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Lung cancer surgical treatment after solid organ transplantation: A single center 30-year experience
Lung Cancer 139 (2020) 55–59
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Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Lung cancer surgical treatment after solid organ transplantation: A single center 30-year experience
T
G. Dreveta,*, Michaël Duruisseauxb,h,i, J.M. Maurya, Riche Benjamind,e,f,g, G. Renauda, Ginoux Maryliseb, J.F. Mornexc, F. Tronca a
Department of Thoracic Surgery, Lung and Heart-Lung Transplantation, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677, Lyon, France Respiratory Medicine Department, Hôpital Louis Pradel, Hospices Civils de Lyon, F-69677, Lyon, France c Université de Lyon, INRA UMR754, Hospices Civils de Lyon, 50 av Tony Garnier, 69007, Lyon, France d Department of Biostatistics-Bioinformatics, Hospices Civils de Lyon, F-69003, Lyon, France e University of Lyon, F-69000, Lyon, France f Lyon 1 University, F-69100, Villeurbanne, France g CNRS UMR 5558, Laboratory of Biometry and Evolutionary Biology, Health Biostatistics Team, F-69310, Pierre Bénite, France h Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France i Anticorps Anticancer Lab, Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France b
A R T I C LE I N FO
A B S T R A C T
Keywords: Lung cancer Solid organ transplantation Pulmonary surgical procedures Post-transplant malignancy
Objectives: Solid organ transplantation is an accepted treatment for end-stage organ failure. Long-lasting immunosuppressive therapy may increase the risk ofde novo malignancies in transplant recipients. Increased risk of bronchogenic carcinoma in this population is controversial but prolonged transplant recipients’ survival (obtained in modern transplantation era) may increase the need for lung cancer surgical resection in immunosuppressed patients. Our aim was to assess morbidity, mortality and long-term survival after lung cancer surgical treatment in this population. Materials and methods: In an observational study, the medical charts of all consecutive patients who had undergone surgical treatment for lung cancer after solid organ transplantation were reviewed. These medical records were extracted from the University of Lyon (France) Transplantation database and Thoracic Surgery database. From 1986–2016, 61 patients underwent a surgical treatment for lung cancer after solid organ transplantation. Results: The surgical procedures consisted of 52 lobectomies, 7 pneumonectomies and 2 wedge-resections. 90day post-operative complications, most of which were pneumonias, affected 31 patients (50.8 %). 90-day postoperative mortality was 9.8 %. Overall survival was 40.6 % at 5 years and 18 % at 10 years. Conclusion: Despite a higher rate of infectious complications and 90-day postoperative mortality, surgical treatment for lung cancer must be offered to these patients as it offers a chance to cure earlier- stage disease. Long-term survival rate is satisfactory and similar to that of the general population. In transplant recipients with former smoking history, close follow-up is mandatory to increase early lung cancer diagnosis.
1. Introduction Solid organ transplantation is nowadays an accepted treatment for end-stage organ failure. The chronic exposure to immunosuppressive therapy may have several adverse effects. One of them is the increased risk of malignancy onset. The use of immunosuppressive drugs impairs immune surveillance against tumor cells and dampens antiviral immunity allowing tumors to develop due to viruses’ proliferation [1]. The mean incidence of cancer in recipients of solid organ
⁎
transplantation is 6 % (ranging from 4 % to 18 %) [2]. Predominant malignancies are lymphomas, skin carcinomas, perineal carcinomas, in situ uterine cervical carcinomas, and Kaposi's sarcoma. The risk of bronchogenic carcinoma is estimated from 0.3 % to 0.85 % in the general transplant population [3,4]. Reported lung cancer incidence was higher after lung and heart transplantation than after liver and kidney transplantation (the ratios were 5.5, 2.9, 2 and 1 respectively) [5]. Considering the increasing number of solid organ transplantations performed with longer survival of transplant recipients in our modern
Corresponding author. E-mail address: [email protected] (G. Drevet).
https://doi.org/10.1016/j.lungcan.2019.10.023 Received 24 July 2019; Received in revised form 18 October 2019; Accepted 24 October 2019 0169-5002/ © 2019 Elsevier B.V. All rights reserved.
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count and percentage for each level of the variable. The missing or unknown values were not included in the denominator for the calculation of the relative frequencies (proportions). The relative frequencies were compared using a Pearson’s chi-2 test or a Fisher’s exact test. When necessary, the exact confidence intervals for the relative frequencies were calculated using binomial distribution. The quantitative variables were described using the following descriptive statistics: the headcount, the number of missing values, the average, the standard deviation, the median, the first and third quartiles, as well as the minimum and the maximum. The comparisons of continuous data between the two arms were performed using Student tests or Wilcoxon tests depending on the verification of the underlying assumptions of normality of the residuals. The distribution of the survival functions were estimated by the Kaplan Meier estimator and the survival distributions compared using a log-rank test. The observations of the subjects alive at the end of followup were censored.
immunosuppressive therapy era, surgical treatment of lung cancer in this population is becoming more necessary since surgical resection is the mainstay of curative lung cancer treatment. Inoperable tumors are treated with chemotherapy or radiotherapy or both. However, immunosuppressive therapy and frequent renal failure may interfere with the feasibility of chemotherapy. The aim of our study is to assess postoperative morbidity, mortality and long-term survival after lung cancer surgical treatment in the solid organ transplant population. 2. Material and methods 2.1. Study design Between 1986 and 2016, a total of 8142 patients underwent solid organ transplantation at the University Hospital of Lyon, France. These operations included heart (n = 1472), kidney (n = 4120), liver (n = 2191) and lung and heart-lung (n = 359) procedures. A total of 145 solid organ transplant recipients were discovered to have primary lung cancer (1.78 %). Among them, 44 (1 % of all kidney transplantations) belonged to the kidney transplant group, 53 (2 % of all liver transplantations) were from the liver transplantation population, 43 (2.9 % of all heart transplantations) had undergone heart transplantations and 5 (1.7 %) had undergone lung transplantation or heart-lung transplantation (Table 1). Among the 145 organ transplantation recipients with lung cancer, a total of 61 (42 %) patients surgically treated for lung cancer were included in the present study. The selection criteria for lung cancer resection after solid organ transplantation were the same as those of the general population after complete oncopneumological assessment and respiratory functional tests. The other 84 patients (58 %) had malignancies deemed unresectable and were excluded. So, in this historical cohort, we studied the medical charts of 61 patients (n = 61) who had undergone surgical treatment for lung cancer after solid organ transplantation between June 1986 and June 2016 at Louis Pradel Hospital. The following data were extracted from the University of Lyon (France) Transplantation database and from the Thoracic Surgery database: demographics, medical history, date and type of transplantation, date of lung cancer surgery, postoperative classification of lung cancer, neoadjuvant or adjuvant therapy, postoperative complications, recurrence and final outcome. Exclusion criteria were other diagnosis than primary lung cancer or unresectable tumor. Data were collected until June 2017. Overall survival was estimated from the date of surgery to occurrence of death. Disease-free survival was estimated from the date of surgery to the date of recurrence diagnosis and this analysis focused on patients whose surgery for lung cancer took place after 2006. Missing data on the occurrence of recurrence was too important for surgeries prior to 2006. The mean time follow up was 47.3 months (0–176). Nine patients were lost to follow up.
3. Results 3.1. Patients’ characteristics There were 56 men and 5 women (Table 2). The median age at the time of diagnosis was 61 years (range 31–77 years). 58 patients had a history of smoking, 34 of them had quit before lung cancer was diagnosed. The average number of packs/year was 36.3. Only 3 patients were nonsmokers. 11 patients had a history of previous malignancy before lung cancer was diagnosed. In our series, heart was the most common solid organ to be transplanted (25 patients, 41 %), followed by kidney (18 patients, 29.5 %), liver (16 patients, 26.2 %) and bilateral lung transplantation (2 patients, 3.3 %). Tumors were mainly diagnosed during the systematic follow-up after transplantation (42 patients, 68.8 %). Only 19 patients (31.2 %) were diagnosed after consulting for specific symptoms. The median interval between solid organ transplantation and surgical treatment for lung cancer was 88 months (range 4 - 347months). Lung malignancies consisted of 32 adenocarcinomas, 28 squamous cell carcinomas and one neuro-endocrine carcinoma (Table 3). The vast majority of patients were R0 (95.1 %) and N0 (78.7 %). The post-operative classification (according to the eighth edition TNM classification for lung cancer) revealed 36 (59 %) stage I, 12 (19.7 %) stage II, 12 (19.7 %) stage III and one (1.6 %) stage IV. For the latter patient, stage IV was diagnosed after surgery. A single pleural nodule was discovered during the procedure and was completely resected. Post-operative histologic examination confirmed completely resected squamous cell carcinoma pleural extension. Only one patient received neo-adjuvant chemotherapy. No patient received neo-adjuvant radiotherapy. On the other hand, 11 patients received adjuvant treatment (6 patients received chemotherapy, 3 radiotherapy and 2 radio-chemotherapy). Lung cancer surgery consisted of wedge resection (2 patients, 3.3 %), lobectomy (49 patients, 80.3 %), bi-lobectomy (3 patients, 4.9 %) or pneumonectomy (7 patients, 11.5 %). No segmentectomy was performed.
2.2. Statistical analysis The qualitative variables were summarized using the following descriptive statistics: the count and percentage of missing values and the
Table 1 Solid organ transplants and lung cancer diagnosis in Lyon from June 1986 to June 2016. Solid organ transplants in Lyon from June 1986 to June 2016
Number of transplant (n = 8142) Post transplant lung cancer (n = 145) Mean time of diagnosis (months)
Liver
Kidney
Heart
Lung
Heart-lung
2191 53 (2%) 84 (8-180)
4120 44 (1%) 108 (2-204)
1472 43 (2.9%) 108 (6-252)
294 5 (1.7%) 60 (5-120)
65 0 /
56
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Table 2 Patients characteristics.
Table 4 90-day post-operative complications. n = 61
Gender male female Medical history smoking stopped smoking Malignancy Transplantation Heart Lung Liver Kidney Surgical treatment Wedge Segmentectomy Lobectomy Bilobectomy Pneumonectomy
56 5
91,8% 8,2%
58 34 11
95% 67% 18%
25 2 16 18
41% 3,3% 26,2% 29,5%
2 0 49 3 7
3,3% 0 80,3% 4,9% 11,5%
Heart n = 25
Lung n=2
Liver n = 16
Kidney n = 18
All (%)
Number of patients with at least one complication Number of complications: Bacterial pneumonia Prolonged drainage Respiratory Atrial fibrillation Renal insuffisiency Others In-hospital death
13
2
8
8
31 (50,8%)
No complications Grade I Grade II Grade III Grade IV Grade V
n = 61
32 28 1
52,5% 45,9% 1,6%
36 12 12 1
59% 19,7% 19,7% 1,6%
23 21 10 7
37,7% 34,4% 16,4% 11,5%
48 5 8
78,7% 8,2% 13,1%
58 3 0
95,1% 4,9%
1 11
1,6% 18%
60 6 6 3 2 4 4 4
0 1 0 0 0 1 1
4 3 5 3 1 2 1
6 3 3 2 1 0 0
16 13 11 7 6 7 6 (9,8%)
Table 5 Classification of surgical complications according to Clavien [6].
Table 3 Lung cancer characteristics.
Anatomopathology Adenocarcinoma Squamous cell carcinoma Neuro endocrine carcinoma Stage I II III IV T classification T1 T2 T3 T4 Lymph node status N0 N1 N2 Resection R0 R1 R2 Treatment Neo-adjuvant Adjuvant
Transplantation
n = 61
%
30 9 11 3 2 6
49,2% 14,8% 18% 4,9% 3,3% 9,8%
(14.7 % versus 7.4 %, p = 0.45). Conversely, lung and heart transplanted patients demonstrated a trend toward higher renal complication rate (14.8 % versus 5.9 %, p = 0.39). 90-day post-operative mortality was 9.8 % (6 patients) and 30-day post-operative mortality rate was 6.5 % (4 patients). Postoperative mortality seemed to be higher in lung or heart transplanted patients compared to renal or hepatic transplanted patients (18.5 % versus 2.9 %). Overall survival was 40.6 % at 5 years (CI95 % [27.4 %;53.4 %]) and 18 % at 10 years ([CI95 % [8.3 %;10.7 %]) (Fig. 1). Median postoperative survival was 41 months (3.41 years). 5-year survival in patients without lymph node extension was 45.12 % (CI95 % [29.76 %;59.29 %]) while 5-year survival in patients with lymph node extension was 22.79 % (CI95 % [4.24 %;50.07 %]); p = 0.17. Seventeen patients died from lung cancer evolution and eighteen patients died from other causes (cardiac failure, myocardial infarction, other malignancy evolution, pneumonia, gas embolism, ARDS). Data on the cause of death are missing for ten patients. Besides, there was no significant difference in survival at 5 years according to transplanted organs, p = 0.92. Disease-free survival rate in patients operated for lung cancer after 2006 was 29.71 % at 5 years (CI95 % [13.07 %;48.49 %]). 5-year disease-free survival rate without lymph node extension was 37.40 % (CI95 % [16.60 %;58.35 %]). In case of lymph node extension, 2-year disease-free survival rate was 20 % (CI95 % [0.84 %;58.19 %]). There was no significant difference in disease-free survival at 5 years according to transplanted organs, p = 0.56. The mean time for recurrence diagnosis was 26.4 months. Most of these patients (75 %) had a metastatic or a multi-metastatic spread at relapse and only 5 patients had a loco-regional recurrence. Preferential sites of metastasis were lung (11 patients; 73.3 %), liver (2 patients; 13.3 %), bone (2 patients; 13.3 %), adrenal glands (1 patient; 6.7 %) and pleura (1 patient; 6.7 %). Nine patients had at least one other diagnosis of cancer during their followup.
3.2. Outcomes 90-day post-operative complications occurred in 31 patients (50.8 %). A total of 60 complications were observed, including 16 bacterial pneumonias (among which: 7 undocumented pneumonias, 2 g-negative bacilli (unspecified bacteria), 1 g-positive anaerobic cocci (unspecified), Legionella pneumophilia, Pseudomonas aeruginosa, Enterobacter cloacae, Proteus vulgaris, Haemophilus influenza and Escherichia coli), 6 renal insufficiencies (2 requiring dialysis), 7 atrial fibrillations, 13 prolonged thoracic drainage and 11 respiratory complications excluding bacterial pneumonia (Table 4). The eleven patients with respiratory complications were diagnosed with ARDS, acute pulmonary edema, pulmonary atelectasis with mucous plug, haemoptysis, symptomatic pleural effusion, pneumothorax and laryngeal edema. Most of these patients had a grade II of the Clavien classification [6] of surgical complications (Table 5). Compared to lung and heart transplanted patients, renal and hepatic transplant recipients had a non-significant higher rate of postoperative pneumonia (35.3 % versus 18.5 %, p = 0.17) and cardiac complications
4. Discussion Compared to the general population, transplant recipients are 57
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Fig. 1. Overall survival of solid organ transplanted patients with surgically treated lung cancer.
advocate earlier anti-infectious treatment and repeated sputum cultures [16]. In the general population, 5-year risk of postoperative recurrence seems to be around 36 % [20] and recurrence is more frequently at a distant site [21]. Comparatively, the 5-year risk of postoperative recurrence in our study was significantly higher, with a rate of 70.29 %. Paradoxically, the mean time to recurrence seems longer in our experience than in the general population (26.4 months versus 13 months [22]). The role of immunosuppression in recurrence is discussed. For renal cell carcinomas and prostate cancer, overall survival seems to be similar between transplantation and dialysis groups [23]. On the other hand, post-solid-organ-transplanted patients with head and neck cancer seem to have a higher risk of loco-regional and distant recurrence [24]. Hence, concluding on the role of immunosuppression on lung cancer relapse is difficult, since transplanted recipients, particularly heart transplant recipients, are a selected group at higher risk of developing lung cancer by virtue of previous heavy smoking history and mean advanced age. In contrast with increased infectious morbidity and mortality and doubt about an increased risk of postoperative recurrence, long-term survival of patients with resectable lung cancer is satisfactory. We report a 5-year survival rate of 40.6 %, which is at the lower limit of that of the general population, ranging from 40.7–50% [25]. Curative surgical treatment can give a real chance to these patients. Median survival without surgical treatment was reported to be 12 months while it is doubled when patients can benefit from surgical resection; and 5-year survival rate was established at 19 % in medically treated patients while it reaches 35 % in resected stage I patients [26]. Our results are in keeping with previous series [16,26]. In this highly monitored population, we find a majority of early-stage cancer. The 5-year survival of N0 patients is satisfactory and in sharp contrast with N + patients (45.12 % vs. 22.79 % respectively). Several studies [3,16,26,27] have emphasized the rapid evolution of lung cancer in transplant recipients with positive lymph nodes. Patient’s reduced natural anti-tumoral immune response may result in more rapid dissemination of the neoplasm. On the other hand, the kidney and liver transplant recipients demonstrated a trend toward shorter survival compared with thoracic transplant recipients (40,7 and 42,5 months respectively), consistent with a delayed detection and more advanced stage disease of the lung cancer among these groups. They did not receive routine follow-up chest radiographs as did thoracic transplant recipients. These findings highlight the need for early detection to improve cancer outcomes in this
known to have an increased risk of cancer. Predominant malignancies are lymphoproliferative disorders and skin cancers. Their occurrence is mainly attributed to the chronic exposure to immunosuppressants. For lung cancer, results are somewhat controversial. In numerous studies, the incidence of bronchogenic carcinoma in the transplant population is relatively low and tends to be similar to that of the overall population after adjusting for age, smoking history and gender [3,7–9]. Moreover, the incidence does not vary according to the type of transplantation and therefore the degree of immunosuppression. On the other hand, compared to the general population, epidemiologic studies found an increased incidence of lung cancer in liver transplant recipients [10], kidney transplant recipients [11] or heart and lung transplant recipients [12]. In the latter study conducted in Australia, Roithmaier et col [12] found a 9.3-fold Increased risk for developing lung cancer after cardiopulmonary transplantation compared with the non-transplant population. The particularly high incidence of lung neoplasms observed in the heart and lung transplant population has been reported by others [13,14], suggesting that these cancers were correlated with smoking history and advanced age rather than with immunosuppressive treatments. Finally, very infrequently, lung cancer is transmitted by the donor and conversely, lung neoplasm may be found in the explanted lungs, even though they were not detected by the pre-transplant CT scan [15]. Although the role of immunosuppressive therapy in the occurrence of these cancers remains controversial, it is known to negatively affect postoperative course. Indeed, we observed an increased risk of postoperative complications and mortality. Like others [16], we observed a high rate of severe postoperative infectious complications. Particularly, the postoperative pneumonia rate we report seems to be sharply higher than that reported in the literature for the general population [17]. Moreover, postoperative mortality in our experience slightly exceeds previously reported rates. Postoperative mortality varies from 1 to 5.2 % [17,18] in the general population while we describe a 6.5 % 30-day postoperative mortality. This higher rate can be explained by respiratory distress, more frequently complicating pneumonias and a high rate of renal insufficiency linked with the need for several nephrotoxic treatments (i.e. calcineurin inhibitors and antibiotics). Post-operative mortality was mostly observed in the heart transplant group. This observation is compatible with data in the literature where post-operative mortality in this population varies from 10 to 12 % [16–19]. The majority of postoperative deaths was due to infectious complications, particularly respiratory failure after pneumonia, leading the authors to 58
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population. This was emphasized by Finkenstedt et al. [28] on a liver transplant recipients group. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9%–13% and for non-skin cancers, the median tumor-related survival significantly improved from 1.2–3.3 years. In 1997, we reported on malignant neoplasms following cardiac transplantation [13]. Out of eleven patients with lung cancer, curative surgery was performed in only 2 cases and mean survival of the whole group after lung neoplasm diagnosis was 9.1 months. Since then, routine chest radiographs are performed in smokers at every post-transplant follow-up control and chest CT scans done annually thereafter in thoracic transplant recipients, enabling early lung cancer diagnosis. Consequently, in the present series, 61 (42 %) patients were amenable to surgery, a high percentage compared to non-transplant patients with lung cancer. These results underline the positive effect of a post-transplant surveillance program, even if there is no definitive protocol for radiologic follow-up of transplanted patients. Our study has several limitations. First, it was an observational study. Second, the number of lung cancer cases was too small to allow meaningful statistical analysis; even if it is the largest study published.
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5. Conclusion Despite a high rate of infectious complications, curative surgical treatment must be proposed to lung cancer patients with a history of solid organ transplantation. Their median survival rate and 5-year survival rate are satisfactory and meet those of the general population. Close follow-up in transplanted patients, particularly in former smokers, is warranted to discover lung cancer at an early stage. Declaration of Competing Interest Dr. Duruisseaux reports personal fees from ROCHE, PFIZER, MSD, Boerhinger Ingelheim, NOvartis, ABBVIE, TAKEDA, BMS, ASTRA ZENECA, outside the submitted work. Acknowledgment The authors thank Karine Debbasch for reviewing the English manuscript. References [1] O.M. Martinez, F.R. de Gruijl, Molecular and immunologic mechanisms of cancer pathogenesis in solid organ transplant recipients, Am. J. Transplant. 8 (2008) 2205, https://doi.org/10.1111/j.1600-6143.2008.02368.x. [2] I. Penn, Incidence and treatment of neoplasia after transplantation, J. Heart Lung Transplant. 12 (1993) S328–S336. [3] M. de Perrot, D.A. Wigle, A.F. Pierre, et al., Bronchogenic carcinoma after solid organ transplantation, Ann. Thorac. Surg. 75 (2) (2003) 367–371. [4] C. Génébès, L. Brouchet, N. Kamar, et al., Characteristics of thoracic malignancies that occur after solid-organ transplantation, J. Thorac. Oncol. 5 (11) (2010) 1789–1795, https://doi.org/10.1097/JTO.0b013e3181f19226. [5] M.S. Sampaio, Y.W. Cho, Y. Qazi, et al., Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database, Transplantation 94 (10) (2012) 990–998, https://doi.org/10.1097/TP. 0b013e318270bc7b. [6] D. Dindo, N. Demartines, P.A. Clavien, Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey,
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Lung cancer surgical treatment after solid organ transplantation: A single center 30-year experience
T
G. Dreveta,*, Michaël Duruisseauxb,h,i, J.M. Maurya, Riche Benjamind,e,f,g, G. Renauda, Ginoux Maryliseb, J.F. Mornexc, F. Tronca a
Department of Thoracic Surgery, Lung and Heart-Lung Transplantation, Louis Pradel Hospital, Hospices Civils de Lyon, F-69677, Lyon, France Respiratory Medicine Department, Hôpital Louis Pradel, Hospices Civils de Lyon, F-69677, Lyon, France c Université de Lyon, INRA UMR754, Hospices Civils de Lyon, 50 av Tony Garnier, 69007, Lyon, France d Department of Biostatistics-Bioinformatics, Hospices Civils de Lyon, F-69003, Lyon, France e University of Lyon, F-69000, Lyon, France f Lyon 1 University, F-69100, Villeurbanne, France g CNRS UMR 5558, Laboratory of Biometry and Evolutionary Biology, Health Biostatistics Team, F-69310, Pierre Bénite, France h Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France i Anticorps Anticancer Lab, Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France b
A R T I C LE I N FO
A B S T R A C T
Keywords: Lung cancer Solid organ transplantation Pulmonary surgical procedures Post-transplant malignancy
Objectives: Solid organ transplantation is an accepted treatment for end-stage organ failure. Long-lasting immunosuppressive therapy may increase the risk ofde novo malignancies in transplant recipients. Increased risk of bronchogenic carcinoma in this population is controversial but prolonged transplant recipients’ survival (obtained in modern transplantation era) may increase the need for lung cancer surgical resection in immunosuppressed patients. Our aim was to assess morbidity, mortality and long-term survival after lung cancer surgical treatment in this population. Materials and methods: In an observational study, the medical charts of all consecutive patients who had undergone surgical treatment for lung cancer after solid organ transplantation were reviewed. These medical records were extracted from the University of Lyon (France) Transplantation database and Thoracic Surgery database. From 1986–2016, 61 patients underwent a surgical treatment for lung cancer after solid organ transplantation. Results: The surgical procedures consisted of 52 lobectomies, 7 pneumonectomies and 2 wedge-resections. 90day post-operative complications, most of which were pneumonias, affected 31 patients (50.8 %). 90-day postoperative mortality was 9.8 %. Overall survival was 40.6 % at 5 years and 18 % at 10 years. Conclusion: Despite a higher rate of infectious complications and 90-day postoperative mortality, surgical treatment for lung cancer must be offered to these patients as it offers a chance to cure earlier- stage disease. Long-term survival rate is satisfactory and similar to that of the general population. In transplant recipients with former smoking history, close follow-up is mandatory to increase early lung cancer diagnosis.
1. Introduction Solid organ transplantation is nowadays an accepted treatment for end-stage organ failure. The chronic exposure to immunosuppressive therapy may have several adverse effects. One of them is the increased risk of malignancy onset. The use of immunosuppressive drugs impairs immune surveillance against tumor cells and dampens antiviral immunity allowing tumors to develop due to viruses’ proliferation [1]. The mean incidence of cancer in recipients of solid organ
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transplantation is 6 % (ranging from 4 % to 18 %) [2]. Predominant malignancies are lymphomas, skin carcinomas, perineal carcinomas, in situ uterine cervical carcinomas, and Kaposi's sarcoma. The risk of bronchogenic carcinoma is estimated from 0.3 % to 0.85 % in the general transplant population [3,4]. Reported lung cancer incidence was higher after lung and heart transplantation than after liver and kidney transplantation (the ratios were 5.5, 2.9, 2 and 1 respectively) [5]. Considering the increasing number of solid organ transplantations performed with longer survival of transplant recipients in our modern
Corresponding author. E-mail address: [email protected] (G. Drevet).
https://doi.org/10.1016/j.lungcan.2019.10.023 Received 24 July 2019; Received in revised form 18 October 2019; Accepted 24 October 2019 0169-5002/ © 2019 Elsevier B.V. All rights reserved.
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count and percentage for each level of the variable. The missing or unknown values were not included in the denominator for the calculation of the relative frequencies (proportions). The relative frequencies were compared using a Pearson’s chi-2 test or a Fisher’s exact test. When necessary, the exact confidence intervals for the relative frequencies were calculated using binomial distribution. The quantitative variables were described using the following descriptive statistics: the headcount, the number of missing values, the average, the standard deviation, the median, the first and third quartiles, as well as the minimum and the maximum. The comparisons of continuous data between the two arms were performed using Student tests or Wilcoxon tests depending on the verification of the underlying assumptions of normality of the residuals. The distribution of the survival functions were estimated by the Kaplan Meier estimator and the survival distributions compared using a log-rank test. The observations of the subjects alive at the end of followup were censored.
immunosuppressive therapy era, surgical treatment of lung cancer in this population is becoming more necessary since surgical resection is the mainstay of curative lung cancer treatment. Inoperable tumors are treated with chemotherapy or radiotherapy or both. However, immunosuppressive therapy and frequent renal failure may interfere with the feasibility of chemotherapy. The aim of our study is to assess postoperative morbidity, mortality and long-term survival after lung cancer surgical treatment in the solid organ transplant population. 2. Material and methods 2.1. Study design Between 1986 and 2016, a total of 8142 patients underwent solid organ transplantation at the University Hospital of Lyon, France. These operations included heart (n = 1472), kidney (n = 4120), liver (n = 2191) and lung and heart-lung (n = 359) procedures. A total of 145 solid organ transplant recipients were discovered to have primary lung cancer (1.78 %). Among them, 44 (1 % of all kidney transplantations) belonged to the kidney transplant group, 53 (2 % of all liver transplantations) were from the liver transplantation population, 43 (2.9 % of all heart transplantations) had undergone heart transplantations and 5 (1.7 %) had undergone lung transplantation or heart-lung transplantation (Table 1). Among the 145 organ transplantation recipients with lung cancer, a total of 61 (42 %) patients surgically treated for lung cancer were included in the present study. The selection criteria for lung cancer resection after solid organ transplantation were the same as those of the general population after complete oncopneumological assessment and respiratory functional tests. The other 84 patients (58 %) had malignancies deemed unresectable and were excluded. So, in this historical cohort, we studied the medical charts of 61 patients (n = 61) who had undergone surgical treatment for lung cancer after solid organ transplantation between June 1986 and June 2016 at Louis Pradel Hospital. The following data were extracted from the University of Lyon (France) Transplantation database and from the Thoracic Surgery database: demographics, medical history, date and type of transplantation, date of lung cancer surgery, postoperative classification of lung cancer, neoadjuvant or adjuvant therapy, postoperative complications, recurrence and final outcome. Exclusion criteria were other diagnosis than primary lung cancer or unresectable tumor. Data were collected until June 2017. Overall survival was estimated from the date of surgery to occurrence of death. Disease-free survival was estimated from the date of surgery to the date of recurrence diagnosis and this analysis focused on patients whose surgery for lung cancer took place after 2006. Missing data on the occurrence of recurrence was too important for surgeries prior to 2006. The mean time follow up was 47.3 months (0–176). Nine patients were lost to follow up.
3. Results 3.1. Patients’ characteristics There were 56 men and 5 women (Table 2). The median age at the time of diagnosis was 61 years (range 31–77 years). 58 patients had a history of smoking, 34 of them had quit before lung cancer was diagnosed. The average number of packs/year was 36.3. Only 3 patients were nonsmokers. 11 patients had a history of previous malignancy before lung cancer was diagnosed. In our series, heart was the most common solid organ to be transplanted (25 patients, 41 %), followed by kidney (18 patients, 29.5 %), liver (16 patients, 26.2 %) and bilateral lung transplantation (2 patients, 3.3 %). Tumors were mainly diagnosed during the systematic follow-up after transplantation (42 patients, 68.8 %). Only 19 patients (31.2 %) were diagnosed after consulting for specific symptoms. The median interval between solid organ transplantation and surgical treatment for lung cancer was 88 months (range 4 - 347months). Lung malignancies consisted of 32 adenocarcinomas, 28 squamous cell carcinomas and one neuro-endocrine carcinoma (Table 3). The vast majority of patients were R0 (95.1 %) and N0 (78.7 %). The post-operative classification (according to the eighth edition TNM classification for lung cancer) revealed 36 (59 %) stage I, 12 (19.7 %) stage II, 12 (19.7 %) stage III and one (1.6 %) stage IV. For the latter patient, stage IV was diagnosed after surgery. A single pleural nodule was discovered during the procedure and was completely resected. Post-operative histologic examination confirmed completely resected squamous cell carcinoma pleural extension. Only one patient received neo-adjuvant chemotherapy. No patient received neo-adjuvant radiotherapy. On the other hand, 11 patients received adjuvant treatment (6 patients received chemotherapy, 3 radiotherapy and 2 radio-chemotherapy). Lung cancer surgery consisted of wedge resection (2 patients, 3.3 %), lobectomy (49 patients, 80.3 %), bi-lobectomy (3 patients, 4.9 %) or pneumonectomy (7 patients, 11.5 %). No segmentectomy was performed.
2.2. Statistical analysis The qualitative variables were summarized using the following descriptive statistics: the count and percentage of missing values and the
Table 1 Solid organ transplants and lung cancer diagnosis in Lyon from June 1986 to June 2016. Solid organ transplants in Lyon from June 1986 to June 2016
Number of transplant (n = 8142) Post transplant lung cancer (n = 145) Mean time of diagnosis (months)
Liver
Kidney
Heart
Lung
Heart-lung
2191 53 (2%) 84 (8-180)
4120 44 (1%) 108 (2-204)
1472 43 (2.9%) 108 (6-252)
294 5 (1.7%) 60 (5-120)
65 0 /
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Table 2 Patients characteristics.
Table 4 90-day post-operative complications. n = 61
Gender male female Medical history smoking stopped smoking Malignancy Transplantation Heart Lung Liver Kidney Surgical treatment Wedge Segmentectomy Lobectomy Bilobectomy Pneumonectomy
56 5
91,8% 8,2%
58 34 11
95% 67% 18%
25 2 16 18
41% 3,3% 26,2% 29,5%
2 0 49 3 7
3,3% 0 80,3% 4,9% 11,5%
Heart n = 25
Lung n=2
Liver n = 16
Kidney n = 18
All (%)
Number of patients with at least one complication Number of complications: Bacterial pneumonia Prolonged drainage Respiratory Atrial fibrillation Renal insuffisiency Others In-hospital death
13
2
8
8
31 (50,8%)
No complications Grade I Grade II Grade III Grade IV Grade V
n = 61
32 28 1
52,5% 45,9% 1,6%
36 12 12 1
59% 19,7% 19,7% 1,6%
23 21 10 7
37,7% 34,4% 16,4% 11,5%
48 5 8
78,7% 8,2% 13,1%
58 3 0
95,1% 4,9%
1 11
1,6% 18%
60 6 6 3 2 4 4 4
0 1 0 0 0 1 1
4 3 5 3 1 2 1
6 3 3 2 1 0 0
16 13 11 7 6 7 6 (9,8%)
Table 5 Classification of surgical complications according to Clavien [6].
Table 3 Lung cancer characteristics.
Anatomopathology Adenocarcinoma Squamous cell carcinoma Neuro endocrine carcinoma Stage I II III IV T classification T1 T2 T3 T4 Lymph node status N0 N1 N2 Resection R0 R1 R2 Treatment Neo-adjuvant Adjuvant
Transplantation
n = 61
%
30 9 11 3 2 6
49,2% 14,8% 18% 4,9% 3,3% 9,8%
(14.7 % versus 7.4 %, p = 0.45). Conversely, lung and heart transplanted patients demonstrated a trend toward higher renal complication rate (14.8 % versus 5.9 %, p = 0.39). 90-day post-operative mortality was 9.8 % (6 patients) and 30-day post-operative mortality rate was 6.5 % (4 patients). Postoperative mortality seemed to be higher in lung or heart transplanted patients compared to renal or hepatic transplanted patients (18.5 % versus 2.9 %). Overall survival was 40.6 % at 5 years (CI95 % [27.4 %;53.4 %]) and 18 % at 10 years ([CI95 % [8.3 %;10.7 %]) (Fig. 1). Median postoperative survival was 41 months (3.41 years). 5-year survival in patients without lymph node extension was 45.12 % (CI95 % [29.76 %;59.29 %]) while 5-year survival in patients with lymph node extension was 22.79 % (CI95 % [4.24 %;50.07 %]); p = 0.17. Seventeen patients died from lung cancer evolution and eighteen patients died from other causes (cardiac failure, myocardial infarction, other malignancy evolution, pneumonia, gas embolism, ARDS). Data on the cause of death are missing for ten patients. Besides, there was no significant difference in survival at 5 years according to transplanted organs, p = 0.92. Disease-free survival rate in patients operated for lung cancer after 2006 was 29.71 % at 5 years (CI95 % [13.07 %;48.49 %]). 5-year disease-free survival rate without lymph node extension was 37.40 % (CI95 % [16.60 %;58.35 %]). In case of lymph node extension, 2-year disease-free survival rate was 20 % (CI95 % [0.84 %;58.19 %]). There was no significant difference in disease-free survival at 5 years according to transplanted organs, p = 0.56. The mean time for recurrence diagnosis was 26.4 months. Most of these patients (75 %) had a metastatic or a multi-metastatic spread at relapse and only 5 patients had a loco-regional recurrence. Preferential sites of metastasis were lung (11 patients; 73.3 %), liver (2 patients; 13.3 %), bone (2 patients; 13.3 %), adrenal glands (1 patient; 6.7 %) and pleura (1 patient; 6.7 %). Nine patients had at least one other diagnosis of cancer during their followup.
3.2. Outcomes 90-day post-operative complications occurred in 31 patients (50.8 %). A total of 60 complications were observed, including 16 bacterial pneumonias (among which: 7 undocumented pneumonias, 2 g-negative bacilli (unspecified bacteria), 1 g-positive anaerobic cocci (unspecified), Legionella pneumophilia, Pseudomonas aeruginosa, Enterobacter cloacae, Proteus vulgaris, Haemophilus influenza and Escherichia coli), 6 renal insufficiencies (2 requiring dialysis), 7 atrial fibrillations, 13 prolonged thoracic drainage and 11 respiratory complications excluding bacterial pneumonia (Table 4). The eleven patients with respiratory complications were diagnosed with ARDS, acute pulmonary edema, pulmonary atelectasis with mucous plug, haemoptysis, symptomatic pleural effusion, pneumothorax and laryngeal edema. Most of these patients had a grade II of the Clavien classification [6] of surgical complications (Table 5). Compared to lung and heart transplanted patients, renal and hepatic transplant recipients had a non-significant higher rate of postoperative pneumonia (35.3 % versus 18.5 %, p = 0.17) and cardiac complications
4. Discussion Compared to the general population, transplant recipients are 57
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Fig. 1. Overall survival of solid organ transplanted patients with surgically treated lung cancer.
advocate earlier anti-infectious treatment and repeated sputum cultures [16]. In the general population, 5-year risk of postoperative recurrence seems to be around 36 % [20] and recurrence is more frequently at a distant site [21]. Comparatively, the 5-year risk of postoperative recurrence in our study was significantly higher, with a rate of 70.29 %. Paradoxically, the mean time to recurrence seems longer in our experience than in the general population (26.4 months versus 13 months [22]). The role of immunosuppression in recurrence is discussed. For renal cell carcinomas and prostate cancer, overall survival seems to be similar between transplantation and dialysis groups [23]. On the other hand, post-solid-organ-transplanted patients with head and neck cancer seem to have a higher risk of loco-regional and distant recurrence [24]. Hence, concluding on the role of immunosuppression on lung cancer relapse is difficult, since transplanted recipients, particularly heart transplant recipients, are a selected group at higher risk of developing lung cancer by virtue of previous heavy smoking history and mean advanced age. In contrast with increased infectious morbidity and mortality and doubt about an increased risk of postoperative recurrence, long-term survival of patients with resectable lung cancer is satisfactory. We report a 5-year survival rate of 40.6 %, which is at the lower limit of that of the general population, ranging from 40.7–50% [25]. Curative surgical treatment can give a real chance to these patients. Median survival without surgical treatment was reported to be 12 months while it is doubled when patients can benefit from surgical resection; and 5-year survival rate was established at 19 % in medically treated patients while it reaches 35 % in resected stage I patients [26]. Our results are in keeping with previous series [16,26]. In this highly monitored population, we find a majority of early-stage cancer. The 5-year survival of N0 patients is satisfactory and in sharp contrast with N + patients (45.12 % vs. 22.79 % respectively). Several studies [3,16,26,27] have emphasized the rapid evolution of lung cancer in transplant recipients with positive lymph nodes. Patient’s reduced natural anti-tumoral immune response may result in more rapid dissemination of the neoplasm. On the other hand, the kidney and liver transplant recipients demonstrated a trend toward shorter survival compared with thoracic transplant recipients (40,7 and 42,5 months respectively), consistent with a delayed detection and more advanced stage disease of the lung cancer among these groups. They did not receive routine follow-up chest radiographs as did thoracic transplant recipients. These findings highlight the need for early detection to improve cancer outcomes in this
known to have an increased risk of cancer. Predominant malignancies are lymphoproliferative disorders and skin cancers. Their occurrence is mainly attributed to the chronic exposure to immunosuppressants. For lung cancer, results are somewhat controversial. In numerous studies, the incidence of bronchogenic carcinoma in the transplant population is relatively low and tends to be similar to that of the overall population after adjusting for age, smoking history and gender [3,7–9]. Moreover, the incidence does not vary according to the type of transplantation and therefore the degree of immunosuppression. On the other hand, compared to the general population, epidemiologic studies found an increased incidence of lung cancer in liver transplant recipients [10], kidney transplant recipients [11] or heart and lung transplant recipients [12]. In the latter study conducted in Australia, Roithmaier et col [12] found a 9.3-fold Increased risk for developing lung cancer after cardiopulmonary transplantation compared with the non-transplant population. The particularly high incidence of lung neoplasms observed in the heart and lung transplant population has been reported by others [13,14], suggesting that these cancers were correlated with smoking history and advanced age rather than with immunosuppressive treatments. Finally, very infrequently, lung cancer is transmitted by the donor and conversely, lung neoplasm may be found in the explanted lungs, even though they were not detected by the pre-transplant CT scan [15]. Although the role of immunosuppressive therapy in the occurrence of these cancers remains controversial, it is known to negatively affect postoperative course. Indeed, we observed an increased risk of postoperative complications and mortality. Like others [16], we observed a high rate of severe postoperative infectious complications. Particularly, the postoperative pneumonia rate we report seems to be sharply higher than that reported in the literature for the general population [17]. Moreover, postoperative mortality in our experience slightly exceeds previously reported rates. Postoperative mortality varies from 1 to 5.2 % [17,18] in the general population while we describe a 6.5 % 30-day postoperative mortality. This higher rate can be explained by respiratory distress, more frequently complicating pneumonias and a high rate of renal insufficiency linked with the need for several nephrotoxic treatments (i.e. calcineurin inhibitors and antibiotics). Post-operative mortality was mostly observed in the heart transplant group. This observation is compatible with data in the literature where post-operative mortality in this population varies from 10 to 12 % [16–19]. The majority of postoperative deaths was due to infectious complications, particularly respiratory failure after pneumonia, leading the authors to 58
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population. This was emphasized by Finkenstedt et al. [28] on a liver transplant recipients group. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9%–13% and for non-skin cancers, the median tumor-related survival significantly improved from 1.2–3.3 years. In 1997, we reported on malignant neoplasms following cardiac transplantation [13]. Out of eleven patients with lung cancer, curative surgery was performed in only 2 cases and mean survival of the whole group after lung neoplasm diagnosis was 9.1 months. Since then, routine chest radiographs are performed in smokers at every post-transplant follow-up control and chest CT scans done annually thereafter in thoracic transplant recipients, enabling early lung cancer diagnosis. Consequently, in the present series, 61 (42 %) patients were amenable to surgery, a high percentage compared to non-transplant patients with lung cancer. These results underline the positive effect of a post-transplant surveillance program, even if there is no definitive protocol for radiologic follow-up of transplanted patients. Our study has several limitations. First, it was an observational study. Second, the number of lung cancer cases was too small to allow meaningful statistical analysis; even if it is the largest study published.
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5. Conclusion Despite a high rate of infectious complications, curative surgical treatment must be proposed to lung cancer patients with a history of solid organ transplantation. Their median survival rate and 5-year survival rate are satisfactory and meet those of the general population. Close follow-up in transplanted patients, particularly in former smokers, is warranted to discover lung cancer at an early stage. Declaration of Competing Interest Dr. Duruisseaux reports personal fees from ROCHE, PFIZER, MSD, Boerhinger Ingelheim, NOvartis, ABBVIE, TAKEDA, BMS, ASTRA ZENECA, outside the submitted work. Acknowledgment The authors thank Karine Debbasch for reviewing the English manuscript. References [1] O.M. Martinez, F.R. de Gruijl, Molecular and immunologic mechanisms of cancer pathogenesis in solid organ transplant recipients, Am. J. Transplant. 8 (2008) 2205, https://doi.org/10.1111/j.1600-6143.2008.02368.x. [2] I. Penn, Incidence and treatment of neoplasia after transplantation, J. Heart Lung Transplant. 12 (1993) S328–S336. [3] M. de Perrot, D.A. Wigle, A.F. Pierre, et al., Bronchogenic carcinoma after solid organ transplantation, Ann. Thorac. Surg. 75 (2) (2003) 367–371. [4] C. Génébès, L. Brouchet, N. Kamar, et al., Characteristics of thoracic malignancies that occur after solid-organ transplantation, J. Thorac. Oncol. 5 (11) (2010) 1789–1795, https://doi.org/10.1097/JTO.0b013e3181f19226. [5] M.S. Sampaio, Y.W. Cho, Y. Qazi, et al., Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database, Transplantation 94 (10) (2012) 990–998, https://doi.org/10.1097/TP. 0b013e318270bc7b. [6] D. Dindo, N. Demartines, P.A. Clavien, Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey,
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