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Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results B. Bj€ ornsson a,b,*, E. Sparrelid c, B. Røsok d, E. Pomianowska d, K. Hasselgren a,b, T. Gasslander a,b, B.A. Bjørnbeth d, B. Isaksson c, P. Sandstr€ om a,b a Department of Surgery, Link€oping University, Link€oping, Sweden Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden c Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden d Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway b
Accepted 21 December 2015 Available online - - -
Abstract Background: Colorectal liver metastases (CRLM) not amenable for resection have grave prognosis. One limiting factor for surgery is a small future liver remnant (FLR). Early data suggests that associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively increases the volume of the FLR allowing for resection in a larger fraction of patients than conventional two-stage hepatectomy (TSH) with portal vein occlusion (PVO). Oncological results of the treatment are lacking. The aim of this study was to assess the intermediate oncological outcomes after ALPPS in patients with CRLM. Material and methods: Retrospective analysis of all patients with CRLM operated with ALPPS at the participating centres between December 2012 and May 2014. Results: Twenty-three patients (16 male, 7 female), age 67 years (28e80) were operated for 6.5 (1e38) metastases of which the largest was 40 mm (14e130). Six (27.3%) patients had extra-hepatic metastases, 16 (72.7%) synchronous presentation. All patients received chemotherapy, 6 cycles (3e25) preoperatively and 16 (70%) postoperatively. Ten patients (43%) were rescue ALPPS after failed PVO. Severe complications occurred in 13.6% and one (4.5%) patient died within 90 days of surgery. After a median follow-up of 22.5 months from surgery and 33.5 months from diagnosis of liver metastases estimated 2 year overall survival was 59% (from surgery) and 73% (from diagnosis). Liver only recurrences (n ¼ 8), were treated with reresection/ablation (n ¼ 7) while lung recurrences were treated with chemotherapy. Conclusion: The overall survival, rate of severe complications and perioperative mortality associated with ALPPS for patients with CRLM is comparable to TSH. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: ALPPS; CRLM; Survival; Oncological results
Introduction Historically, colorectal liver metastases (CRLM) not amenable for surgical removal have a grave prognosis, with a 6e9 months median overall survival and no 5 year * Corresponding author. Department of Surgery, Link€oping University, Link€ oping, Sweden. E-mail address: [email protected] (B. Bj€ornsson).
survival.1 With advances in oncological treatment median survival with chemotherapy alone approaches 30 months in sub-cohorts of patients with CRLM.2 Patients with tumor load in the liver that approaches the palliative situation but is still possible to remove, provided that growth of the future liver remnant (FLR) can be stimulated, have until recently only had two-stage hepatectomy (TSH) with portal vein embolization (PVE) or portal vein ligation (PVL) as
http://dx.doi.org/10.1016/j.ejso.2015.12.013 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
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treatment option. The results from such approaches vary in regard to several factors. First of all, the feasibility (the percentage of patients completing the whole surgical treatment) is often less than 80%, either because of insufficient growth of FLR or because of tumor progression.5 Recurrences are common with reported 39% disease free survival (DFS) at one year follow-up and 20% at 3 years and importantly, no survival benefit is seen for patients that do not complete both stages.6 Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel method first described in a report of 3 patients in 2011.7 In 2012, the first article describing this surgical method was published and a high morbidity and mortality rate was noted.8 The method is typically applied to patients with low or extremely low FLR and may be offered to patients failing to reach adequate growth of the FLR with PVO as well as patients that would not have been offered surgical resection at all. Despite large interest for this treatment concerns have been raised about early tumor recurrences as well as high morbidity and mortality rates.9,10 Although, the complication rate has been found to be lower in patients with CRLM than in patients with primary hepatobiliary malignancies, the morbidity seems to be higher than with “conventional” liver surgery.11 This comparison is however hardly relevant as ALPPS is only offered to patients that would otherwise have either palliative oncological treatment or at best two-stage hepatectomy. The reported mortality with two-stage hepatectomy in large series is in the range of or higher than recent reports for ALPPS in the context of CRLM.6,9,12e14 Regarding the oncological outcomes for patients with CRLM only series with limited follow-up have been published so far and the aim of this study was to analyze the intermediate oncological outcomes after ALPPS for CRLM performed in three Scandinavian HPB centers. Material and methods All ALPPS treatments performed for CRLM at the participating centers between December 2012 and May 2014 were included. The start date was set when the first reported ALPPS treatment for CRLM was performed in Scandinavian and the finish date was the start date of a randomized controlled trial comparing ALPPS and conventional methods to stimulate FLR growth in patients with CRLM (LIGRO Trial NCT02215577). Patient files were retrospectively reviewed when the last included patient had 1 year follow-up time. Part of the data included in this study has previously been published in other context and this cohort has been included in a safety and feasibility study that included non-CRLM patients as well.11,15,16 Patients were accepted for the ALPPS procedure after preoperative chemotherapy. Some of the patients had failed PVO before the ALPPS procedure. Methods of PVO and criteria for failed PVO have been published previously.16
A FLR volume (measured radiologically) of at least 30% of the total estimated liver volume (TELV) or a FLR/ body weight (BW) ratio >0.5 was considered as cut-off value for resectability.17 TELV was calculated according to previously published formula.18 Preoperative staging was achieved with computed tomography (CT) and in some cases additional magnetic resonance imaging (MRI). Ras or raf mutation status was not routinely assessed. Patients successfully treated by ALPPS with completion of both stages of the procedure were followed in the outpatient clinic with CT scans performed of the abdomen and thorax every 3e4 months during the first year, and in most cases CEA and CA19/9 was analyzed at the same time points. If elevated levels of the tumor markers were found but the CT scan was negative a PET CT was performed. Postoperative complications were graded according to ClavieneDindo classification system with only the highest occurring complication presented.19 Statistics Data is presented as median (range), follow-up time was calculated with the reversed Kaplan Meyer method.20 Statistical analysis was performed using IBM SPSS Statistics version 22 (IBM Corporation, Armonk, NY, USA). A p value < 0.05 was considered significant. Results Twenty-three patients were included, 16 males and 7 females. The median age was 67 years (28e80). The median number of metastases was 6 (1e38) and the median size of the largest lesion was 40 mm (14e130). Six (26%) patients had known extrahepatic disease at the time of ALPPS; 4 isolated to the lungs, 1 in the lungs as well as in lymph nodes in the liver hilum and one in the peritoneum (localized). The lung metastases were considered non-resectable in all patients and planned for oncological treatment after treatment of liver metastases. In four cases, only one metastasis was present (60e120 mm), Table 1 shows the details of disease burden. All patients received chemotherapy before surgical treatment and regression or stable disease was Table 1 Disease burden in 23 patients with CRLM treated with ALPPS. Number of metastases Size of largest metastasis (mm) 1 metastasis, number (size) 2e10 metastasis, number (size of largest) 11e20 metastasis, number (size of largest) 21e30 metastasis, number (size of largest) >30 metastasis, number (size of largest) Extra hepatic tumor (patients) Primary tumor in situ (patients)
6 (1e38) 40 (14e130) 4 (60e120 mm) 12 (36 mm (14e130)) 5 (20e70 mm) 0 2 (39, 40 mm) 6 (26%) 3 (13%)
Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
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found before decision to proceed to surgery in all patients, Table 2 shows the details of the oncological treatment. Monoclonal antibody was added to conventional chemotherapy in 10 patients. No correlation was found between number of chemotherapy cycles and FLR growth (data not shown). After surgery, 16 (70%) patients received adjuvant chemotherapy, starting in median 66 days after operation. For the two patients operated according to liver first receiving adjuvant chemotherapy first after the bowel surgery the date of surgery was set to the date of bowel surgery when calculating time to adjuvant chemotherapy. The reasons for not receiving chemotherapy were; not deemed indicated 3, patient physically unfit for treatment 3 and patient died 1. In 10 (43%) cases, ALPPS was applied as a “rescue procedure” when PVO had failed to induce the growth needed in the FLR. Previous liver surgery had been performed in 6 (26%) patients. In 6 (26%) patients, the presentation of liver metastasis was metachronous while 17 (74%) had synchronous presentation. In 3 (18%) of the 17 patients with synchronous presentation the bowel tumor was in situ at the time of liver resection (liver first) while in the remaining 14 (82%) it had been removed earlier. There were no cases of simultaneous surgery of either colon/rectum and liver or lung and liver. Surgery All patients completed both stages of the ALPPS treatment with a median of 77e10 days elapsing between stage 1 and stage 2. In 3 (13%) cases, the ALPPS treatment was decided upon intraoperatively while in the remaining 20 (87%) it was planned “upfront”. In the three cases of intraoperative decision about performing ALPPS more extensive tumor disease compared to preoperative radiology was found in two and in one case the macroscopic appearance of the liver after extensive chemotherapy raised concerns about the quality of the liver. The resections were mainly extended right sided hemihepatectomies (n ¼ 19, 83%) but right sided hemihepatectomies (n ¼ 4, 17%) were also performed. The median duration of stage 1 surgery was 282 min (164e498) and intraoperative blood loss was 650 ml
Table 2 Preoperative oncological treatment data for 23 patients with CRLM treated with ALPPS. Neoadjuvant chemotherapy (patients) Number of cycles Main treatment, patients (with monoclonal antibody) FOLFOX/FLOX XELOX FOLFIRI FLIRI Capecitabine
23 (100%) 6 (3e25) 13 (4) 5 (3) 3 (2) 1 (1) 1 (1)
3
(150e5600). In 11 patients (48%), resections (7, 30%) or ablations (1, 4%) or both (3, 13%) were performed in the FLR during stage 1. For stage 2, operation time was 63 min (30e150) and estimated blood loss 100 ml (25e700) ml. Future liver remnant and growth The median volume of the FLR before treatment was 349 ml (260e1169) and the ratio of FLR to TELV, i.e., sFLR, was 20.2% (16.1e39.2). The patient with calculated sFLR 39.2% was preoperatively planned for 1 staged resection but new metastases discovered during the operation were the basis for a decision about performing ALPPS. After the first stage of ALPPS treatment sFLR increased by 64.3% (17 to 238) after 5 (5e8) days and at the time of stage 2 of ALPPS treatment sFLR was 35.5% (25.9e59.5). The patient with sFLR 25.9% had FLR/ BW > 0.5 and was therefore accepted for stage 2 operation. There was no difference between patients previously treated with PVO and untreated regarding growth (data not shown). Hospital stay and morbidity Any postoperative complication occurred in 21 (91%) of the patients. Twelve (52%) had grade IeII, 6 (26%) had grade IIIA. Of patients with complication grade IIIA, four developed pleural effusion that required percutaneous drainage, one had bile leakage that was percutaneously drained and one patient had both these complications. Three (13%) patients had grade IIIB complication, two reoperations for bowel obstruction and for wound dehiscence and one ERCP for bile leakage performed in general anesthesia. No 30 day mortality was observed but one patient (4%) died within 90 days after operation due to tumor progression. All patients stayed in hospital between the two operations. The median hospital stay after stage 2 operation was 9 days (2e50). Pathology Twenty-two patients (96%) were macroscopically radically operated while microscopic radicality (R0) was confirmed in 15 (65%), Fig. 1A compares survival for R0 and R1 (considering liver only) operated patients. Patients with R0 resections had 6 (1e38) metastases while patients with R1 resections had 14 (1e35) metastases, the difference is however not statistically significant. Follow-up The median follow-up time after stage 2 operation was 22.5 months (95% CI 18e27) while it was 33.5 months (95% CI 28e39) from diagnosis of liver metastases.
Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
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Figure 1. Survival of patients with CRLM operated with ALPPS. The overall survival (OS) of 23 CRLM patients operated with associating liver partition and portal vein ligation (ALPPS) from operation at one year was 83% and at 2 years 59%. Progression free survival (PFS) at one year was 27% (6.2 months in median).
Currently 18 (82%) of 22 macroscopically radically operated patients have recurrent disease or have died with recurrence, in addition one patient that had R2 resection is deceased (Table 3). Median time from stage 2 operation to recurrence was 6.2 months (95% CI 4e9). Progression free survival (PFS) at one year from stage 2 operation was 27% and median PFS was 6.2 months (95% CI 4e9). Overall survival (OS) one year from stage 2 operation was 83% and 2 year OS was 59% (Fig. 1). From diagnosis of liver metastases 1 year OS was 96%, 2 year OS 73% and 3 year survival 60%. OS did not differ for patients above 60 years of age compared to patients below 60 years of age (data not shown). The ten patients operated with ALPPS after previous PVO had same survival as patients operated with ALPPS without previous attempted classical TSH. Patients with R0 resection had significantly (p ¼ 0.037) better OS than Table 3 Pattern of recurrences, treatment and status in 22 patients operated with ALPPS for CRLM. Number of patients
Recurrence site
Treatment
4 8 8 2 1
None Liver Liver and lungs Lungs R2 resection
Na 2 deceased, 4 re-resections, 3 ablation 5 deceased, oncological treatment only 1 deceased, oncological treatment only Deceased
did patients with R1 resections (Fig. 2A). Patient with extrahepatic manifestation (n ¼ 6) had tendency towards less favorable OS from surgery (median 12 months) than did patients without extrahepatic disease although the difference did not reach statistical significance (Fig. 2B).
Discussion This is the first study to report intermediate oncological results after ALPPS for CRLM. All patients are followed for at least one year after the ALPPS procedure and we see a 82% recurrence rate after a median follow-up of 22.5 months from surgery, and an overall survival one year after stage 2 operation of 83% and 59% after 2 year. Earlier short term results are diverging with 14.3% recurrence after a median follow-up of 9.4 months reported from Canada and 85.7% recurrence rate occurring 8 months (median) after surgery reported from Germany.9,14 These series are somewhat different from the present study, besides the difference in follow-up time the patients in the Canadian series are younger and fewer had synchronous presentation. Extrahepatic disease is not described in these reports. The current cohort has more similarities to the German cohort regarding age, synchronous presentation, follow-up time and outcomes although OS is better in the present series. Also, the present study contains patients who had received third line chemotherapy with stable
Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
B. Bj€ornsson et al. / EJSO xx (2016) 1e7
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Figure 2. Survival of patients with CRLM, operated with ALPPS. Overall survival from operation of patients with CRLM operated with ALPPS. A) Comparison of R0 and R1 resections, R0 operated patients had significantly better survival than R1 operated patients (p ¼ 0.037, LogRank (ManteleCox). B) Patients without extrahepatic disease compared to patients with extrahepatic disease (ns).
Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
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disease only, suggesting unfavorable biological disease. The findings of this study support earlier conclusion that CRLM patients treated with ALPPS are at high risk of recurrence.9 Similar material with somewhat shorter follow-up has been published from a patient cohort including 19 patients operated with ALPPS for CRLM, 17 of whom received neo-adjuvant chemotherapy and one previously treated with PVO with insufficient hypertrophy.21 The higher rate of severe (grade 3B) complications seen in that study compared to our study can probably be explained by the fact that the cohort includes primary hepatobiliary malignancies and higher rate of associated procedures than in the current study. Another possible explanation is cautious introduction of ALPPS in Scandinavia as this cohort of patients represents a learning curve in the three centers involved.16 The one year OS for patients with CRLM was the same as in our study while the 1 year DFS was higher (56%). When comparing the results to other available treatments for CRLM it must be kept in mind that patients treated with ALPPS represent a subgroup that can be expected to have a dismal prognosis compared to the “general population” of surgically treated CRLM patients. Comparison to conventional one stage hepatectomy is hardly relevant. These results have to be compared to chemotherapy alone and at best to two-stage hepatectomy with FLR augmentation by means of PVO. When comparing with chemotherapy alone, survival from diagnosis of metastases is the most relevant indicator. After 33.5 months follow-up the median OS was not reached and estimated 3 year OS was 60%, this still exceeds what can be expected with chemotherapy alone. In addition details about ras and raf mutation status are lacking, further complicating comparisons. It should be mentioned though, that the current study does not include intention to treat analysis and therefore the amount of selection bias cannot be estimated. It is possible that some of the patients included in this cohort could have been managed with conventional two-stage hepatectomy (TSH) and therefore comparison to that treatment strategy is motivated. The 2 year OS in this series (59%) is similar to a report from Johns Hopkins when the fate of patients that fail to reach the second operation is included.12 The mentioned study from John Hopkins had slightly higher perioperative mortality than the current study though. The largest European experience with TSH comes from Paul Brousse Hospital and presents 42% 5 year OS and 7% perioperative mortality.13 These results do however only apply to the 69% of patients that completed both hepatectomies. When drop outs are included the two year OS is around 55% compared to 59% in the current study. In this context, it is important to keep in mind that in the current study some 43% of the patients were operated with ALPPS after failed hypertrophy following PVO and this subgroup had the same survival as those operated with ALPPS without previous PVO. Despite the limited number of patients included in this study a significant difference was found in the fate of
patients receiving R0 resections compared to those with R1 resections only. Although, this may be explained by difference in disease severity the results indicate that R0 resections should be the goal when CRLM are treated with ALPPS. Furthermore, a tendency towards worse OS was seen among patients with extrahepatic disease and ALPPS should probably be applied with large caution in this settings. In conclusion, ALPPS is highly feasible in selected patients with advanced CRLM, perioperative mortality and OS are at least comparable to results achieved with conventional two-stage hepatectomy, this seems to apply equally to patients that have not responded to PVO with adequate liver hypertrophy. A prospective randomized study comparing ALPPS and TSH is ongoing. Conflict of interest The authors of the abovementioned manuscript have no conflict of interest to declare. References 1. Rougier P, Milan C, Lazorthes F, et al. Prospective study of prognostic factors in patients with unresected hepatic metastases from colorectal cancer. Fondation Francaise de Cancerologie Digestive. Br J Surg 1995;82(10):1397–400. 2. Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol 2015;33(16):1809–24. 5. Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB Oxf 2013;15(7):483–91. 6. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after twostage resection of advanced colorectal liver metastases: responsebased selection and complete resection define outcome. J Clin Oncol 2011;29(8):1083–90. 7. Baumgart J, Lang S, Lang H. A new method for induction of liver hypertrophy prior to right trisectionectomy: a report of three cases. HPB 2011;13(Suppl. 2):1–145. 8. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012;255(3):405–14. 9. Oldhafer KJ, Donati M, Jenner RM, Stang A, Stavrou GA. ALPPS for patients with colorectal liver metastases: effective liver hypertrophy, but early tumor recurrence. World J Surg 2014;38(6):1504–9. 10. Robles R, Parrilla P, Lopez-Conesa A, et al. Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. Br J Surg 2014;101(9):1129–34. discussion 34. 11. Schadde E, Ardiles V, Robles-Campos R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014;260(5):829–36. discussion 36e8. 12. Tsai S, Marques HP, de Jong MC, et al. Two-stage strategy for patients with extensive bilateral colorectal liver metastases. HPB Oxf 2010; 12(4):262–9. 13. Wicherts DA, Miller R, de Haas RJ, et al. Long-term results of twostage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 2008;248(6):994–1005. 14. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, Croome KP. Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy
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B. Bj€ornsson et al. / EJSO xx (2016) 1e7 (ALPPS) procedure in the management of colorectal liver metastases? Surgery 2015 Feb;157(2):194–201. 15. Bj€ornsson B, Gasslander T, Sandstr€om P. In situ split of the liver when portal venous embolization fails to induce hypertrophy e a report of two cases. Case Rep Surg 2013;2013. Article ID: 238675, 4 pp. 16. Rosok BI, Bjornsson B, Sparrelid E, et al. Scandinavian multicenter study on the safety and feasibility of the associating liver partition and portal vein ligation for staged hepatectomy procedure. Surgery 2015 Nov 19. http://dx.doi.org/10.1016/j.surg.2015.10.004 pii: S0039-6060(15)00831-4 [Epub ahead of print]. 17. Abdalla EK, Adam R, Bilchik AJ, Jaeck D, Vauthey JN, Mahvi D. Improving resectability of hepatic colorectal metastases: expert consensus statement. Ann Surg Oncol 2006;13(10):1271–80.
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18. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002;8(3):233–40. 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240(2):205–13. 20. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17(4):343–6. 21. Alvarez FA, Ardiles V, de Santibanes M, Pekolj J, de Santibanes E. Associating liver partition and portal vein ligation for staged hepatectomy offers high oncological feasibility with adequate patient safety: a prospective study at a single center. Ann Surg 2015; 261(4):723–32.
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Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results B. Bj€ ornsson a,b,*, E. Sparrelid c, B. Røsok d, E. Pomianowska d, K. Hasselgren a,b, T. Gasslander a,b, B.A. Bjørnbeth d, B. Isaksson c, P. Sandstr€ om a,b a Department of Surgery, Link€oping University, Link€oping, Sweden Department of Clinical and Experimental Medicine, Link€oping University, Link€oping, Sweden c Department of Clinical Science, Intervention and Technology, Division of Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden d Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway b
Accepted 21 December 2015 Available online - - -
Abstract Background: Colorectal liver metastases (CRLM) not amenable for resection have grave prognosis. One limiting factor for surgery is a small future liver remnant (FLR). Early data suggests that associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively increases the volume of the FLR allowing for resection in a larger fraction of patients than conventional two-stage hepatectomy (TSH) with portal vein occlusion (PVO). Oncological results of the treatment are lacking. The aim of this study was to assess the intermediate oncological outcomes after ALPPS in patients with CRLM. Material and methods: Retrospective analysis of all patients with CRLM operated with ALPPS at the participating centres between December 2012 and May 2014. Results: Twenty-three patients (16 male, 7 female), age 67 years (28e80) were operated for 6.5 (1e38) metastases of which the largest was 40 mm (14e130). Six (27.3%) patients had extra-hepatic metastases, 16 (72.7%) synchronous presentation. All patients received chemotherapy, 6 cycles (3e25) preoperatively and 16 (70%) postoperatively. Ten patients (43%) were rescue ALPPS after failed PVO. Severe complications occurred in 13.6% and one (4.5%) patient died within 90 days of surgery. After a median follow-up of 22.5 months from surgery and 33.5 months from diagnosis of liver metastases estimated 2 year overall survival was 59% (from surgery) and 73% (from diagnosis). Liver only recurrences (n ¼ 8), were treated with reresection/ablation (n ¼ 7) while lung recurrences were treated with chemotherapy. Conclusion: The overall survival, rate of severe complications and perioperative mortality associated with ALPPS for patients with CRLM is comparable to TSH. Ó 2016 Elsevier Ltd. All rights reserved.
Keywords: ALPPS; CRLM; Survival; Oncological results
Introduction Historically, colorectal liver metastases (CRLM) not amenable for surgical removal have a grave prognosis, with a 6e9 months median overall survival and no 5 year * Corresponding author. Department of Surgery, Link€oping University, Link€ oping, Sweden. E-mail address: [email protected] (B. Bj€ornsson).
survival.1 With advances in oncological treatment median survival with chemotherapy alone approaches 30 months in sub-cohorts of patients with CRLM.2 Patients with tumor load in the liver that approaches the palliative situation but is still possible to remove, provided that growth of the future liver remnant (FLR) can be stimulated, have until recently only had two-stage hepatectomy (TSH) with portal vein embolization (PVE) or portal vein ligation (PVL) as
http://dx.doi.org/10.1016/j.ejso.2015.12.013 0748-7983/Ó 2016 Elsevier Ltd. All rights reserved. Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
2
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treatment option. The results from such approaches vary in regard to several factors. First of all, the feasibility (the percentage of patients completing the whole surgical treatment) is often less than 80%, either because of insufficient growth of FLR or because of tumor progression.5 Recurrences are common with reported 39% disease free survival (DFS) at one year follow-up and 20% at 3 years and importantly, no survival benefit is seen for patients that do not complete both stages.6 Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a novel method first described in a report of 3 patients in 2011.7 In 2012, the first article describing this surgical method was published and a high morbidity and mortality rate was noted.8 The method is typically applied to patients with low or extremely low FLR and may be offered to patients failing to reach adequate growth of the FLR with PVO as well as patients that would not have been offered surgical resection at all. Despite large interest for this treatment concerns have been raised about early tumor recurrences as well as high morbidity and mortality rates.9,10 Although, the complication rate has been found to be lower in patients with CRLM than in patients with primary hepatobiliary malignancies, the morbidity seems to be higher than with “conventional” liver surgery.11 This comparison is however hardly relevant as ALPPS is only offered to patients that would otherwise have either palliative oncological treatment or at best two-stage hepatectomy. The reported mortality with two-stage hepatectomy in large series is in the range of or higher than recent reports for ALPPS in the context of CRLM.6,9,12e14 Regarding the oncological outcomes for patients with CRLM only series with limited follow-up have been published so far and the aim of this study was to analyze the intermediate oncological outcomes after ALPPS for CRLM performed in three Scandinavian HPB centers. Material and methods All ALPPS treatments performed for CRLM at the participating centers between December 2012 and May 2014 were included. The start date was set when the first reported ALPPS treatment for CRLM was performed in Scandinavian and the finish date was the start date of a randomized controlled trial comparing ALPPS and conventional methods to stimulate FLR growth in patients with CRLM (LIGRO Trial NCT02215577). Patient files were retrospectively reviewed when the last included patient had 1 year follow-up time. Part of the data included in this study has previously been published in other context and this cohort has been included in a safety and feasibility study that included non-CRLM patients as well.11,15,16 Patients were accepted for the ALPPS procedure after preoperative chemotherapy. Some of the patients had failed PVO before the ALPPS procedure. Methods of PVO and criteria for failed PVO have been published previously.16
A FLR volume (measured radiologically) of at least 30% of the total estimated liver volume (TELV) or a FLR/ body weight (BW) ratio >0.5 was considered as cut-off value for resectability.17 TELV was calculated according to previously published formula.18 Preoperative staging was achieved with computed tomography (CT) and in some cases additional magnetic resonance imaging (MRI). Ras or raf mutation status was not routinely assessed. Patients successfully treated by ALPPS with completion of both stages of the procedure were followed in the outpatient clinic with CT scans performed of the abdomen and thorax every 3e4 months during the first year, and in most cases CEA and CA19/9 was analyzed at the same time points. If elevated levels of the tumor markers were found but the CT scan was negative a PET CT was performed. Postoperative complications were graded according to ClavieneDindo classification system with only the highest occurring complication presented.19 Statistics Data is presented as median (range), follow-up time was calculated with the reversed Kaplan Meyer method.20 Statistical analysis was performed using IBM SPSS Statistics version 22 (IBM Corporation, Armonk, NY, USA). A p value < 0.05 was considered significant. Results Twenty-three patients were included, 16 males and 7 females. The median age was 67 years (28e80). The median number of metastases was 6 (1e38) and the median size of the largest lesion was 40 mm (14e130). Six (26%) patients had known extrahepatic disease at the time of ALPPS; 4 isolated to the lungs, 1 in the lungs as well as in lymph nodes in the liver hilum and one in the peritoneum (localized). The lung metastases were considered non-resectable in all patients and planned for oncological treatment after treatment of liver metastases. In four cases, only one metastasis was present (60e120 mm), Table 1 shows the details of disease burden. All patients received chemotherapy before surgical treatment and regression or stable disease was Table 1 Disease burden in 23 patients with CRLM treated with ALPPS. Number of metastases Size of largest metastasis (mm) 1 metastasis, number (size) 2e10 metastasis, number (size of largest) 11e20 metastasis, number (size of largest) 21e30 metastasis, number (size of largest) >30 metastasis, number (size of largest) Extra hepatic tumor (patients) Primary tumor in situ (patients)
6 (1e38) 40 (14e130) 4 (60e120 mm) 12 (36 mm (14e130)) 5 (20e70 mm) 0 2 (39, 40 mm) 6 (26%) 3 (13%)
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found before decision to proceed to surgery in all patients, Table 2 shows the details of the oncological treatment. Monoclonal antibody was added to conventional chemotherapy in 10 patients. No correlation was found between number of chemotherapy cycles and FLR growth (data not shown). After surgery, 16 (70%) patients received adjuvant chemotherapy, starting in median 66 days after operation. For the two patients operated according to liver first receiving adjuvant chemotherapy first after the bowel surgery the date of surgery was set to the date of bowel surgery when calculating time to adjuvant chemotherapy. The reasons for not receiving chemotherapy were; not deemed indicated 3, patient physically unfit for treatment 3 and patient died 1. In 10 (43%) cases, ALPPS was applied as a “rescue procedure” when PVO had failed to induce the growth needed in the FLR. Previous liver surgery had been performed in 6 (26%) patients. In 6 (26%) patients, the presentation of liver metastasis was metachronous while 17 (74%) had synchronous presentation. In 3 (18%) of the 17 patients with synchronous presentation the bowel tumor was in situ at the time of liver resection (liver first) while in the remaining 14 (82%) it had been removed earlier. There were no cases of simultaneous surgery of either colon/rectum and liver or lung and liver. Surgery All patients completed both stages of the ALPPS treatment with a median of 77e10 days elapsing between stage 1 and stage 2. In 3 (13%) cases, the ALPPS treatment was decided upon intraoperatively while in the remaining 20 (87%) it was planned “upfront”. In the three cases of intraoperative decision about performing ALPPS more extensive tumor disease compared to preoperative radiology was found in two and in one case the macroscopic appearance of the liver after extensive chemotherapy raised concerns about the quality of the liver. The resections were mainly extended right sided hemihepatectomies (n ¼ 19, 83%) but right sided hemihepatectomies (n ¼ 4, 17%) were also performed. The median duration of stage 1 surgery was 282 min (164e498) and intraoperative blood loss was 650 ml
Table 2 Preoperative oncological treatment data for 23 patients with CRLM treated with ALPPS. Neoadjuvant chemotherapy (patients) Number of cycles Main treatment, patients (with monoclonal antibody) FOLFOX/FLOX XELOX FOLFIRI FLIRI Capecitabine
23 (100%) 6 (3e25) 13 (4) 5 (3) 3 (2) 1 (1) 1 (1)
3
(150e5600). In 11 patients (48%), resections (7, 30%) or ablations (1, 4%) or both (3, 13%) were performed in the FLR during stage 1. For stage 2, operation time was 63 min (30e150) and estimated blood loss 100 ml (25e700) ml. Future liver remnant and growth The median volume of the FLR before treatment was 349 ml (260e1169) and the ratio of FLR to TELV, i.e., sFLR, was 20.2% (16.1e39.2). The patient with calculated sFLR 39.2% was preoperatively planned for 1 staged resection but new metastases discovered during the operation were the basis for a decision about performing ALPPS. After the first stage of ALPPS treatment sFLR increased by 64.3% (17 to 238) after 5 (5e8) days and at the time of stage 2 of ALPPS treatment sFLR was 35.5% (25.9e59.5). The patient with sFLR 25.9% had FLR/ BW > 0.5 and was therefore accepted for stage 2 operation. There was no difference between patients previously treated with PVO and untreated regarding growth (data not shown). Hospital stay and morbidity Any postoperative complication occurred in 21 (91%) of the patients. Twelve (52%) had grade IeII, 6 (26%) had grade IIIA. Of patients with complication grade IIIA, four developed pleural effusion that required percutaneous drainage, one had bile leakage that was percutaneously drained and one patient had both these complications. Three (13%) patients had grade IIIB complication, two reoperations for bowel obstruction and for wound dehiscence and one ERCP for bile leakage performed in general anesthesia. No 30 day mortality was observed but one patient (4%) died within 90 days after operation due to tumor progression. All patients stayed in hospital between the two operations. The median hospital stay after stage 2 operation was 9 days (2e50). Pathology Twenty-two patients (96%) were macroscopically radically operated while microscopic radicality (R0) was confirmed in 15 (65%), Fig. 1A compares survival for R0 and R1 (considering liver only) operated patients. Patients with R0 resections had 6 (1e38) metastases while patients with R1 resections had 14 (1e35) metastases, the difference is however not statistically significant. Follow-up The median follow-up time after stage 2 operation was 22.5 months (95% CI 18e27) while it was 33.5 months (95% CI 28e39) from diagnosis of liver metastases.
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Figure 1. Survival of patients with CRLM operated with ALPPS. The overall survival (OS) of 23 CRLM patients operated with associating liver partition and portal vein ligation (ALPPS) from operation at one year was 83% and at 2 years 59%. Progression free survival (PFS) at one year was 27% (6.2 months in median).
Currently 18 (82%) of 22 macroscopically radically operated patients have recurrent disease or have died with recurrence, in addition one patient that had R2 resection is deceased (Table 3). Median time from stage 2 operation to recurrence was 6.2 months (95% CI 4e9). Progression free survival (PFS) at one year from stage 2 operation was 27% and median PFS was 6.2 months (95% CI 4e9). Overall survival (OS) one year from stage 2 operation was 83% and 2 year OS was 59% (Fig. 1). From diagnosis of liver metastases 1 year OS was 96%, 2 year OS 73% and 3 year survival 60%. OS did not differ for patients above 60 years of age compared to patients below 60 years of age (data not shown). The ten patients operated with ALPPS after previous PVO had same survival as patients operated with ALPPS without previous attempted classical TSH. Patients with R0 resection had significantly (p ¼ 0.037) better OS than Table 3 Pattern of recurrences, treatment and status in 22 patients operated with ALPPS for CRLM. Number of patients
Recurrence site
Treatment
4 8 8 2 1
None Liver Liver and lungs Lungs R2 resection
Na 2 deceased, 4 re-resections, 3 ablation 5 deceased, oncological treatment only 1 deceased, oncological treatment only Deceased
did patients with R1 resections (Fig. 2A). Patient with extrahepatic manifestation (n ¼ 6) had tendency towards less favorable OS from surgery (median 12 months) than did patients without extrahepatic disease although the difference did not reach statistical significance (Fig. 2B).
Discussion This is the first study to report intermediate oncological results after ALPPS for CRLM. All patients are followed for at least one year after the ALPPS procedure and we see a 82% recurrence rate after a median follow-up of 22.5 months from surgery, and an overall survival one year after stage 2 operation of 83% and 59% after 2 year. Earlier short term results are diverging with 14.3% recurrence after a median follow-up of 9.4 months reported from Canada and 85.7% recurrence rate occurring 8 months (median) after surgery reported from Germany.9,14 These series are somewhat different from the present study, besides the difference in follow-up time the patients in the Canadian series are younger and fewer had synchronous presentation. Extrahepatic disease is not described in these reports. The current cohort has more similarities to the German cohort regarding age, synchronous presentation, follow-up time and outcomes although OS is better in the present series. Also, the present study contains patients who had received third line chemotherapy with stable
Please cite this article in press as: Bj€ornsson B, et al., Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases e Intermediate oncological results, Eur J Surg Oncol (2016), http://dx.doi.org/10.1016/j.ejso.2015.12.013
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Figure 2. Survival of patients with CRLM, operated with ALPPS. Overall survival from operation of patients with CRLM operated with ALPPS. A) Comparison of R0 and R1 resections, R0 operated patients had significantly better survival than R1 operated patients (p ¼ 0.037, LogRank (ManteleCox). B) Patients without extrahepatic disease compared to patients with extrahepatic disease (ns).
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disease only, suggesting unfavorable biological disease. The findings of this study support earlier conclusion that CRLM patients treated with ALPPS are at high risk of recurrence.9 Similar material with somewhat shorter follow-up has been published from a patient cohort including 19 patients operated with ALPPS for CRLM, 17 of whom received neo-adjuvant chemotherapy and one previously treated with PVO with insufficient hypertrophy.21 The higher rate of severe (grade 3B) complications seen in that study compared to our study can probably be explained by the fact that the cohort includes primary hepatobiliary malignancies and higher rate of associated procedures than in the current study. Another possible explanation is cautious introduction of ALPPS in Scandinavia as this cohort of patients represents a learning curve in the three centers involved.16 The one year OS for patients with CRLM was the same as in our study while the 1 year DFS was higher (56%). When comparing the results to other available treatments for CRLM it must be kept in mind that patients treated with ALPPS represent a subgroup that can be expected to have a dismal prognosis compared to the “general population” of surgically treated CRLM patients. Comparison to conventional one stage hepatectomy is hardly relevant. These results have to be compared to chemotherapy alone and at best to two-stage hepatectomy with FLR augmentation by means of PVO. When comparing with chemotherapy alone, survival from diagnosis of metastases is the most relevant indicator. After 33.5 months follow-up the median OS was not reached and estimated 3 year OS was 60%, this still exceeds what can be expected with chemotherapy alone. In addition details about ras and raf mutation status are lacking, further complicating comparisons. It should be mentioned though, that the current study does not include intention to treat analysis and therefore the amount of selection bias cannot be estimated. It is possible that some of the patients included in this cohort could have been managed with conventional two-stage hepatectomy (TSH) and therefore comparison to that treatment strategy is motivated. The 2 year OS in this series (59%) is similar to a report from Johns Hopkins when the fate of patients that fail to reach the second operation is included.12 The mentioned study from John Hopkins had slightly higher perioperative mortality than the current study though. The largest European experience with TSH comes from Paul Brousse Hospital and presents 42% 5 year OS and 7% perioperative mortality.13 These results do however only apply to the 69% of patients that completed both hepatectomies. When drop outs are included the two year OS is around 55% compared to 59% in the current study. In this context, it is important to keep in mind that in the current study some 43% of the patients were operated with ALPPS after failed hypertrophy following PVO and this subgroup had the same survival as those operated with ALPPS without previous PVO. Despite the limited number of patients included in this study a significant difference was found in the fate of
patients receiving R0 resections compared to those with R1 resections only. Although, this may be explained by difference in disease severity the results indicate that R0 resections should be the goal when CRLM are treated with ALPPS. Furthermore, a tendency towards worse OS was seen among patients with extrahepatic disease and ALPPS should probably be applied with large caution in this settings. In conclusion, ALPPS is highly feasible in selected patients with advanced CRLM, perioperative mortality and OS are at least comparable to results achieved with conventional two-stage hepatectomy, this seems to apply equally to patients that have not responded to PVO with adequate liver hypertrophy. A prospective randomized study comparing ALPPS and TSH is ongoing. Conflict of interest The authors of the abovementioned manuscript have no conflict of interest to declare. References 1. Rougier P, Milan C, Lazorthes F, et al. Prospective study of prognostic factors in patients with unresected hepatic metastases from colorectal cancer. Fondation Francaise de Cancerologie Digestive. Br J Surg 1995;82(10):1397–400. 2. Fakih MG. Metastatic colorectal cancer: current state and future directions. J Clin Oncol 2015;33(16):1809–24. 5. Lam VW, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB Oxf 2013;15(7):483–91. 6. Brouquet A, Abdalla EK, Kopetz S, et al. High survival rate after twostage resection of advanced colorectal liver metastases: responsebased selection and complete resection define outcome. J Clin Oncol 2011;29(8):1083–90. 7. Baumgart J, Lang S, Lang H. A new method for induction of liver hypertrophy prior to right trisectionectomy: a report of three cases. HPB 2011;13(Suppl. 2):1–145. 8. Schnitzbauer AA, Lang SA, Goessmann H, et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012;255(3):405–14. 9. Oldhafer KJ, Donati M, Jenner RM, Stang A, Stavrou GA. ALPPS for patients with colorectal liver metastases: effective liver hypertrophy, but early tumor recurrence. World J Surg 2014;38(6):1504–9. 10. Robles R, Parrilla P, Lopez-Conesa A, et al. Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure. Br J Surg 2014;101(9):1129–34. discussion 34. 11. Schadde E, Ardiles V, Robles-Campos R, et al. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014;260(5):829–36. discussion 36e8. 12. Tsai S, Marques HP, de Jong MC, et al. Two-stage strategy for patients with extensive bilateral colorectal liver metastases. HPB Oxf 2010; 12(4):262–9. 13. Wicherts DA, Miller R, de Haas RJ, et al. Long-term results of twostage hepatectomy for irresectable colorectal cancer liver metastases. Ann Surg 2008;248(6):994–1005. 14. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, Croome KP. Can we improve the morbidity and mortality associated with the associating liver partition with portal vein ligation for staged hepatectomy
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18. Vauthey JN, Abdalla EK, Doherty DA, et al. Body surface area and body weight predict total liver volume in Western adults. Liver Transpl 2002;8(3):233–40. 19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240(2):205–13. 20. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17(4):343–6. 21. Alvarez FA, Ardiles V, de Santibanes M, Pekolj J, de Santibanes E. Associating liver partition and portal vein ligation for staged hepatectomy offers high oncological feasibility with adequate patient safety: a prospective study at a single center. Ann Surg 2015; 261(4):723–32.
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