven’t been able to characterize it yet. DR SUDISH MURTHY (Cleveland, OH): Just so you know that there is no variable in the lung allocation score for cancer. So these patients are getting transplants on the basis of lung failure, usually a walk distance, hypoxia. So that is an aside. Cancer happens to be the disease that got them into a listing situation. And so that needs to be kept in mind and maybe needs to be worked into the lung allocation score.

GENERAL THORACIC

Ann Thorac Surg 2012;94:935– 41