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Lung cancer in lung transplantation: incidence and outcome
  1. David Pérez-Callejo1,
  2. María Torrente1,
  3. Consuelo Parejo1,
  4. Rosalia Laporta2,
  5. Piedad Ussetti2,
  6. Mariano Provencio1
  1. 1 Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
  2. 2 Department of Pulmonology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
  1. Correspondence to Dr David Pérez-Callejo, Servicio de Oncolog­ía Médica, Hospital Universitario Puerta de Hierro-Majadahonda, Calle Manuel de Falla, Madrid 28222, Spain; davidperezc{at}hotmail.com

Abstract

Introduction Malignancies are one of the causes of mortality after lung transplantation. However, little is known about lung cancer outcome after lung transplantation.

Methods We performed a retrospective search of the lung transplantation database at our institution to identify patients diagnosed with lung cancer after lung transplantation.

Results Out of 633 lung transplant patients, lung cancer was detected in 23 of them (3.63%). The most common causes for transplantation were idiopathic pulmonary fibrosis (47.8%) and emphysema (43.4%). A total of 18 patients were diagnosed during follow-up, 12 cases in the native lung (52.2%) and 6 cases in the donor lung (26.1%). The diagnosis was evidenced in the explanted lung in five patients (21.7%). The median of time from transplantation to cancer diagnosis was 39.7 months (24.356.6). Lung cancer was the cause of death in 16 patients. Survival rate at1year from diagnosis of lung cancer was 45.64% (95% CI 0.2431 to 0.6473).

Conclusions Lung transplant recipients constitute a high-risk group for developing lung cancer. Among our patients, lung cancer was predominantly diagnosed in the native lung and at an advanced stage. The primary tumour was the main cause of death in most of these patients.

  • lung transplantation
  • lung cancer
  • idiopathic pulmonary fibrosis
  • emphysema

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Introduction

Over the past 25 years, lung transplantation has become a viable treatment option for patients with a variety of end-stage lung diseases. Between 1988 and 2012, the number of lung transplantations performed worldwide, reported to the International Society for Heart and Lung Transplantation (ISHLT) Registry, increased dramatically from 89 to 3700 overall.1

According to data from the European Commission, one-third of solid organ transplantations, and specifically 40% of lung transplantations, worldwide took place in Europe in 2012.2

Outcome and survival after lung transplantation, however, remain subject to several underlying causes. Primary graft dysfunction and infections are the major causes of death in the first year post-transplantation, and chronic lung allograft dysfunction, due to bronchiolitis obliterans syndrome, is the major cause of death after the first year, accounting for over 40% of deaths.1 3

Malignancy accounts for a small percentage of mortality in the first year after transplantation. Nevertheless, beyond the first year, current data from the ISHLT Registry report that malignancy accounts for 15% of deaths between 5 and 10 years after transplantation and for 16% of reported deaths after 10 years.4

Several causes increase the risk of developing cancer after lung transplantation, including high-dose immunosuppression, infections caused by oncogenic viruses and the main pretransplant risk factor, tobacco. Non-melanoma skin cancer is the most prevalent malignancy overall, but post-transplant lymphoproliferative disease (PTLD) is the most common malignancy in the first year after transplantation and second most common overall.4 Other malignancies include colon and breast cancer. However, lung cancer, including non-small cell and small cell lung carcinoma, is increasingly becoming a frequent complication in these patients.5

Lung cancer after lung transplantation can be diagnosed as a result of three scenarios: transmission from the donor to the recipient (cancer being present at the time of transplantation in the transplanted lung); as a finding in the explanted lung (native lung that was explanted at the time of transplantation); and during follow-up, either in the graft or in the native lung in those patients undergoing unilateral transplantation.3 6

Specific risk factors for developing lung cancer related to lung transplantation can be differentiated between recipient and donor risk factors. Genetic, cellular, molecular and environmental factors all play significant roles. Recipient risk factors are mainly associated with occupational and environmental exposure, tobacco being the leading cause, but also exposure to asbestos and silica. Immunosuppression schemes used in lung transplantation recipients,7 and chronic lung diseases, mainly idiopathic pulmonary fibrosis (IPF) and emphysema, are also risk factors that should be considered. As for the donor risk factors, the increased use of marginal lung donors, including smokers and elderly, may increase this risk. As a matter of fact, data from the United Network for Organ Sharing Registry reveal that lung transplantations from donors aged over 55 years old have doubled from 2000 (5.8%) to 2009 (10.0%).8

The aim of our study was to retrospectively review our institution’s incidence and treatment outcomes of lung cancer after lung transplantation.

Methods

We performed a retrospective search of the lung transplantation database at Puerta de Hierro University Hospital (Madrid, Spain) to identify patients diagnosed with lung cancer at the time or after lung transplantation. Records were reviewed for demographics (age and sex), risk factors for malignancy, pretransplantation cytomegalovirus (CMV) and Epstein-Barr virus (EBV) serologies, lung transplantation characteristics, lung cancer characteristics, treatment and outcome. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) traslocations were tested in tumour samples from patients diagnosed of an adenocarcinoma or an squamous non-small cell lung cancer, when they were non-smokers.

Diagnosis was confirmed in all cases by pathological analysis, and lung cancer staging was assessed according to the 7th edition of the American Joint Committee on Cancer staging manual.9

All transplantation candidates underwent an extensive preoperative study that included full laboratory work-up, serological markers for HIV, C and B hepatitis viruses, EBV, CMV, and herpes simplex virus, pulmonary function testing, and an echocardiogram to assess cardiac function. Imaging follow-up every 6–12 months for reassessment until surgery was performed included serial CT scans of chest and abdomen.

Following transplantation, all patients received standard immunosuppression following the institution’s protocol with basiliximab (Simulect) 20 mg intravenously on days 1 and 4 after surgery, with a bolus of methylprednisolone. Immunosuppression maintenance therapy included a calcineurin inhibitor (CNI) (ciclosporin A or tacrolimus), a nucleotide blocking agent (mycophenolate or azathioprine) and corticosteroids.

Post-transplantation period follow-up included a clinical evaluation, routine laboratory testing, and pulmonary function testing and chest radiography at 1, 2 and 3 months and then every 3 months for the first 2 years. Clinical evaluation, spirometry and chest radiography were performed every 3 months thereafter. A surveillance bronchoscopy was performed 1 month after the surgery.

A Medline and PubMed search of the English-language literature was performed for reported series studies of lung carcinoma after lung transplantation, excluding single case reports.

This study was approved by Puerta de Hierro Hospital Ethics Committee.

Statistical analysis

Descriptive demographics were reported as median, SD and range. Overall survival was calculated as date of transplant to date of death from all-cause mortality or last follow-up as of May 2016. Survival analysis was calculated with standard Kaplan-Meier method. Statistical analyses were performed by using Stata V.14.1.

Results

Between May 1994 and March 2016, 633 lung transplantations were performed at our institution. Of these, 212 were single lung transplantations and 421 were bilateral lung transplantations.

Lung cancer was diagnosed in 23 of these patients at the time of surgery or postsurgery. Patient characteristics are described in table 1. The median of age of the recipients at the time of transplantation was 60 (range 40–66) years old; 19 were men and 4 were women. Of the 23 cases, seven were bilateral lung transplantations. The two most common causes for lung transplantation were IPF (47.8%) and emphysema (43.4%). The majority of patients had a smoking history, quit more than a year before the surgery (74%). The majority of the serologies of recipients (95.6%) pretransplantation were CMV-positive and EBV-positive.

Table 1

Patient and transplantation characteristics

Lung cancer was detected in 18 cases during follow-up (78.3%), being predominantly diagnosed in the native lung (12 cases, 52.2%) and to a lesser extent in the graft (donor lung) (6 cases, 26.1%). In five patients (21.7%) lung cancer was diagnosed in the explanted lung of the recipient (two patients with a bilateral transplantation and three with unilateral transplantation) after lung transplant procedure (table 2).

Table 2

Lung cancer characteristics

Regarding tumour histology, adenocarcinoma was more common (56.5%), followed by squamous cell lung carcinoma (30.4%). Metastatic stages were the predominant stages (56.4%), followed by locally advanced and early stages.

After cancer diagnosis, the immunosuppression therapy scheme was modified (mainly dose reduction and mycophenolate mofetil suspension). Moreover, everolimus, a mammalian target of rapamycin (m-TOR) inhibitor, was introduced in the immunosuppression scheme in five patients.

Tumour in the native lung after lung transplantation was detected in 12 patients post unilateral transplantation. Of these patients, eight were former smokers prior to transplantation, while the rest were non-smokers. The causes of transplantation were IPF in seven patients and emphysema in five patients. Among the histologies in this subgroup, adenocarcinoma was diagnosed in six cases, squamous cell carcinoma in five cases and a single case of large cell carcinoma. On cancer diagnosis, nine of the patients presented metastatic disease, three cases stage IVa and six cases stage IVb. One patient presented a locally advanced stage IIIB, with proven mediastinal involvement, treated with thoracic radiotherapy, with no response to the treatment.

The other two patients underwent surgery, one with lung squamous cell carcinoma T1N0M0, stage 1A, and another one after a clinical diagnosis of lung adenocarcinoma T2N0M0, who had finally a pathological diagnosis of T2N2M0, both with total response of the disease, without further progression. The first patient after a recurrence-free time period of 24 months died due to a metastatic bladder cancer, while the second patient died due to a respiratory complication after 5 months of transplantation.

Three patients with metastatic diseases received chemotherapy with platinum-based schemes, with two partial responses and one progressive disease. Likewise, one patient received radiation therapy and one received EGFR tyrosine kinase inhibitor (TKI), both without significant benefit. Of note, four patients did not receive any treatment given the poor performance status (PS) at the time of diagnosis with advanced disease.

The causes of death were due to lung cancer in nine cases, a single case was due to progressive metastatic urothelial carcinoma and a single case due to respiratory infection.

Lung cancer in the transplanted lung was diagnosed in six patients during follow-up; transplantation was bilateral in four of them and unilateral in two. Out of the six patients, five had smoking history; three of them had lung transplantation due to IPF, two were due to emphysema and one was due to haemosiderosis.

Three of the patients developed adenocarcinoma, one squamous cell carcinoma, one lung carcinoma not otherwise specified and one small cell carcinoma. On diagnosis, four of the six patients presented metastatic disease.

Regarding response to treatment, one patient with a metastatic adenocarcinoma was treated with an EGFR TKI, with no response to the treatment. The patient with small cell lung carcinoma and a localised disease received four cycles of carboplatin-etoposide and subsequent consolidation chest radiotherapy with a partial response and good haematological tolerance. A third patient with stage IV squamous cell carcinoma is currently being treated with carboplatin-gemcitabine, and an assessment of treatment response is pending. Three patients were not treated due to poor PS.

Lung cancer in the explanted lung was diagnosed in five patients; four of them were former smokers, who quit smoking at least 12 months prior to their evaluations as a condition of being a transplant candidate. Emphysema was the cause of transplantation in three of these patients, and one suffered from IPF. The other patient was a never-smoker who suffered from non-specific interstitial pneumonia (NSIP). Four of the histologies were adenocarcinomas and one was a squamous cell carcinoma, all localised stages. None of the patients received adjuvant chemotherapy. Four of the patients were free of disease at the time of data collection with a median follow-up from diagnosis of 3.5 years, and one presented a relapse with brain, liver and gastric involvement with fatal outcome after 2.5 years later.

Overall survival for all patients with lung cancer was calculated as date of transplant to date of death from all-cause mortality. One-year survival was 74.9% (95% CI 0. 7121–0.7825) and 5-year survival was 57.25% (95% CI 0.5286 to 0.6139) (figure 1). Survival rate at 1 year from diagnosis of lung cancer was 45.64% (95% CI 0.2431 to 0.6473) and 32.6% (95% CI 0.1331 to 0.5364) at 2 years.

Figure 1

Kaplan-Meier survival estimates in lung transplant patients from the time of transplantation: overall cohort versus lung cancer cohort

Regarding those patients who developed lung cancer, the cause of death in 16 patients was due to the primary tumour. Time from transplantation to cancer diagnosis was 39.7 months (24.3–56.6). The median of age at the time of cancer diagnosis was 62 (46–70), and the median of time from cancer diagnosis to death was 10.6 months (2–27) (figure 2).

Figure 2

Kaplan-Meier survival estimates in lung transplantation patients from lung cancer diagnosis

Discussion

Over the past 25 years, lung transplantation has become a viable treatment option for patients with a variety of end-stage lung diseases. Malignancy is a recognised complication of transplantation and can occur, in order of prevalence in our cohort, de novo in the native lung, in the transplanted lung or as a finding in the explanted lung.

A variety of solid organ cancers have been reported in transplant recipients, and there is a mounting strength in the association between immune deficiency and the risk of developing cancer.

Overall, the incidence of lung cancer has increased approximately 2.7-fold in HIV patients and 1.4-fold to 5.4-fold in transplant recipients,10 with similar standardised incidence ratios in the different geographical regions, compared with the general population.11 12

The incidence risk of lung cancer after lung transplantation has been reported to date as small case series, which are listed in table 3,13–25 ranging between 1% and 9%. We report in our series an incidence of lung cancer after lung transplantation of 3.63%, in line with those previously published.

Table 3

Prevalence of lung cancer among case series of lung transplantation recipients

In addition to smoking, which stands as the main risk factor for lung cancer development in our cohort (74%), a variety of other risk factors have also been proposed, including EBV, a well-known risk factor for developing PTLD.26 More than 95% patients in our series were EBV-seropositive prior to transplantation; therefore a donor/recipient human-leukocyte antigen (HLA) matching analysis in order to analyse a possible association as a risk factor also for lung cancer could not be performed. However, several studies have tried to establish this causal relationship, with inconclusive results. Despite being associated with lymphoepithelioma-like carcinoma in the lung, mainly in Asian patients,27 different publications have failed to correlate EBV as a risk factor in the Western population. Koshiol et al 28 recently reported an evaluation of EBV miRNA, DNA, RNA and protein in adenocarcinoma and squamous cell lung carcinoma cases from Caucasian patients, showing little evidence of EBV in lung tumour.A lack of association has also been proposed in the tumourigenesis of small cell lung carcinoma.29

In spite of immunosuppression being a risk factor for developing malignancy, its management in patients with lung cancer still lacks of established recommendations.6 Several authors have proposed different strategies for clinical management of post-transplant malignancies. One of these strategies proposes a change to a regimen with an antiproliferative effect, such as mycophenolate mofetil or an m-TOR inhibitor, such as everolimus or sirolimus.30 Nevertheless, m-TOR inhibitors are typically reserved for patients who do not tolerate the nucleotide blocking agents (mycophenolate and azathioprine) or have allograft rejection that is refractory to the latter. m-TOR inhibitors have also been used in the setting of progressive renal disease to allow reduction in CNI dosing or as part of a CNI-free regimen.31

Regarding treatment options, we suggest that surgery may be an appropriate procedure for early-stage diseases, with curative intent, preventing damage in the new vasculature in the transplanted organ and taking the decision in a multidisciplinary committee. Among our patients, only two of them underwent surgery with radical intention; none of them presented disease progression after surgery and both presented the tumour in the native lung.

Other treatment options include radiation therapy, chemotherapy or targeted therapies. Radiation therapy has been used as radical treatment or palliative in various tumours. In our series, two patients were treated with radiotherapy with palliative intent, and their cause of death was due to the primary tumour.

Different chemotherapy regimens have been used to treat lung carcinomas in this subgroup of patients, usually with platinum-based doublets, without developing a greater toxicity compared with immunocompetent patients. Drug interactions between immunosuppressors and cytotoxic drugs, along with the analytical status of the patient, should be taken into account. Monitoring creatinine clearance and risk of myelotoxicity may condition the use of carboplatin or cisplatin, respectively.3

Little is known about the effectiveness of targeted therapies with TKIs in lung transplant patients. According to the scientific evidence,32 we suggest assessing the mutational status of EGFR and ALK in these patients in order to be able to offer them a targeted treatment.

In our institution, 56% of lung cancer diagnoses are metastatic, suggesting a lack of early detection. Survival primarily depended on the time of diagnosis, stage and the possibility of receiving active treatments. The prognosis of localised stages may be comparable to that of the general population in our series, as previously published by Olland et al 6 whereas patients with advanced stage have lower survival than expected, mainly due to a high comorbidity burden that makes these patients unfit for receiving chemotherapy.

Overall survival of patients with lung cancer from the time of diagnosis in our series was longer (1-year survival was 45.64%) than that observed in previous studies13 15 17 despite having treated our patients with basiliximab, which is known to have a higher immunosuppressant effect and suggests a higher risk of developing malignancies.33

Although the subgroup of patients with cancer diagnosis in the explanted lung presented significantly better prognosis, we reported a relatively high incidence (five cases, 21.7%). This may be due to the fact that the imaging follow-up is limited to every 6–12 months prior to transplantation. In order to achieve early detection of the lung nodule, another chest CT performed just before lung transplantation should be included.

To summarise, lung transplant recipients constitute a high-risk group for developing lung cancer, mainly in native lungs, due to a smoking habit and to an underlying lung disease. A comprehensive assessment of these patients is necessary from the time of enrolment in a transplant programme to the follow-up after surgery. In our case, high-risk patients to developing lung cancer, such as those with IPF and emphysema, should have a more extended follow-up including low-dose chest CT for cancer screening.

Main messages

  • Lung transplant recipients constitute a high-risk group for developing lung cancer.

  • Malignancy can occur de novo in the native lung, in the transplanted lung or as a finding in the explanted lung.

  • Lung cancer is diagnosed mainly in native lungs, due to a smoking habit and to emphysema or idiopathic fibrosis.

Current research questions

  • Should CT-based screening be performed among lung transplant recipients at a high risk for developing lung cancer?

  • Should changes in the immunosuppression regimen be performed after a diagnosis of lung cancer in order to improve their outcome?

  • What is the real effectiveness of targeted therapies with tyrosine kinase inhibitors in lung transplant patients?

References

Footnotes

  • Contributors All authors have contributed to conception and design, acquisition of data, analysis and interpretation of data, drafting the article, and final approval of the last version.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Puerta de Hierro Hospital Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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