LETTER-PRELIMINARY REPORT/TECHNIQUE
A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases The RAPID Concept P˚al-Dag Line, MD, PhD,∗ Morten Hagness, MD, PhD,∗ Audun Elnaes Berstad, MD, PhD,† Aksel Foss, MD, PhD,∗ § and Svein Dueland, MD, PhD‡ Objective: Selected patients with nonresectable colorectal liver metastases benefit from liver transplantation and have acceptable 5-year survival rates. However, allocating full-sized grafts to this group of patients is difficult due to the scarcity of grafts. This could be improved by utilizing small partial grafts, which mandates effective strategies to overcome the problems regarding insufficient functional liver mass. Methods: We have developed a protocol incorporating previously reported experiences from living donor transplantation and recent developments in liver surgery, facilitating transplantation of very small liver grafts. At the time of transplantation, segments 1 to 3 are resected in the recipient and orthotopically replaced by a segment 2 to 3 allograft. Portal inflow is modulated by redirecting the portal flow to the graft with concomitant focus on keeping the portal vein pressure below 20 mm Hg. A second-stage hepatectomy is performed as soon as the graft has regenerated to a sufficient volume. Results: A graft weighing 330 g was transplanted to a 50-year-old man weighing 92 kg, and the portal vein to the right remnant liver was closed. The volume of the liver graft was doubled 2 weeks after the first procedure, and it increased further after the second procedure, with extended right hepatectomy performed at day 23 after transplantation. There were no signs of liver failure or small-for-size syndrome. Conclusions: The current protocol and ongoing study could represent a possible strategy to increase the availability of liver transplantation to patients with nonresectable liver tumors such as hepatocellular carcinoma and colorectal liver metastases. Keywords: auxiliary liver transplantation, colorectal cancer, liver metastases, 2-staged hepatectomy (Ann Surg 2015;262:e5–e9)
C
olorectal cancer (CRC) is a frequent malignant disease in Western societies with an incidence of about 700 per million population. About 50% of the patients will develop liver metastases (CRC-metastases), and liver resection is the main potential curative treatment option. To maximize resectability, various techniques like 2-stage hepatectomy,1 portal vein embolization to expand the future liver remnant (FLR)2,3 have been developed. Recently an alternative approach to increase FLR volume termed Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has been introduced, and this provides a much faster increase in volume of the FLR than portal vein embolization. Despite the great advances in surgical techniques, only about From the Departments of ∗ Transplantation Medicine, †Radiology, and ‡Oncology, Oslo University Hospital, Oslo, Norway; and §Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Disclosure: The authors declare no conflicts of interest. Reprints: P˚al-Dag Line, MD, PhD, Department of Transplantation Medicine, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]. C 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/15/26201-e0005 DOI: 10.1097/SLA.0000000000001165
Annals of Surgery r Volume 262, Number 1, July 2015
20% of the patients become surgically resectable. We have demonstrated that selected patients with nonresectable CRC-metastases can be treated by liver transplantation with a dramatic improvement in 5-year survival rates compared to chemotherapy, which is the only alternative treatment option in this patient cohort.4,5 Recurrence of disease is, however, frequent with a median diseasefree survival of 10 months.5 In the majority of cases, the recurrences are slow-growing lung metastases that often can be resected.6 The CRC-metastases candidates with the best prognosis after liver transplantation seem to be patients with metachronous disease, pN0 primary, largest lesion of less than 5.5 cm, carcinoembryonic antigen less than 80, response or stable disease on chemotherapy, and more than 2 years from diagnosis to transplantation.4 Optimal morphological response to preoperative chemotherapy has been shown to be of high prognostic value after liver resection for CRC-metastases,7 and this also holds true for liver transplantation in CRC-metastases.4 Nonresectable colorectal liver metastasis is commonly considered a contraindication to liver transplantation due to the scarcity of available grafts for transplantation in most countries. Only few patients with CRC-metastases can realistically be offered transplantation, and this should be as a part of prospective studies. One way to expand the number of available liver grafts could be an increased use of split liver donor transplantation. Classical split liver transplantation with an extended right graft (segment 1+4−8) for adults and segment 2+3 to a pediatric recipient has been shown to be an excellent option for expanding the donor pool and provides good-quality liver grafts.8 Segment 2+3 is, however, almost never sufficient for normal-sized adults.9 The clinical utility of both partial liver transplantation and liver resection is restricted by limitations related to inadequate functional liver volume. Extended right lobe grafts containing segments 4 to 8 have comparable outcome as full-size liver grafts, whereas insufficient size of a partial graft or liver remnant will result in postoperative liver failure due to inability to meet metabolic demands. Furthermore, a small liver volume can lead to development of the small-for-size syndrome (SFSS), characterized by sinusoidal disruption and hemorrhage and elevated portal pressure and portal hyperperfusion with concomitant arterial ischemia due to the hepatic buffer response.10,11 In liver transplantation, a graft to body weight ratio (GBWR) of more than 0.8 is generally considered safe in terms of both metabolic needs and avoidance of SFSS, given an acceptable graft quality. Below this level, the risk of graft failure due to SFSS is greatly increased. Interestingly, a GBWR of less than 0.8 might be tolerated if the damaging effects of elevated portal pressure is attenuated by means of a temporal portocaval shunt.12 The tolerable portal pressure limit seems to be at about 20 mm Hg and below in liver transplantation. A similar strong association between elevated portal vein pressure values above 22 mm Hg and postoperative liver dysfunction after liver resection have been reported.13 Here, we report a new combination of techniques, utilizing an ALLPS-like approach to make an auxiliary segment 2+3 donor liver expand to a sufficient size for an adult recipient suffering from nonresectable colorectal liver metastases. www.annalsofsurgery.com | e5
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Annals of Surgery r Volume 262, Number 1, July 2015
Line et al
AIM AND HYPOTHESES The aim of this report was to describe a possible surgical strategy that could enable liver transplantation of patients with nonresectable CRC metastases by means of small partial grafts and planned 2-staged hepatectomy. The principal requirements that must be addressed are insufficient metabolic mass, excessive hemodynamic forces on a small vascular bed, and the need for rapid regeneration. Possible solutions to the management of each of these separate problems can be found in previous reports and, based on this, the following hypotheses can be proposed:
r SFSS syndrome and associated liver tissue damage can be avoided by keeping portal vein pressure below 20 mm Hg posttransplantation r The insufficient metabolic mass of the graft (segment 2+3) at time of transplantation can be tackled by maintaining a temporary native liver remnant for a short period of time that can ensure adequate liver function, allowing a 2-staged hepatectomy procedure. r Rapid regeneration could be anticipated by diverting portal blood flow from the liver remnant to the graft like in the ALPPS procedure while keeping the portal vein pressure within safe limits
PROTOCOL AND METHOD On the basis of the hypotheses outlined earlier, a protocol for the RAPID study (Resection And Partial Liver Segment 2/3 Transplantation With Delayed Total Hepatectomy) was designed and approved by the regional committee for research ethics and registered at Clinicaltrials.gov (study number NCT02215889). The primary endpoints are to determine the safety of combined transplantation of liver segment 2 to 3 transplantation and 2-staged hemihepatectomy and to explore if total hepatectomy can be achieved within 4 weeks posttransplant. Inclusion criteria are good performance status (Eastern Cooperative Oncology Group 0 or 1), histologically verified adenocarcinoma in colon/rectum, nonresectable liver metastases with no signs of extrahepatic metastatic abdominal disease or local recurrence according to PET/CT (positron emission tomography/computed tomography) scan within 4 weeks before listing. Resectability is assessed at weekly multidisciplinary meetings with hepatobiliary surgeons, medical oncologist, liver transplant surgeons, and hepatobiliary radiologist. Patients may have 1 to 3 resectable lung lesions all smaller than 15 mm. All patients should have received at least 8 weeks of chemotherapy. Eligible patients should have satisfactory blood tests at the time of listing [hemoglobin > 10 g/dL, neutrophils > 1.0 (after any granulocyte colony stimulating factor), thrombocytes > 75, Bilirubin < 2 x upper normal level, aspartate aminotransferase, alanine aminotransferase < 5 x upper normal level, Creatinine < 1.25 x upper normal level, albumin above lower normal level]. At the time of transplant, the liver is completely mobilized and dissected free from the retrohepatic vena cava. A partial hepatectomy, removing segment 1 to 3 and avoiding cutting through tumor tissue is performed. Directly following resection, a segment 2 to 3 graft from a deceased donor is transplanted orthotropically with portal vein and arterial conduit anastomosed to the corresponding vessels in an end-to-side fashion in the recipient, whereas the bile duct should be reconstructed by hepaticojejunostomy to make the second-stage hepatectomy easier to perform. At least 15 minutes after revascularization, a pressure catheter is placed in the portal vein and flow probes attached to the portal vein and hepatic artery. Portal vein pressure is monitored after revascularization for 5 minutes during basal, stable conditions and during clamping of the right portal vein branch to the native liver remnant. If the pressure remains stable below 20 mm Hg, the portal vein to the right remnant liver is ligated. If the pressure is e6 | www.annalsofsurgery.com
higher than 20 mm Hg during clamping, the splenic artery is ligated. If this does not alleviate graft portal hypertension, a banding of the portal vein to the right liver remnant is performed to form a stenosis that results in a stable portal pressure value to the graft of less than 20 mm Hg. If this does not reduce the portal pressure sufficiently, a portocaval shunt may be constructed using the right portal vein in an end to side fashion to the cava. The weight of the transplanted liver graft is recorded, and standard liver volume (SLV) for the recipient is calculated according to the formula as SLV = 1072.8 × body surface area (m2 ) − 345.7.14 CT scans with volumetry of the transplanted segment is performed at postoperative days 1, 7, 14, 21, and 28, and thereafter monthly. During the phase of graft regeneration, the portal occluded liver remnant is left in situ with immunosuppression and no chemotherapy is given in order not to negatively impact liver regeneration. As soon as the donor graft has obtained a size approaching 0.8% of body weight or 35% to 40% of recipient standard liver volume (whichever occurs first), a secondary completing hepatectomy of the na¨ıve liver remnant is performed leaving only the donor segments in place. The immunosuppressive regimen consists of basiliximab induction of 20 mg intravenously. on day 0 and day 4. Corticosteroids are administered as bolus injection of 250 mg methylprednisolone at the start of the transplantation, and thereafter the patients receive 20 mg of prednisolone daily for the first 28 days, tapering by 5 mg for each month until withdrawal or a maintenance dose of 5 mg if needed. Mycophenolate mofetil is given from day 1 in a dose of 1 g 2 times daily. Tacrolimus is introduced on day 1, aiming at through levels of 4 to 6 ng/mL. Four weeks after the second-stage hepatectomy, tacrolimus is replaced by sirolimus. Target trough levels for sirolimus is in the first 2 weeks: 5 to 10 ng/mL, thereafter 10 to 20 ng/mL if tolerated. Complications are registered according to the Clavien-Dindo classification.15
CASE REPORT A 50-year-old previously healthy man was diagnosed in 2013 with locally advanced rectal cancer and synchronous liver metastases and 2 small lesions (10) and bilobar distribution. He was initially treated by 4 cycles of Nordic FLOX, and underwent preoperative pelvic radiotherapy (5 Gy × 5). He then received total mesorectal excision and a sigmoidostomy. Pathological examination revealed an adenocarcinoma of the rectum, ypT4 (40 mm) ypN1(1/32) M1. The tumor was KRAS/BRAF (kirsten rat sarcoma viral oncogene homolog/B-Raf proto-oncogene, serine/threonine kinase) wild type. Postoperatively he received FLIRI (5-flfluorouracil/irinotecan)/Cetuximab with stable disease by CT evaluation. By radiological reevaluation, he had still nonresectable liver metastases and no progress of his lung metastases. The patient gave his written informed consent to participation in the RAPID study and preoperative colonoscopy and PET/CT scans revealed no apparent signs of extrahepatic disease apart from the 2 already known small, resectable lung lesions. He underwent transplantation in June 2014 with a segment 2 to 3 graft from a young donor. His preoperative liver tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, and INR) were within normal limits. Splitting of the donor graft was required due to a small size recipient receiving the right part of the liver, and no suitable pediatric recipient was at the time point listed. Recipient weight was 92 kg and his SLV was estimated to 1916 mL. The weight of the transplanted graft was 330 g, representing a GBWR of 0.36 and 17.2% of the SLV. As first part of the operation, the liver was completely mobilized and dissected free from the retrohepatic vena cava. Thereafter, a resection of the patient segments 1 to 3 was performed, carefully avoiding tumor-affected parts of the liver. The weight of the C 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Annals of Surgery r Volume 262, Number 1, July 2015
resected segments 1 to 3 was 651 g. The left hepatic vein junction and adjacent vena cava were clamped to be used as site for graft liver vein anastomosis. To avoid interference with the remnant liver, and to facilitate the planned final hepatectomy, the portal vein and the hepatic artery of the graft were anastomosed in an end-to-side fashion to the main portal trunk and the common hepatic artery, respectively (Fig. 1). The portal pressure after revascularization was 6 mm Hg with a portal flow to the graft of 250 mL/min. After clamping of portal flow to the liver remnant, the portal pressure rose to 14 mm Hg on repeated measurements and portal flow to the graft was 680 mL/min. Hepatic artery flow to the graft was 150 mL/min. The values were stable over several minutes and 3 repeated measurements; consequently, the portal inflow to the right liver remnant was closed by a vascular stapler, without dividing the portal vein. Biliary reconstruction to the graft was accomplished by hepaticojejunostomy. The posttransplant course was uneventful apart from ascites production that gradually decreased over the course of the first 14 days. CT volumetry was performed on day 1 and every 7 to 14 days thereafter. The growth rate of the graft determined by CT scans is shown in Figure 2. On day 23, when the graft reached an estimated volume of about 700 mL, the second-stage hepatectomy was performed. Portal flow at second-stage surgery was 580 mL/min and portal pressure was 14 mm Hg on 3 repeated measurements. Postoperative liver function was good, without signs of liver failure (Fig. 3). Ascites production was initially high, but gradually decreased in the course of the next 2 weeks. From day 50, increased ascites production was again noted, and ultrasound and CT examination revealed a significant liver vein stenosis in the graft. This was treated by endovascular stenting, and the ascites production disappeared in the course of 4 days. The only complication observed was manageable with a Clavien-Dindo grade of 3a due to the need of endovascular stenting.
DISCUSSION The current concept and the present case demonstrate that transplantation of very small grafts with associated partial hepatectomy and modulation of portal inflow is feasible and could possibly represent a strategy that could enable the utilization of segment 2 to 3 grafts in adult patients with liver tumors. Eligible patients must have
FIGURE 1. Schematic overview of the operative field after first-stage resection of segments 1 to 3 leaving an extended right liver remnant (R) and the transplanted segment 2 to 3 graft (G). Note the mode of vascular anastomosis with end-toside anastomosis of the graft portal vein (1) and graft hepatic artery (2) to the main portal trunk and common hepatic artery, respectively. C 2015 Wolters Kluwer Health, Inc. All rights reserved.
Auxiliary Transplant and Liver Resection
a liver function allowing resection surgery, and the distribution of tumors within the parenchyma must enable dissection in a tumor-free plane. A somewhat similar technique with auxiliary transplantation was reported by the group of Dokmak et al in 2013; however, they used a small, full-sized graft with a GBWR of 0.77.16 Furthermore, they only partially ligated the portal vein to the liver remnant, did not monitor pressure, and performed a percutaneous portal vein embolization at day 14. The interval between primary and secondary hepatectomy was also 30 days, so although there are similarities, the RAPID concept is fundamentally different. We are not aware of any other reports on successful transplantation of a GBWR of 0.36. Hence, the RAPID concept could potentially have a broader applicability than intended by Belghiti et al. Significant factors for succeeding with such small graft are probably that the metabolic consequences of insufficient liver mass can be safely avoided by keeping a liver remnant of sufficient size during the phase of hypertrophy of the graft itself. Furthermore, to prevent SFSS and ensure optimal regeneration, modulation of portal inflow is most likely essential. Patients with colorectal metastases do not have portal hypertension and no hyperdynamic splanchnic circulation and are thus probably ideal for modulating portal inflow. The principles outlined have distinct similarities with the ALPPS procedure, but is technically more demanding. It is likely that the inflammatory response to parenchymal transection is an important signal for increased expression of the regeneration primers interleukin 6 and tumor necrosis factor α. This has been clearly demonstrated in an elegant animal model of ALPPS by Schlegel and coworkers.17 In the RAPID procedure, this stimulus could be linked to both the liver resection in the recipient and hypothetically also to the splitting of the graft. Our patient underwent the final hepatectomy 23 days after the transplantation. When assessing the volumetry and liver function data retrospectively, this could probably have been done 1 week earlier. The growth rate of the graft displayed a biphasic pattern with a rapid increase in volume during the first 14 days, but then reached a plateau. After the final hepatectomy, the growth rate increased again and reached a volume exceeding 400% of the initial graft weight by day 50. The case demonstrates the importance of optimal venous outflow. Interestingly, the venous outflow obstruction was not apparent until 6 weeks after transplantation, and one might speculate whether the rapid hypertrophy of the graft plays a role in this context. The oncological aspects of the RAPID procedure cannot be evaluated for long-term in the current protocol, and the effects of the treatment must be interpreted with care given for the short observation period and only a single case. It is theoretically possible that the combination of a 2-staged procedure, a strong regeneration signal during 2 to 3 weeks and concomitant immunosuppression could adversely affect tumor growth and dissemination. This will be further elucidated in the ongoing pilot study. From a theoretical point of view, a promoting effect of immunosuppression on tumor growth and spread constitutes a concern, particularly until the time of the secondstage hepatectomy. In our previous study about liver transplantation for CRC-metastases, we have demonstrated that patients who develop relapse on immunosuppression have a 53% of 5-year overall survival from time of relapse compared to about 0% in patients receiving palliative chemotherapy.5 This may suggest that the immunosuppressive regimen used does not accelerate the progression of malignant disease to a clinical apparent or relevant level. If the aforementioned theoretical disadvantages prove to be of minor significance or can be managed by additional interventions, the RAPID approach could be and alternative strategy to increase graft availability for selected patients with technically nonresectable liver tumors. Another important aspect is, that, given a successful development of the RAPID concept the prospect of living donation of segment 2 to 3 grafts to this cohort www.annalsofsurgery.com | e7
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Annals of Surgery r Volume 262, Number 1, July 2015
Line et al
FIGURE 2. CT volumetry of the transplanted graft during the first 50 posttransplant days and corresponding representative CT images at days 1, 21, and 50 (R: liver remnant, G: graft).
FIGURE 3. Overview of bilirubin (mmol/L), international normalized ratio (INR), aspartate amino transferase AST (U/L), and alanine amino transferase ALT (U/L) during the first 50 days after surgery.
e8 | www.annalsofsurgery.com
C 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Annals of Surgery r Volume 262, Number 1, July 2015
of patients might be conceivable, because the risk of segment 2 to 3 donation is very much lower and vastly different to donation of a right or left liver lobe.18 We would currently warn against widespread expansion of this technique regarding indications and use of living donors prematurely. It is of utmost importance to evaluate this new innovation in a scientifically controlled and staged manner according to the principles outlined by Barkun and coworkers.19
REFERENCES 1. Adam R, Laurent A, Azoulay D, et al. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg. 2000;232:777–785. 2. Hemming A, Reed A, Howard R, et al. Preoperative portal vein embolization for extended hepatectomy. Ann Surg. 2003;237:686–691; discussion 691–693. 3. Jaeck D, Oussoultzoglou E, Rosso E, et al. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg. 2004;240:1037–1049; discussion 1049–1051. 4. Hagness M, Foss A, Line P-D, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg. 2013;257:800–806. 5. Dueland S, Guren TK, Hagness M, et al. Chemotherapy or liver transplantation for nonresectable liver metastases from colorectal cancer? Ann Surg. 19 June 2014. [ePub ahead of print] 6. Hagness M, Foss A, Egge TS, et al. Patterns of recurrence after liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg Oncol. 2014;21:1323–1329. 7. Shindoh J, Loyer EM, Kopetz S, et al. Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases. J Clin Oncol. 2012;30:4566–4572.
C 2015 Wolters Kluwer Health, Inc. All rights reserved.
Auxiliary Transplant and Liver Resection
8. Renz JF, Yersiz H, Reichert PR, et al. Split-liver transplantation: a review. Am J Transplant. 2003;3:1323–1335. 9. Heaton N, Srinivasan P, Prachalias A, et al. Overcoming the limitations of living donor and split liver transplantation: a proposal for adult recipients (the best of the East in the West). Liver Transpl. 2008;14:932–934. 10. Heaton N. Small-for-size liver syndrome after auxiliary and split liver transplantation: donor selection. Liver Transpl. 2003;9:S26–S28. 11. Ito T, Kiuchi T, Yamamoto H, et al. Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications. Transplantation. 2003;75:1313–1317. 12. Takada Y, Ueda M, Ishikawa Y, et al. End-to-side portocaval shunting for a small-for-size graft in living donor liver transplantation. Liver Transpl. 2004;10:807–810. 13. Allard M-A, Adam R, Bucur P-O, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg. 2013;258:822–829; discussion 829–830. 14. Heinemann A, Wischhusen F, P¨uschel K, et al. Standard liver volume in the Caucasian population. Liver Transpl Surg. 1999;5:366–368. 15. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213. 16. Dokmak S, Elkrief L, Belghiti J. Auxiliary liver transplantation with a small deceased liver graft for cirrhotic liver complicated by hepatocellular carcinoma. Transpl Int. 2013;26:e102–e104. 17. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–847. 18. Clavien P-A, Petrowsky H, DeOliveira ML, et al. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356:1545–1559. 19. Barkun JS, Aronson JK, Feldman LS, et al. Evaluation and stages of surgical innovations. The Lancet. 2009;374:1089–1096.
www.annalsofsurgery.com | e9
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A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases The RAPID Concept P˚al-Dag Line, MD, PhD,∗ Morten Hagness, MD, PhD,∗ Audun Elnaes Berstad, MD, PhD,† Aksel Foss, MD, PhD,∗ § and Svein Dueland, MD, PhD‡ Objective: Selected patients with nonresectable colorectal liver metastases benefit from liver transplantation and have acceptable 5-year survival rates. However, allocating full-sized grafts to this group of patients is difficult due to the scarcity of grafts. This could be improved by utilizing small partial grafts, which mandates effective strategies to overcome the problems regarding insufficient functional liver mass. Methods: We have developed a protocol incorporating previously reported experiences from living donor transplantation and recent developments in liver surgery, facilitating transplantation of very small liver grafts. At the time of transplantation, segments 1 to 3 are resected in the recipient and orthotopically replaced by a segment 2 to 3 allograft. Portal inflow is modulated by redirecting the portal flow to the graft with concomitant focus on keeping the portal vein pressure below 20 mm Hg. A second-stage hepatectomy is performed as soon as the graft has regenerated to a sufficient volume. Results: A graft weighing 330 g was transplanted to a 50-year-old man weighing 92 kg, and the portal vein to the right remnant liver was closed. The volume of the liver graft was doubled 2 weeks after the first procedure, and it increased further after the second procedure, with extended right hepatectomy performed at day 23 after transplantation. There were no signs of liver failure or small-for-size syndrome. Conclusions: The current protocol and ongoing study could represent a possible strategy to increase the availability of liver transplantation to patients with nonresectable liver tumors such as hepatocellular carcinoma and colorectal liver metastases. Keywords: auxiliary liver transplantation, colorectal cancer, liver metastases, 2-staged hepatectomy (Ann Surg 2015;262:e5–e9)
C
olorectal cancer (CRC) is a frequent malignant disease in Western societies with an incidence of about 700 per million population. About 50% of the patients will develop liver metastases (CRC-metastases), and liver resection is the main potential curative treatment option. To maximize resectability, various techniques like 2-stage hepatectomy,1 portal vein embolization to expand the future liver remnant (FLR)2,3 have been developed. Recently an alternative approach to increase FLR volume termed Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) has been introduced, and this provides a much faster increase in volume of the FLR than portal vein embolization. Despite the great advances in surgical techniques, only about From the Departments of ∗ Transplantation Medicine, †Radiology, and ‡Oncology, Oslo University Hospital, Oslo, Norway; and §Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Disclosure: The authors declare no conflicts of interest. Reprints: P˚al-Dag Line, MD, PhD, Department of Transplantation Medicine, Oslo University Hospital, Postboks 4950 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]. C 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/15/26201-e0005 DOI: 10.1097/SLA.0000000000001165
Annals of Surgery r Volume 262, Number 1, July 2015
20% of the patients become surgically resectable. We have demonstrated that selected patients with nonresectable CRC-metastases can be treated by liver transplantation with a dramatic improvement in 5-year survival rates compared to chemotherapy, which is the only alternative treatment option in this patient cohort.4,5 Recurrence of disease is, however, frequent with a median diseasefree survival of 10 months.5 In the majority of cases, the recurrences are slow-growing lung metastases that often can be resected.6 The CRC-metastases candidates with the best prognosis after liver transplantation seem to be patients with metachronous disease, pN0 primary, largest lesion of less than 5.5 cm, carcinoembryonic antigen less than 80, response or stable disease on chemotherapy, and more than 2 years from diagnosis to transplantation.4 Optimal morphological response to preoperative chemotherapy has been shown to be of high prognostic value after liver resection for CRC-metastases,7 and this also holds true for liver transplantation in CRC-metastases.4 Nonresectable colorectal liver metastasis is commonly considered a contraindication to liver transplantation due to the scarcity of available grafts for transplantation in most countries. Only few patients with CRC-metastases can realistically be offered transplantation, and this should be as a part of prospective studies. One way to expand the number of available liver grafts could be an increased use of split liver donor transplantation. Classical split liver transplantation with an extended right graft (segment 1+4−8) for adults and segment 2+3 to a pediatric recipient has been shown to be an excellent option for expanding the donor pool and provides good-quality liver grafts.8 Segment 2+3 is, however, almost never sufficient for normal-sized adults.9 The clinical utility of both partial liver transplantation and liver resection is restricted by limitations related to inadequate functional liver volume. Extended right lobe grafts containing segments 4 to 8 have comparable outcome as full-size liver grafts, whereas insufficient size of a partial graft or liver remnant will result in postoperative liver failure due to inability to meet metabolic demands. Furthermore, a small liver volume can lead to development of the small-for-size syndrome (SFSS), characterized by sinusoidal disruption and hemorrhage and elevated portal pressure and portal hyperperfusion with concomitant arterial ischemia due to the hepatic buffer response.10,11 In liver transplantation, a graft to body weight ratio (GBWR) of more than 0.8 is generally considered safe in terms of both metabolic needs and avoidance of SFSS, given an acceptable graft quality. Below this level, the risk of graft failure due to SFSS is greatly increased. Interestingly, a GBWR of less than 0.8 might be tolerated if the damaging effects of elevated portal pressure is attenuated by means of a temporal portocaval shunt.12 The tolerable portal pressure limit seems to be at about 20 mm Hg and below in liver transplantation. A similar strong association between elevated portal vein pressure values above 22 mm Hg and postoperative liver dysfunction after liver resection have been reported.13 Here, we report a new combination of techniques, utilizing an ALLPS-like approach to make an auxiliary segment 2+3 donor liver expand to a sufficient size for an adult recipient suffering from nonresectable colorectal liver metastases. www.annalsofsurgery.com | e5
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 1, July 2015
Line et al
AIM AND HYPOTHESES The aim of this report was to describe a possible surgical strategy that could enable liver transplantation of patients with nonresectable CRC metastases by means of small partial grafts and planned 2-staged hepatectomy. The principal requirements that must be addressed are insufficient metabolic mass, excessive hemodynamic forces on a small vascular bed, and the need for rapid regeneration. Possible solutions to the management of each of these separate problems can be found in previous reports and, based on this, the following hypotheses can be proposed:
r SFSS syndrome and associated liver tissue damage can be avoided by keeping portal vein pressure below 20 mm Hg posttransplantation r The insufficient metabolic mass of the graft (segment 2+3) at time of transplantation can be tackled by maintaining a temporary native liver remnant for a short period of time that can ensure adequate liver function, allowing a 2-staged hepatectomy procedure. r Rapid regeneration could be anticipated by diverting portal blood flow from the liver remnant to the graft like in the ALPPS procedure while keeping the portal vein pressure within safe limits
PROTOCOL AND METHOD On the basis of the hypotheses outlined earlier, a protocol for the RAPID study (Resection And Partial Liver Segment 2/3 Transplantation With Delayed Total Hepatectomy) was designed and approved by the regional committee for research ethics and registered at Clinicaltrials.gov (study number NCT02215889). The primary endpoints are to determine the safety of combined transplantation of liver segment 2 to 3 transplantation and 2-staged hemihepatectomy and to explore if total hepatectomy can be achieved within 4 weeks posttransplant. Inclusion criteria are good performance status (Eastern Cooperative Oncology Group 0 or 1), histologically verified adenocarcinoma in colon/rectum, nonresectable liver metastases with no signs of extrahepatic metastatic abdominal disease or local recurrence according to PET/CT (positron emission tomography/computed tomography) scan within 4 weeks before listing. Resectability is assessed at weekly multidisciplinary meetings with hepatobiliary surgeons, medical oncologist, liver transplant surgeons, and hepatobiliary radiologist. Patients may have 1 to 3 resectable lung lesions all smaller than 15 mm. All patients should have received at least 8 weeks of chemotherapy. Eligible patients should have satisfactory blood tests at the time of listing [hemoglobin > 10 g/dL, neutrophils > 1.0 (after any granulocyte colony stimulating factor), thrombocytes > 75, Bilirubin < 2 x upper normal level, aspartate aminotransferase, alanine aminotransferase < 5 x upper normal level, Creatinine < 1.25 x upper normal level, albumin above lower normal level]. At the time of transplant, the liver is completely mobilized and dissected free from the retrohepatic vena cava. A partial hepatectomy, removing segment 1 to 3 and avoiding cutting through tumor tissue is performed. Directly following resection, a segment 2 to 3 graft from a deceased donor is transplanted orthotropically with portal vein and arterial conduit anastomosed to the corresponding vessels in an end-to-side fashion in the recipient, whereas the bile duct should be reconstructed by hepaticojejunostomy to make the second-stage hepatectomy easier to perform. At least 15 minutes after revascularization, a pressure catheter is placed in the portal vein and flow probes attached to the portal vein and hepatic artery. Portal vein pressure is monitored after revascularization for 5 minutes during basal, stable conditions and during clamping of the right portal vein branch to the native liver remnant. If the pressure remains stable below 20 mm Hg, the portal vein to the right remnant liver is ligated. If the pressure is e6 | www.annalsofsurgery.com
higher than 20 mm Hg during clamping, the splenic artery is ligated. If this does not alleviate graft portal hypertension, a banding of the portal vein to the right liver remnant is performed to form a stenosis that results in a stable portal pressure value to the graft of less than 20 mm Hg. If this does not reduce the portal pressure sufficiently, a portocaval shunt may be constructed using the right portal vein in an end to side fashion to the cava. The weight of the transplanted liver graft is recorded, and standard liver volume (SLV) for the recipient is calculated according to the formula as SLV = 1072.8 × body surface area (m2 ) − 345.7.14 CT scans with volumetry of the transplanted segment is performed at postoperative days 1, 7, 14, 21, and 28, and thereafter monthly. During the phase of graft regeneration, the portal occluded liver remnant is left in situ with immunosuppression and no chemotherapy is given in order not to negatively impact liver regeneration. As soon as the donor graft has obtained a size approaching 0.8% of body weight or 35% to 40% of recipient standard liver volume (whichever occurs first), a secondary completing hepatectomy of the na¨ıve liver remnant is performed leaving only the donor segments in place. The immunosuppressive regimen consists of basiliximab induction of 20 mg intravenously. on day 0 and day 4. Corticosteroids are administered as bolus injection of 250 mg methylprednisolone at the start of the transplantation, and thereafter the patients receive 20 mg of prednisolone daily for the first 28 days, tapering by 5 mg for each month until withdrawal or a maintenance dose of 5 mg if needed. Mycophenolate mofetil is given from day 1 in a dose of 1 g 2 times daily. Tacrolimus is introduced on day 1, aiming at through levels of 4 to 6 ng/mL. Four weeks after the second-stage hepatectomy, tacrolimus is replaced by sirolimus. Target trough levels for sirolimus is in the first 2 weeks: 5 to 10 ng/mL, thereafter 10 to 20 ng/mL if tolerated. Complications are registered according to the Clavien-Dindo classification.15
CASE REPORT A 50-year-old previously healthy man was diagnosed in 2013 with locally advanced rectal cancer and synchronous liver metastases and 2 small lesions (10) and bilobar distribution. He was initially treated by 4 cycles of Nordic FLOX, and underwent preoperative pelvic radiotherapy (5 Gy × 5). He then received total mesorectal excision and a sigmoidostomy. Pathological examination revealed an adenocarcinoma of the rectum, ypT4 (40 mm) ypN1(1/32) M1. The tumor was KRAS/BRAF (kirsten rat sarcoma viral oncogene homolog/B-Raf proto-oncogene, serine/threonine kinase) wild type. Postoperatively he received FLIRI (5-flfluorouracil/irinotecan)/Cetuximab with stable disease by CT evaluation. By radiological reevaluation, he had still nonresectable liver metastases and no progress of his lung metastases. The patient gave his written informed consent to participation in the RAPID study and preoperative colonoscopy and PET/CT scans revealed no apparent signs of extrahepatic disease apart from the 2 already known small, resectable lung lesions. He underwent transplantation in June 2014 with a segment 2 to 3 graft from a young donor. His preoperative liver tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, and INR) were within normal limits. Splitting of the donor graft was required due to a small size recipient receiving the right part of the liver, and no suitable pediatric recipient was at the time point listed. Recipient weight was 92 kg and his SLV was estimated to 1916 mL. The weight of the transplanted graft was 330 g, representing a GBWR of 0.36 and 17.2% of the SLV. As first part of the operation, the liver was completely mobilized and dissected free from the retrohepatic vena cava. Thereafter, a resection of the patient segments 1 to 3 was performed, carefully avoiding tumor-affected parts of the liver. The weight of the C 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Annals of Surgery r Volume 262, Number 1, July 2015
resected segments 1 to 3 was 651 g. The left hepatic vein junction and adjacent vena cava were clamped to be used as site for graft liver vein anastomosis. To avoid interference with the remnant liver, and to facilitate the planned final hepatectomy, the portal vein and the hepatic artery of the graft were anastomosed in an end-to-side fashion to the main portal trunk and the common hepatic artery, respectively (Fig. 1). The portal pressure after revascularization was 6 mm Hg with a portal flow to the graft of 250 mL/min. After clamping of portal flow to the liver remnant, the portal pressure rose to 14 mm Hg on repeated measurements and portal flow to the graft was 680 mL/min. Hepatic artery flow to the graft was 150 mL/min. The values were stable over several minutes and 3 repeated measurements; consequently, the portal inflow to the right liver remnant was closed by a vascular stapler, without dividing the portal vein. Biliary reconstruction to the graft was accomplished by hepaticojejunostomy. The posttransplant course was uneventful apart from ascites production that gradually decreased over the course of the first 14 days. CT volumetry was performed on day 1 and every 7 to 14 days thereafter. The growth rate of the graft determined by CT scans is shown in Figure 2. On day 23, when the graft reached an estimated volume of about 700 mL, the second-stage hepatectomy was performed. Portal flow at second-stage surgery was 580 mL/min and portal pressure was 14 mm Hg on 3 repeated measurements. Postoperative liver function was good, without signs of liver failure (Fig. 3). Ascites production was initially high, but gradually decreased in the course of the next 2 weeks. From day 50, increased ascites production was again noted, and ultrasound and CT examination revealed a significant liver vein stenosis in the graft. This was treated by endovascular stenting, and the ascites production disappeared in the course of 4 days. The only complication observed was manageable with a Clavien-Dindo grade of 3a due to the need of endovascular stenting.
DISCUSSION The current concept and the present case demonstrate that transplantation of very small grafts with associated partial hepatectomy and modulation of portal inflow is feasible and could possibly represent a strategy that could enable the utilization of segment 2 to 3 grafts in adult patients with liver tumors. Eligible patients must have
FIGURE 1. Schematic overview of the operative field after first-stage resection of segments 1 to 3 leaving an extended right liver remnant (R) and the transplanted segment 2 to 3 graft (G). Note the mode of vascular anastomosis with end-toside anastomosis of the graft portal vein (1) and graft hepatic artery (2) to the main portal trunk and common hepatic artery, respectively. C 2015 Wolters Kluwer Health, Inc. All rights reserved.
Auxiliary Transplant and Liver Resection
a liver function allowing resection surgery, and the distribution of tumors within the parenchyma must enable dissection in a tumor-free plane. A somewhat similar technique with auxiliary transplantation was reported by the group of Dokmak et al in 2013; however, they used a small, full-sized graft with a GBWR of 0.77.16 Furthermore, they only partially ligated the portal vein to the liver remnant, did not monitor pressure, and performed a percutaneous portal vein embolization at day 14. The interval between primary and secondary hepatectomy was also 30 days, so although there are similarities, the RAPID concept is fundamentally different. We are not aware of any other reports on successful transplantation of a GBWR of 0.36. Hence, the RAPID concept could potentially have a broader applicability than intended by Belghiti et al. Significant factors for succeeding with such small graft are probably that the metabolic consequences of insufficient liver mass can be safely avoided by keeping a liver remnant of sufficient size during the phase of hypertrophy of the graft itself. Furthermore, to prevent SFSS and ensure optimal regeneration, modulation of portal inflow is most likely essential. Patients with colorectal metastases do not have portal hypertension and no hyperdynamic splanchnic circulation and are thus probably ideal for modulating portal inflow. The principles outlined have distinct similarities with the ALPPS procedure, but is technically more demanding. It is likely that the inflammatory response to parenchymal transection is an important signal for increased expression of the regeneration primers interleukin 6 and tumor necrosis factor α. This has been clearly demonstrated in an elegant animal model of ALPPS by Schlegel and coworkers.17 In the RAPID procedure, this stimulus could be linked to both the liver resection in the recipient and hypothetically also to the splitting of the graft. Our patient underwent the final hepatectomy 23 days after the transplantation. When assessing the volumetry and liver function data retrospectively, this could probably have been done 1 week earlier. The growth rate of the graft displayed a biphasic pattern with a rapid increase in volume during the first 14 days, but then reached a plateau. After the final hepatectomy, the growth rate increased again and reached a volume exceeding 400% of the initial graft weight by day 50. The case demonstrates the importance of optimal venous outflow. Interestingly, the venous outflow obstruction was not apparent until 6 weeks after transplantation, and one might speculate whether the rapid hypertrophy of the graft plays a role in this context. The oncological aspects of the RAPID procedure cannot be evaluated for long-term in the current protocol, and the effects of the treatment must be interpreted with care given for the short observation period and only a single case. It is theoretically possible that the combination of a 2-staged procedure, a strong regeneration signal during 2 to 3 weeks and concomitant immunosuppression could adversely affect tumor growth and dissemination. This will be further elucidated in the ongoing pilot study. From a theoretical point of view, a promoting effect of immunosuppression on tumor growth and spread constitutes a concern, particularly until the time of the secondstage hepatectomy. In our previous study about liver transplantation for CRC-metastases, we have demonstrated that patients who develop relapse on immunosuppression have a 53% of 5-year overall survival from time of relapse compared to about 0% in patients receiving palliative chemotherapy.5 This may suggest that the immunosuppressive regimen used does not accelerate the progression of malignant disease to a clinical apparent or relevant level. If the aforementioned theoretical disadvantages prove to be of minor significance or can be managed by additional interventions, the RAPID approach could be and alternative strategy to increase graft availability for selected patients with technically nonresectable liver tumors. Another important aspect is, that, given a successful development of the RAPID concept the prospect of living donation of segment 2 to 3 grafts to this cohort www.annalsofsurgery.com | e7
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Annals of Surgery r Volume 262, Number 1, July 2015
Line et al
FIGURE 2. CT volumetry of the transplanted graft during the first 50 posttransplant days and corresponding representative CT images at days 1, 21, and 50 (R: liver remnant, G: graft).
FIGURE 3. Overview of bilirubin (mmol/L), international normalized ratio (INR), aspartate amino transferase AST (U/L), and alanine amino transferase ALT (U/L) during the first 50 days after surgery.
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Annals of Surgery r Volume 262, Number 1, July 2015
of patients might be conceivable, because the risk of segment 2 to 3 donation is very much lower and vastly different to donation of a right or left liver lobe.18 We would currently warn against widespread expansion of this technique regarding indications and use of living donors prematurely. It is of utmost importance to evaluate this new innovation in a scientifically controlled and staged manner according to the principles outlined by Barkun and coworkers.19
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Auxiliary Transplant and Liver Resection
8. Renz JF, Yersiz H, Reichert PR, et al. Split-liver transplantation: a review. Am J Transplant. 2003;3:1323–1335. 9. Heaton N, Srinivasan P, Prachalias A, et al. Overcoming the limitations of living donor and split liver transplantation: a proposal for adult recipients (the best of the East in the West). Liver Transpl. 2008;14:932–934. 10. Heaton N. Small-for-size liver syndrome after auxiliary and split liver transplantation: donor selection. Liver Transpl. 2003;9:S26–S28. 11. Ito T, Kiuchi T, Yamamoto H, et al. Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications. Transplantation. 2003;75:1313–1317. 12. Takada Y, Ueda M, Ishikawa Y, et al. End-to-side portocaval shunting for a small-for-size graft in living donor liver transplantation. Liver Transpl. 2004;10:807–810. 13. Allard M-A, Adam R, Bucur P-O, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg. 2013;258:822–829; discussion 829–830. 14. Heinemann A, Wischhusen F, P¨uschel K, et al. Standard liver volume in the Caucasian population. Liver Transpl Surg. 1999;5:366–368. 15. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213. 16. Dokmak S, Elkrief L, Belghiti J. Auxiliary liver transplantation with a small deceased liver graft for cirrhotic liver complicated by hepatocellular carcinoma. Transpl Int. 2013;26:e102–e104. 17. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–847. 18. Clavien P-A, Petrowsky H, DeOliveira ML, et al. Strategies for safer liver surgery and partial liver transplantation. N Engl J Med. 2007;356:1545–1559. 19. Barkun JS, Aronson JK, Feldman LS, et al. Evaluation and stages of surgical innovations. The Lancet. 2009;374:1089–1096.
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