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Ann Thorac Surg 2005;79:980-983
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Lung Cancer After Heart Transplantation: A 17-Year Experience

Konstantinos Potaris, MDa, Branislav Radovancevic, MDa,*, Cynthia D. Thomas, RNa, Igor Gregoric, MDa, Ara A. Vaporciyan, MDd, Shirley A. Riggs, MDb, Rajko Radovancevic, MDa, William K. Vaughn, PhDc, O.H. Frazier, MDa

a Department of Cardiopulmonary Transplantation, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas, USA
b Department of Hematology/Oncology, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas, USA
c Department of Biostatistics and Epidemiology, Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas, USA
d Department of Thoracic and Cardiovascular Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA

Accepted for publication May 7, 2004.

* Address reprint requests to Dr Radovancevic, Texas Heart Institute, St. Luke's Episcopal Hospital, PO Box 20345, MC 2–114A, Houston, TX 77225–0345, USA
bradovancevic{at}sleh.com


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: The effects of heart transplantation on lung cancer incidence in heart transplant recipients are unclear.

METHODS: In an observational study, we retrospectively reviewed the charts of all patients undergoing heart transplantation at our institution from July 1982 to July 1999. Data on lung cancer incidence, risk factors, treatment, and outcome were collected.

RESULTS: Five hundred seventy-two patients (mean age, 50 ± 11 years; range, 18 to 73) were considered at risk for lung cancer. Of these, 324 (57%) had a more than 20 pack-year history of smoking before transplantation. Lung cancer developed in 2 patients 1 year or less after transplantation and in 8 patients more than 1 year after transplantation (incidence, 2.2 per 1,000 patients per year of follow-up). Non-small cell lung cancer was diagnosed in all cases. Median survival was 10.8 months (range, 2 to 37.5). Routine annual chest radiographs after transplantation enabled early diagnosis in 5 cases (stages Ia and IIa), which correlated with better mean survival (28.1 months [range, 19 to 37.5] versus 5.1 months [range, 2 to 10.8]; p = 0.0002).

CONCLUSIONS: The incidence of lung cancer in our population of heart transplant recipients appears to be no higher than in nontransplant populations with similar risk factors (ie, smoking and age). Routine radiographic imaging of transplant recipients may allow earlier detection of lung cancer and thus offer a survival benefit.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
It is well documented that organ transplant recipients have a higher incidence of cancer than does the general population. Many cancers (eg, those of the lung, breast, prostate, colon, and uterus) seem to occur with equal frequency in both populations, but some (eg, skin and in situ uterine carcinomas) occur more frequently in transplant recipients [1, 2]. Patients who have received a heart transplant are at increased risk of lymphoproliferative disorders, but whether this holds true for the risk of other tumors has not been established.

Lung cancer is one of the most common cancers in the United States and the most common cause of cancer-related death, accounting for more deaths than colon, prostate, and breast cancer combined. A number of retrospective studies have reported an increased risk of lung cancer after heart transplantation, but these studies have had some limitations [3–7]. These limitations include giving no information on the number of transplant recipients with a history of smoking, a significant risk factor for the development of lung cancer, and making no distinction between the prevalence and the incidence of lung cancer. If these limitations could be addressed, then perhaps the overall incidence of lung cancer in heart transplant recipients would turn out to be similar to that in nontransplant recipients with similar risk factors (ie, smoking and age). Therefore, we conducted an observational study in which we retrospectively reviewed our institution's experience with lung cancer in heart transplant recipients, paying particular attention to the incidence of lung cancer, the frequency of known risk factors for lung cancer, and the treatment and outcome in our patients with lung cancer.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
A retrospective chart review of all patients who underwent heart transplantation at our institution between July 1982 and July 1999 was performed. Patients eligible for inclusion in the study were adults (older than 18 years) who survived more than 30 days after transplantation and were at risk for development of lung cancer.

We reviewed our patient records to determine the incidence of lung cancer, incidence and severity of rejection episodes, types of immunosuppressive therapy used, and outcomes. Significant rejection episodes were defined as those assigned a score of IIIA or greater on the International Society for Heart and Lung Transplantation (ISHLT) scale [8], regardless of the patient's clinical symptoms. Follow-up data included data collected according to a standard protocol: periodic physical examinations, laboratory tests, or endomyocardial biopsies up to 5 years; annual physical examination and heart catheterization; and annual chest radiographs. Our institution's standard protocol now includes a chest roentgenogram before and 1 year after transplantation (unless there is a complication) and, if suspicious lesions are identified by the chest roentgenogram, a computed tomography (CT) scan.

The prevalence of lung cancer was defined as the number of cases of radiographically determined lung cancer present at transplantation and, for this study, was reported as 0. Incidence was defined as the number of patients in whom lung cancer developed after transplantation and was reported as the number of cases of lung cancer per 1,000 patients per year of follow-up. A two-tailed unpaired Student's t test was used to compare the mean survival of patients with early diagnosis of carcinoma with the survival of the rest of the group.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Between July 1982 and July 1999, 731 patients underwent a total of 754 cardiac transplantation procedures (23 patients underwent retransplantation) at our institution. A total of 159 patients who did not meet the inclusion criteria were excluded: 90 patients who were less than 18 years old and 69 patients who died within 30 days of transplantation. One of these patients who died less than 30 days after transplantation apparently did have a lung cancer before transplantation, but it was identified only at autopsy and not by routine pretransplantation chest roentgenogram imaging. The remaining 572 patients (mean age, 50 ± 11 years; range, 18 to 73) were considered at risk for lung cancer. Of these, 324 (57%) had a smoking history of more than 20 pack-years before transplantation.

A review of our transplantation database revealed that a total of 58 tumors, excluding skin cancer, developed in 52 heart transplant recipients (Table 1). Six of these recipients had more than one cancer. Lymphoma occurred at the highest rate (34%, 20 of 58), followed by lung cancer (17%, 10 of 58) and prostate cancer (17%, 10 of 58).


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  		Table 1. Cancers Other Than Skin Cancer Diagnosed in Heart Transplant Recipients

 
As just noted, 10 cases of lung cancer were identified in the study group (Table 2). All 10 patients were men; 9 were white, and 1 was Hispanic. Their mean age at time of transplantation was 58.2 years (median, 61.5; range, 42 to 67). One patient was a pipe smoker; the other 9 had a mean reported smoking history of 60 pack-years (range, 20 to 100). The mean interval from transplantation to lung cancer diagnosis was 62.4 months (median, 64.5; range, 1.5 to 128.5). Two patients had lung cancer develop within 1 year of transplantation. Eight patients had lung cancer develop more than 1 year after transplantation (mean time to diagnosis, 78.1 months; range, 23 to 129). The mean follow-up period for these patients was 7.98 ± 3.84 years (range, 2.5 to 13.2). The overall lung cancer incidence was 2.2 per 1,000 patients per year of follow-up.


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  		Table 2. Demographics, Tumor Staging, Treatment, and Outcome of 10 Heart Transplant Recipients Who Developed Lung Cancer

 
All 10 patients received triple immunosuppressive therapy consisting of cyclosporin A, azathioprine, and steroids. Immunosuppressive therapy was individualized in some patients according to their drug metabolism rates and rejection risks. In the more recent cases, mycophenolate mofetil was used in place of azathioprine.

Significant rejection episodes were treated with pulsed steroids and, depending on the degree of rejection and the patient's clinical status, with OKT3 or antithymocyte globulin [9]. One patient had four such episodes and died 3 years after heart transplantation of chronic rejection and cardiac allograft vasculopathy with no evidence of recurrent lung cancer. Two patients had two episodes each. Four patients had one episode each. Once chemotherapy was started, azathioprine was removed from the immunosupression therapy regimen.

In all 10 patients with lung cancer, tumors were initially diagnosed by chest roentgenogram. Five patients were asymptomatic for lung cancer; the other 5 exhibited clinical symptoms (eg, cough, shortness of breath, weight loss, anorexia). Of the 5 asymptomatic patients, 3 had their tumors diagnosed at an early stage (stage I or II): 2 are still alive, and 1 died of an acute myocardial infarction 19 months after initial diagnosis with no evidence of cancer progression. Of the 5 symptomatic patients, 2 had their tumors diagnosed at an early stage (stage I or II); the other 3 had their tumors diagnosed at a late stage (stage III or IV) and had limited survival (range, 2 to 7 months).

In 9 of 10 patients, a suspicious cancer nodule or mass was visualized by chest roentgenogram as well as by subsequent CT of the chest. Diagnostic details for the 10th patient were unavailable because he was treated for his lung cancer elsewhere. In 4 patients, the diagnosis of lung cancer was confirmed by bronchoscopy with either biopsy or aspiration cytology; in 2 patients, by fine-needle aspiration biopsy; and in 1 patient whose chest roentgenogram showed a pleural effusion, by thoracentesis. Four patients had second malignancies: colon cancer in 1 (this patient ultimately died of a cerebrovascular accident), colon and skin cancer in 1 (this patient is still alive), and prostate and skin cancer in 2 (these patients died of lung cancer 3 and 7 months, respectively, after lung cancer diagnosis).

Surgical treatment of lung cancer consisted of lobectomy in 4 patients (including the 1 patient treated elsewhere, who underwent pulmonary and chest wall resection), bilobectomy in 1, and wedge resection in 2. Tumors were inoperable in the other 3 cases.

Adjuvant treatment consisted of chemotherapy in the 3 patients with inoperable tumors (in combination with radiation of the mediastinum in 1 case), radiation of the mediastinum in the 1 patient who underwent a bilobectomy, and chest wall radiation therapy for T3 disease in 1 patient who underwent a lobectomy. The 1 patient treated elsewhere was being considered for adjuvant therapy but did not receive it because he died only 2 months after the diagnosis of lung cancer.

The tumor histology was squamous cell carcinoma in 5 patients, adenosquamous cell carcinoma in 2, and adenocarcinoma in 2 patients. The tumor histology for the 1 patient treated elsewhere was not available.

Mean survival after diagnosis was 16.5 months (median, 15; range, 2 to 37.5). Eight patients died. The causes of death were local and metastatic progression of lung cancer (n = 4); neutropenic septic shock after chemotherapy 2 months after diagnosis of lung cancer (n = 1); acute myocardial infarction 19 months after diagnosis and surgical treatment of lung cancer, but with no evidence of recurrence on autopsy (n = 1); stroke 2 days after colectomy to treat an adenocarcinoma of the transverse colon and 23 months after diagnosis of lung cancer, but with no evidence of recurrence on autopsy (n = 1); and multiple rejection episodes and coronary vasculopathy of the cardiac allograft resulting in unrelenting heart failure (n = 1). Two patients are still alive 30 and 31 months, respectively, after diagnosis and treatment of their lung cancers. One of these 2 has also undergone resection of secondary malignancies (ie, colon and skin cancers).

Routine posttransplantation radiographic imaging enabled early diagnosis in 5 patients (stages Ia and IIa). That in turn correlated with better mean survival: 28.1 months (range, 19 to 37.5) versus 5.1 months (range, 2 to 10.8; p = 0.0002).

All 8 patients who died maintained the follow-up schedule until their deaths. The 2 surviving patients continue to maintain the follow-up schedule.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
According to US cancer statistics from 1997, lung cancer remains the leading cause of cancer-related deaths in both sexes [10]. After lymphomas, we found lung cancer (17%, 10 of 58) and prostate cancer (17%, 10 of 58) to be the most common cancers (1 patient developed both) in our study population. This agrees with the findings of several earlier studies in heart transplant recipients [1–7].

The overall prevalence of lung cancer in our study population was 0%. This was to be expected, as patients with known cancer would be denied transplantation.

The overall incidence of lung cancer in our patients was 2.2 per 1,000 patients per year of follow-up. Although there is no appropriate nontransplant comparison group for our particular patient population, several published studies of lung cancer screening in smokers do provide useful data for comparisons (Table 3) [11–13]. Given that the risk factors in our population were similar to those in the studies just mentioned (ie, smoking and age), the incidence of lung cancer in our population does not appear to be different from these published data.


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  		Table 3. Incidence of Lung Cancer in Other Studies

 
Our study considered smoking, age, sex, and immunosuppressive therapy as potentially important risk factors for lung cancer in heart transplant recipients. Smoking history is a major risk factor for lung cancer, and all 10 heart transplant recipients with lung cancer in our study population were heavy smokers (with a mean reported smoking history of 60 pack-years). Smoking is also the most important risk factor for ischemic cardiomyopathy, and 6 of our 10 patients with lung cancer had ischemic cardiomyopathy. The interval from transplantation to lung cancer diagnosis varied widely in our sample population (range, 1.5 to 128.5 months; median, 64.5; mean, 63.7). Yet, only 1 patient had multiple (more than 2) significant rejection episodes and received aggressive immunosuppressive therapy for them. However, this patient, who had a stage IIa tumor, died of chronic rejection almost 3 years after diagnosis of lung cancer with no evidence of tumor recurrence. Thus, one should hesitate to correlate lung cancer occurrence with immunosupression therapy. Conversely, one may consider as preexisting the lung cancer that developed in 1 patient 1.5 months after his heart transplantation. He died 23 months later of stroke, after resection of a second primary tumor (colon cancer).

Each of the lung cancers in our sample population was initially diagnosed on a routine follow-up chest roentgenogram. Early-stage cancer was found in 3 of 5 asymptomatic patients and in 2 of 5 symptomatic patients. As expected, the survival of patients with late-stage tumors (stage IIIa or greater) was poor (mean, 5.1 months; range, 2 to 10.8) and significantly lower than the survival of patients with early-stage tumors (stages Ia and IIa: mean, 28.1 months; range, 19 to 37.5).

In a previously reported series, Pham and coworkers [3] noted that, despite an aggressive follow-up regimen of a chest roentgenogram every 6 months, 8 of 10 patients had advanced lung cancer (stage IIIa or greater) at diagnosis and a median survival of only 27 days. Goldstein and colleagues [4, 5] noted similar findings. In their series, the only treatable patient with lung cancer had a carcinoid tumor; the remaining 6 patients received only palliative treatment, and their mean survival was 5.3 months.

Despite its strengths in reporting on a major transplant center's long-term experience of lung cancer in heart transplant recipients, our study had several limitations. First, it was an observational study. Second, the number of lung cancer cases seen in the study population was too small to allow meaningful statistical analysis. Third, there was no appropriate nontransplant control group against which to compare our study population. Thus, any conclusions drawn from our findings are not necessarily generalizable. However, it is hoped that these shortcomings can be overcome in larger, more appropriately powered studies.

In conclusion, our data suggest that the incidence of lung cancer in heart transplant recipients at our institution is no higher than in a nontransplant population with similar risk factors (ie, smoking and age). They also suggest that immunosuppressive drug therapy as performed after transplantation at our institution does not correlate with lung cancer development.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Penn I. Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 1993;12(6 Pt 2):S328–36
  2. Penn I. Neoplasms after renal and cardiac transplantation. Hematol Oncol Clin North Am. 1993;7:431–445[Medline]
  3. Pham SM, Kormos RL, Landreneau RJ, et al. Solid neoplasms after heart transplantation: lethality of lung cancer. Ann Thorac Surg. 1995;60:1623–1626[Abstract/Free Full Text]
  4. Goldstein DJ, William DL, Oz MC, Weinberg AD, Rose EA, Michler RE. De novo solid malignancies after cardiac transplantation. Ann Thorac Surg. 1995;60:1783–1789[Abstract/Free Full Text]
  5. Goldstein DJ, Austin JHM, Zuech N, et al. Carcinoma of the lung after heart transplantation. Transplantation. 1996;62:772–775[Medline]
  6. Curtil A, Robin J, Tronc F, Ninet J, Boissonat P, Champsaur G. Malignant neoplasms following cardiac transplantation. Eur J Cardiothorac Surg. 1997;12:101–106[Abstract]
  7. Taniguchi S, Cooper DKC, Chaffin JS, Zuhdi N. Primary bronchogenic carcinoma in recipients of heart transplants. Transpl Int. 1997;10:312–316[Medline]
  8. McAllister HA Jr. Endomyocardial biopsy, conditions leading to heart transplantation, and the evaluation of cardiac allograft rejection: morphologic considerations. Frazier OH, Macris MP, Radovancevic B. Support and replacement of the failing heart. Philadelphia: Lippincott-Raven; 1996. p. 140
  9. Frazier OH, Macris MP. Management of the transplant recipient. Frazier OH, Macris MP, Radovancevic B. Support and replacement of the failing heart. Philadelphia: Lippincott-Raven; 1996. p. 205
  10. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics 1997. CA Cancer J Clin. 1997;47:5–27[Medline]
  11. Kubik A, Polak J. Lung cancer detection: results of a randomized prospective study in Czechoslovakia. Cancer. 1986;57:2427–2437[Medline]
  12. Melamed MR, Flehinger BJ, Zaman MB, et al. Screening for early lung cancer: results of the Memorial Sloan-Kettering Study in New York. Chest. 1984;86:44–53[Abstract/Free Full Text]
  13. Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer. 1991;67(Suppl):1154–1164



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