World J Surg (2014) 38:3193–3198 DOI 10.1007/s00268-014-2693-x
Preliminary Report of Major Surgery in Liver Transplant Recipients Receiving m-TOR Inhibitors without Therapeutic Discontinuation Lilian Schwarz • Franc¸ois Cauchy • Filomena Conti • Ailton Sepulveda • Fabiano Perdigao • Denis Bernard Yvon Calmus • Olivier Soubrane • Olivier Scatton
•
Published online: 25 July 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Introduction Mammalian target rapamycin inhibitors (m-TORi) are increasingly used in patients undergoing liver transplantation (LT). Yet, there is rising concern that they also could impair wound healing and favor the development of several surgical complications. This report was designed to evaluate both feasibility and safety of major surgery in liver transplant recipients receiving m-TORi–based immunosuppression without therapeutic discontinuation. Methods From 2007 to 2012, six liver transplant recipients underwent nine major abdominal or thoracic surgical procedures without m-TORi discontinuation or specific dosage adjustment. Their characteristics and postoperative outcomes were retrospectively analyzed. Results Indications for m-TORi were de novo or recurrent malignant disease in five patients and calcineurin inhibitors related neurologic toxicity in one patient. Abdominal procedures, thoracic procedures, and combined thoracic and abdominal procedures were performed in six, two, and one cases respectively. Emergency surgery was performed in one case and elective procedures were performed in eight cases, including five for malignant disease
L. Schwarz (&) F. Cauchy F. Conti A. Sepulveda F. Perdigao D. Bernard Y. Calmus O. Soubrane O. Scatton Department of Hepatobiliary and Liver Transplantation Surgery, Hopital Saint Antoine, Assistance publique-Hopitaux de Paris, 184 rue du Faubourg Saint-Antoine, 75012 Paris Cedex, France e-mail:
[email protected] O. Scatton e-mail:
[email protected] F. Conti Y. Calmus O. Soubrane O. Scatton Universite´ Pierre et Marie Curie, Paris, France
and three for late surgical complications following LT. No patient died postoperatively. One major complication was observed, but no patient required reoperation. No evisceration, incisional surgical site infection, or lymphocele occurred. Conclusions Major surgery in liver transplant recipients receiving m-TOR inhibitors appears both feasible and safe without therapeutic discontinuation or specific dosage adjustment.
Introduction Calcineurin inhibitors (CNI) have had a revolutionary effect on the overall success of liver transplantation (LT) allowing survival rates reaching up to 90 % at 1 year [1]. While these agents have become the cornerstone of immunosuppressive regimen, they also are associated with increased risk of nephrotoxicity [2], neurotoxicity [3], and cancer recurrence or de novo malignancies [4]. New immunosuppressive drugs therefore have been developed [5]. Mammalian target rapamycin inhibitors (m-TORi), such as sirolimus and everolimus, are evolutionarily conserved PI3-kinase family members, which affect broad aspects of cellular functions [6, 7]. In patients undergoing LT, m-TORi have shown encouraging immunosuppressive effects and recent evidences suggest that they could be associated with improved kidney function, better antitumoral control, antiatherogenic effects, and decreased HCV infection recurrence [8–10]. While there is currently growing enthusiasm regarding the use of m-TORi in patients undergoing LT, there also has been raising concerns regarding the potential increased incidence of surgical complications [11, 12]. In such setting, it however remains unclear whether they should be discontinued and
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switched for other immunosuppressive regimen in case of surgery following LT. The purpose of this report was to assess both feasibility and safety of major surgery in liver transplant recipients receiving m-TORi–based immunosuppression without therapeutic discontinuation.
Materials and methods Patient selection Among 327 consecutive patients undergoing LT at Cochin Hospital and subsequently at Saint Antoine Hospital between January 2007 and December 2012, 38 (11.6 %) received m-TORi as primary or secondary immunosuppressive therapy. Of these, 6 (15.7 %) patients underwent major emergency or planned abdominal or thoracic surgical procedures without m-TORi discontinuation. We hypothesized that the potential risk of surgical complications related to the use of m-TORi did not exceed that of the transient over immunosuppressive effect occurring at the reintroduction of CNI. Data collection Analyzed data included: (1) demographic characteristics; (2) general health status before surgery; (3) primary underlying liver disease before LT; (4) initial immunosuppressive regimen; (5) m-TORi-related data such as indication, preoperative duration, dosage, and residual blood concentration; (6) surgical characteristics including indication and type of surgical procedure; (7) postoperative complications according to the Dindo et al. [13] classification; and (8) long-term follow-up.
Results Patient characteristics and indication for m-TORi As shown in Table 1, there were five males and one female. Median age was 49 [range 45–57] years. Indications for LT were malignant disease related to cirrhosis in four patients, MELD 40 alcoholic cirrhosis in one patient, and primary sclerosing cholangitis (PSC) in the remaining patient. This latter patient received m-TORi as primary immunosuppressive therapy because of pathological finding of a preoperatively undiagnosed intrahepatic cholangiocarcinoma. The five others were secondarily switched from CNIs to m-TORi for HCC recurrence or prevention in three patients, de novo colorectal cancer in one patient, and posterior reversible encephalopathy syndrome related to
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tacrolimus in one patient. By the time of surgery, the median body mass index was 24.6 [range 20.8–25.5], and the median albumin level was 31 g/l [range 28–35]. Immunosuppression management Three patients received everolimus and three received sirolimus. Everolimus and sirolimus were used at a median dosage of 2 [range 1.5–2] mg/day and 4 [range 3–5] mg/ day respectively. Median residual blood concentrations were 9 [range 8–10] lg/l for sirolimus and 7 [range 6–8] lg/l for everolimus. Median preoperative duration of m-TORi therapy was 11 [range 2–25] months. Neither m-TORi dosage reduction nor switch was performed during the perioperative period. Associated immunosuppressive regimens at the time of introduction of m-TORi were cyclosporin in one case or mycophenolate mofetil in five cases. All patients received low-dose steroids in combination with these therapies. Surgical procedures Details of the surgical indications in the six patients are provided in Table 2. A total of nine major surgeries were performed. Eight elective surgeries for recurrent or de novo malignant disease as well as late complications related to LT were performed in five patients, and one emergency procedure was performed for gastric perforation following percutaneous endoscopic gastrostomy insertion in a patient with de novo pharyngal carcinoma. Abdominal procedures using large laparotomy were performed in six cases. These included Roux-en-Y hepaticojejunostomy in two cases, pancreaticoduodenectomy in one case, right hepatic lobectomy on the liver graft after portal vein embolization in one case, prosthetic repair of a giant incisional hernia in one case, and exploratory laparotomy with gastric suture in one case. Thoracic procedures using thoracotomy were performed in two cases and consisted in lung lobectomy and tumor en bloc resection with lymphadenectomy in both cases. One patient with xiphosternal recurrence of an HCC associated to abdominal incisional hernia underwent simultaneous abdominal and thoracic procedures. Median blood loss was 200 [range 50–500] mL, and no perioperative transfusion was required. Postoperative m-TORi–related complications The postoperative mortality was nil, and no patient required reoperation. A total of six postoperative complications were observed following five procedures (Table 2). Of these complications, four occurred in patients who received sirolimus and two complications occurred in patients who received everolimus. One major complication
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Table 1 Patient characteristics Patient
Age (yr)
BMI
Gender
LT indication
MELD LT
Primary IS type
m-TORi introduction
Indication for m-TORi
m-TORi type
m-TORi dosage (mg/d)
1
48
25.5
M
HCC on HBV/ HCV cirrhosis
26
Tacrolimus/ MMF
Secondary switch
HCC recurrence prevention
Sirolimus
4
2
45
20.9
M
HCC on HBV cirrhosis
20
CsA
Secondary switch
Colorectal cancer
Everolimus
1,5
3
50
20.8
M
PSC (?IHC)
23
Tacrolimus/ MMF/ SRL
Primary
Cholangiocarcinoma recurrence prevention
Sirolimus
5
4
50
25.5
M
HCC on HCV/ alcoholic cirrhosis
32
Tacrolimus/ MMF
Secondary switch
HCC recurrence
Everolimus
2
5
57
25.5
M
HCC on NASH cirrhosis
9
Tacrolimus/ MMF
Secondary switch
HCC recurrence prevention
Sirolimus
3
6
47
23.8
F
Alcoholic cirrhosis
40
Tacrolimus/ MMF
Secondary switch
Tacrolimus neurological complication/PRES Syndrome
Everolimus
2
BMI body mass index; CsA cyclosporine A; HBV hepatitis B virus; HCC hepatocellular carcinoma; HCV hepatitis C virus; IHC intrahepatic cholangiocarcinoma; LTx liver transplantation; MMF mycophenolate mofetil; m-TORi mammalian target rapamycin inhibitors; NASH nonalcoholic steatohepatitis; PSC primary sclerosing cholangitis
was observed in a patient who received sirolimus who experienced an abdominal collection after Roux-en-Y hepaticojejunostomy and required repeated radiological drainage. The five other minor complications included pulmonary infections in three cases and acute renal insufficiency in two cases. No evisceration, incisional surgical site infection, nor lymphocele was reported. Median follow-up was 23 months. Two patients developed incisional hernias at 12 and 18 months respectively.
Discussion Several experimental reports have highlighted that m-TORi might be associated with both decreased cellular proliferation and angiogenesis of endothelial cells and fibroblasts [14], leading to decreased fibrosis and overall impaired healing processes [15, 16]. Hence, it has been suggested that m-TORi could favor the development of surgical complications following solid organ transplantation, such as impaired wound healing [17, 18], surgical site infection, effusion but also lymphocele [19], as well as anastomotic dehiscence [20]. Nevertheless, it remained unclear whether major surgery in solid organ transplant recipients who received m-TORi–based immunosuppression could be done without therapeutic discontinuation or specific adjustment. To the best of our knowledge, the current report is the first to address these issues. Considering the growing enthusiasm regarding the potential benefits of m-TORi in its oncological applications
[8] or in reducing kidney and brain toxicities related to CNI but also to limit viral recurrence in HCV patients, it is likely that an overall increasing number of patients will receive m-TORi as immunosuppressive therapy. At our center, surgical procedures were required in as many as 15.7 % of patients who received m-TORi immunosuppressive therapy after LT, which is in line with the reported rates of liver transplant recipients eventually undergoing repeat surgical procedures following late surgical complications, such as biliary stricture [21], bowel obstruction [22], abdominal wall incisional hernias [23], but also as a consequence of HCC recurrence [24] or de novo malignancy [25]. In the present series, five of six patients furthermore received m-TORi in a context of malignant disease. Without evidence-based proof, all major surgical procedures were performed without m-TORi discontinuation or specific dose adjustment in accordance with our policy of optimal and personalized management of immunosuppressive therapy. Indeed, it is well accepted that discontinuation of immunosuppressive therapy even for short period carries a risk of graft rejection [26]. This is even more relevant for renal or heart transplant recipients. Moreover, in the situation of malignancy, there are few available solutions for immunosuppression changes. For those reason, our policy was not to discontinue m-TORi— (1) to prevent graft rejection, and (2) not to stimulate tumor progression with acute reduced immunocompetence. No postoperative death occurred; only one major postoperative complication was observed. Therefore, the
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Table 2 Surgical procedures Patient
Surgery
mTORi type
Preoperative duration (months)
Surgical disease
Surgical procedure
Blood loss/ RBC
Postoperative complications
DindoClavien
1
1
SRL
5
Biliary stenosis—failure of endoscopic management
Laparotomy—Roux-en-Y hepaticojejunostomy
200/0
Postoperative intraabdominal collection
III A
–
2
SRL
16
IH
50/0
2
3
EVRL
11
Pulmonary metastasis of colorectal cancer
Laparotomy—prosthetic repair of IH Thoracotomy—lung lobectomy with lymphadenectomy
3
4
SRL
4
Biliary stenosis—failure of endoscopic management
Laparotomy—Roux-en-Y hepaticojejunostomy
100/0
0
–
5
SRL
16
Extrahepatic bile duct papillomatosis with cholangiocarcinoma
Laparotomy— pancreaticoduodenectomy
300/0
0
4
6
EVRL
8
Hepatic HCC recurrence
Laparotomy—Right hepatic lobectomy after PVE
500/0
0
5
7
SRL
2
Solitary 80 mm mediastinal HCC recurrence (diaphragmatic/ pericardial/pleural involvement)
Thoracotomy—tumour ‘‘en bloc’’ resection/lymphadenectomy/ prosthetic closure (vicryl)
300/0
250/0
0 Pulmonary infection
Pulmonary infection
II
II
/renal insufficiency
–
8
SRL
20
IH/40 mm xiphosternal HCC recurrence/ Pulmonary HCC recurrence
Laparoto/phrenotomy— recurrence ‘‘en bloc’’ resection/ prosthetic repair of IH/diagnosis thoracoscopy—2 wedge resections
200/0
Pulmonary infection
II
6
9
EVRL
25
Peritonitis following percutaneous gastrostomy for pharyngal carcinoma
Laparotomy—peritoneal lavage and drainage/gastric suture
50/0
Renal insufficiency
II
SRL sirolimus, EVRL everolimus, HCC hepatocellular carcinoma, IH incisional hernia, m-TORi mammalian target rapamycin inhibitors, PVE portal vein embolization, RBC red blood cell transfusion
present study suggests for the first time that m-TOR do not seem to jeopardize the immediate postoperative course of liver transplant recipients who require major surgery. These encouraging results raise several hypotheses. First, it has been established that the incidence of postoperative complications in patients who received m-TORi was dose or concentration-dependent [27–29]. Prolonged m-TORi exposure was reduced using lower maintenance dosage as well as abandoning loading dose [27]. None of our patients received m-TORi loading doses and only moderate doses were therefore used. Second, it has been suggested that despite similar mechanisms of action between sirolimus and everolimus, the latter had shorter half-life, higher bioavailability, lower plasma protein binding [30], and therefore could be associated with less postoperative complications than sirolimus. No conclusions regarding the respective influences of these two drugs could be done in the present study, regarding the small number of patients
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included. Finally, it should be pointed out that despite the extensive nature of the procedures, median blood loss was 200 ml and no patient required transfusion. In that sense, it is likely that the anticipated higher operative risk in these patients receiving m-TOR might have led to a more careful perioperative management as previously reported [31]. After LT, between 5 and 13 % undergo incisional hernia repair [23, 32, 33], and it is likely that the rate of patients actually experiencing incisional hernia following LT is probably underestimated. Contrary to experimental data, various clinical reports with low-dosage exposure do not reveal that mTORi had a negative impact on wound healing in organ recipients [33]. In the current study, two patients experienced incisional hernia at 12 and 18 months respectively. The observed rate of incisional hernia (22 %) accounts both prolonged m-TORi therapy and accumulation of surgical procedures in LT recipients. However, the purpose of this preliminary series was to focus on severe
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morbidity and life-threatening complication following major surgical procedures. The present study has several limitations. First, only six patients undergoing nine major procedures were included. This is probably the consequence of the former use of m-TORi, which was indicated as immunosuppressive therapy only in very specific clinical situations. Second, our patients were not compared to matched controls undergoing similar procedures during the same period. Indeed, the limited indications of m-TORi make the existence of such a control group unlikely and theoretical comparison between such small numbers of patients would have precluded relevant statistical analysis interpretation. Nevertheless, this study suggests for the first time that major surgery may be performed without m-TORi discontinuation or specific dosage adjustment in liver transplant recipients. Further investigations in larger and comparative cohorts will be required to confirm these findings. Conflict of interest of interest.
All authors declare that they have no conflicts
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