- Email: [email protected]
Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy
ARTICLE IN PRESS Surgery ■■ (2017) ■■–■■
Contents lists available at ScienceDirect
Surgery j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y m s y
Original Communications
Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy Kerollos Nashat Wanis a, Victoria Ardiles b, Fernando A. Alvarez b, Mauro Enrique Tun-Abraham a, David Linehan c, Eduardo de Santibañes b, and Roberto Hernandez-Alejandro d,* a
Department of Surgery, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Buenos Aires, Argentina c Department of Surgery, University of Rochester, Rochester, NY d Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, Rochester, NY b
A R T I C L E
I N F O
Article history: Accepted 13 September 2017
A B S T R A C T
Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an innovative, 2-staged hepatectomy which has elicited controversy within the international hepatobiliary community. Uptake of ALPPS has been limited due to concerns related to evidence of high morbidity and mortality and scant oncologic and quality of life outcome data and quality of life (Ool). Demonstrating reasonable long-term benefits with a short-term risk is necessary to support more widespread endorsement of ALPPS. Our aim was to describe the intermediate-term survival and patient-reported quality of life outcomes after an ALPPS. Methods. Prospectively collected data from 2 high-volume ALPPS centers, who were pioneers with the technique, were combined and analyzed for disease-free and overall survival from date of the ALLPS. Only patients treated for colorectal liver metastases with >6 month postoperative follow-up were included. All patients had bilateral colorectal liver metastases with an initially unresectable tumor load, and received preoperative chemotherapy. Information concerning the demographics of the patients, characteristics of the tumor, and treatment were analyzed. The well-validated European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire version 3.0 questionnaire was used to assess patient quality of life. Results. A total of 58 patients underwent ALPPS for colorectal liver metastases, and 47 patients met our inclusion criteria. There were no perioperative mortalities, and the rate of severe complications was 21%. At 3 years post-ALPPS, the overall survival was 50%, while the disease-free survival was 13%. The commonest site of first recurrence was the liver alone (38%). Patient-reported quality of life after ALPPS was similar to reference values for general population. Conclusion. In select patients operated at experienced centers, ALPPS results in low perioperative risk, satisfactory overall survival, and excellent quality of life. Hepatic recurrence and not systemic recurrence is the most common site of relapse after ALPPS. (Surgery 2017;160:XXX-XXX.) © 2017 Elsevier Inc. All rights reserved.
During the past few years, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an innovative modification on classic 2-staged hepatectomy (TSH) with portal vein embolization, the goal of ALLPS has been to increase resectability. As with other innovations in their infancy, ALPPS has inspired considerable controversy. This controversy has not been
* Corresponding author. University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: [email protected] (R. Hernandez-Alejandro).
without merit, because many of the earlier publications reported relatively high rates of morbidity and mortality.1-7 Others, however, have managed to perform ALPPS and its subsequent modifications with acceptable perioperative risk.8-12 As this technique continues to gain momentum within the international hepatobiliary community, further evidence is necessary to corroborate its safety. The main advantage of ALPPS is its ability to generate extensive and accelerated hypertrophy of the future liver remnant (FLR), achieving adequate volume for completion of the second stage of the ALPPS in as short as 1 week.13-16 This possibility allows ALPPS to address the major flaw of classic TSH, which is that a substantial
https://doi.org/10.1016/j.surg.2017.09.044 0039-6060/© 2017 Elsevier Inc. All rights reserved.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
2
proportion (≈30%) of patients are unable to complete the second stage due to inadequate FLR growth and short-interval progression of the disease.17,18 Some groups have proposed that shortinterval disease progression represents a manifestation of a true tumor true biology, and that inter-stage drop-out in classic TSH is an oncologic selection process, identifying those patients who would not benefit from major liver resection.19 This hypothesis, however, has not been proven, and many patients who would fail to complete the second stage of classic TSH may derive oncologic benefit from complete metastasectomy. Although it has been >5 years since the first publications describing ALPPS with ≈1,000 cases now documented in the International ALPPS Registry, it remains unknown whether improving the feasibility of 2-stage hepatectomy using the ALPPS approach results in clinically and oncologically acceptable long-term outcomes, and whether patients are able to resume ordinary life after such an extensive operation. Demonstrating reasonable long-term benefits with acceptable short-term risk would support more widespread endorsement of the approach. As early-adopters of the ALPPS approach, the authors present primary data on intermediate-term outcomes at 3 years post ALPPS for patients with colorectal liver metastases (CRLM). We also describe the first patient reported quality of life (QoL) results after an ALPPS. Methods Study design Prospectively collected data from a cohort of patients who underwent ALPPS for CRLM at 2, early-adopting ALPPS centers was analyzed. A telephone survey was conducted to determine patientreported QoL for survivors. The study was approved by the Western University Office of Research Ethics and the Hospital Italiano University Ethics Committee. Patients and data We analyzed the data on all patients undergoing ALPPS for initially unresectable CRLM at London Health Sciences Centre and Hospital Italiano de Buenos Aires between June 2011 and June 2016. Patients undergoing ALPPS for non-CRLM indications were excluded from this study. Both centers were early adopters of the ALPPS technique, and surgeons at both institutions share similar attitudes regarding patient selection and perioperative management of patients with advanced CRLM undergoing ALPPS. Pilot studies have been published from both of our institutions detailing our initial experience with ALPPS.8-10 After these pilot experiences identifying a low perioperative risk and greater feasibility of completion of the 2-staged hepatectomy with ALPPS, our centers adopted the ALPPS technique primarily for patients with extensive, bilobar CRLM and a small FLR. While PVE continued to be used over the study period, it was reserved for patients whose FLR did not require extensive hypertrophy, and in patients who typically did not require a 2-staged resection. In our ongoing experience with ALPPS, we have continued to observe and confirm a near 100% feasibility of secondstage completion, in contrast to the historically reported rate of ≈70% for classic TSH with PVE. All patients in this study who underwent ALPPS had a FLR ≤30% of total liver volume. Patients were considered for ALPPS only if they had resectable metastases in the FLR, a resectable (or already removed) primary tumor, and absence of unresectable extrahepatic metastases. Other important selection criteria included morphologic response to chemotherapy or lack of tumor progression on chemotherapy, excellent performance status, absence of major medical comorbidities, extensive bilobar or central metastases
necessitating extended hepatectomy, and technical feasibility of R0 resection. All patients were discussed at a multidisciplinary tumor board prior to resection with input from radiologists, colorectal surgeons, hepatobiliary surgeons, medical oncologists, and radiation oncologists. Prior to ALPPS, induction chemotherapy was given in all cases at both centers. Only patients with ≥6-month follow-up were included. Data on patient demographics, primary and secondary tumor characteristics, FLR hypertrophy, chemotherapy and radiation treatments, operative details, perioperative outcomes, follow-up, recurrence, and survival were recorded. Outcomes The primary outcomes were overall survival (OS) and patientreported QoL. The secondary outcomes were disease-free survival (DFS) and pattern of recurrence. OS was defined as the time from the date of the second stage of ALPPS to the date of death. DFS was defined as the time from the date of the second stage of ALPPS to the date of disease recurrence. Patients who died without recurrence, were lost to follow-up without evidence of recurrence, or were alive at the end of the study were censored on the date of death or date of last follow-up. The anatomic location(s) of recurrence were identified on the first imaging test to demonstrate evidence of recurrent disease. Morbidity in the perioperative period was graded using the Clavien-Dindo classification.20 Severe complications and major but not severe complications were defined as those classified as ClavienDindo ≥3b and Clavien-Dindo = 3a, respectively. In-hospital mortality was calculated. Survey We conducted a survey of patient-reported QoL after completion of ALPPS. The European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) version 3.0 was used to assess QoL.21 The QLQ-C30 is comprised of a 2-item, global health scale, 5 multi-item functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 3 multi-item symptom scales (fatigue, nausea and vomiting, and pain), and 6, single-item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire assesses QoL during the 1-week time period prior to assessment. Responses are elicited on a 4-point range (“not at all,” “a little,” “quite a bit,” and “very much”), except for the global health scale which is reported on a 7-point range from very poor to excellent. Scores in each scale are converted to values on a range from 0 to 100. High scores in the global health status and functional scales indicate better QoL. Conversely, higher scores in the symptom scales suggest worse QoL. QoL scores from our population of patients who underwent ALPPS were compared to reference values of the general population reported in an aggregate sample of individuals from Germany, Norway, Austria, Denmark, and the United States.22 To reduce the risk of type I error, a single summary score was used to assess whether any variables had an impact on QoL. The summary score used was derived from the model validated by Giesinger et al23 and is the mean score of 13 of the 15 scales, excluding the global health scale and financial difficulties scale. All surveys were conducted via telephone using a standardized script. Telephone administration of the EORTC QLQ-C30 has been validated with no impact of mode of administration on reliability or scores.24 The QLQ-C30 survey has been translated and validated in several languages, and the survey was administered in the primary language of the patient (English or Spanish). Surgeons who performed ALPPS were not involved in conducting the survey to
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
decrease the risk of response bias. All surveys were conducted in October and November of 2016. Statistical analysis Continuous variables were expressed as means with standard deviations (SD) for normally distributed data and as medians with inter-quartile ranges (IQR) for non-normally distributed data. Categorical variables were expressed as percentages. OS and DFS probabilities were calculated using the Kaplan-Meier method and were reported at 1-year, 2-years, and 3-years with standard errors. A multivariable linear regression was performed to identify whether any variables were independent predictors of worse QoL after ALPPS. Variables were selected a priori, because a number of factors may be expected to impact QoL. The selected variables included age, sex, receipt of adjuvant chemotherapy, presence of recurrence, and duration of time from operation. All statistical analysis was performed using IBM SPSS Statistics for Windows, version 23 (IBM Corp., Armonk, NY).
3
colectomy (n = 11, 23%), and sigmoidectomy (n = 7, 15%). Only a few patients had abdominoperineal resection (n = 2, 4%), subtotal colectomy (n = 2, 4%), or segmental colectomy (n = 1, 2%). All patients received induction chemotherapy prior to ALPPS with a median of 6 (IQR: 5–7) cycles. Most patients received oxaliplatin-based induction chemotherapy (FOLFOX+bevacizumab [n = 17, 36%], FOLFOX [n = 12, 26%], FOLFOX+cetuximab [n = 6, 13%], CapeOx+bevacizumab [n = 3, 6%], CapeOx [n = 1, 2%], TOMOX [n = 1, 2%]). Others received irinotecan-based therapy (FOLFIRI [n = 3, 6%], FOLFIRI+bevacizumab [n = 1, 2%]) or 5-fluorouracil only (capecitabine [n = 2, 4%], 5-fluorouracil [n = 1, 2%]). The type of ALPPS performed was right trisectionectomy (n = 32, 68%), right hepatectomy (n = 12, 26%), left trisectionectomy (n = 1, 2%), or left hepatectomy (n = 2, 4%). Forty (85%) patients required tumor clearance from the FLR (median number of lesions: 2 [IQR: 1–3]) during stage 1. Of the patients with synchronous liver metastases (n = 37), 17 (46%) had colorectal resection during stage 1 of ALPPS. Patients experienced a median inter-stage period of 8 days (IQR: 7–11) prior to stage 2. After stage 2 ALPPS, 36 (77%) patients received adjuvant chemotherapy.
Results Perioperative outcomes Cohort characteristics ALPPS was performed for 58 patients with initially unresectable CRLM during the study period. One additional patient underwent stage one of ALPPS, but had partial thrombosis of the left portal vein resulting in inadequate hypertrophy of the left lateral sector and inability to proceed with stage 2; this patient had a metastasis abutting the left portal vein requiring dissection and manipulation of the vein using an energy device, which were the likely factors resulting in postoperative thrombosis. The patient received palliative chemotherapy. No other patients at either center failed to complete both stages of the ALPPS since our adoption of the technique. A total of 47 patients met the inclusion criteria, having ≥6month follow-up after the ALPPS for CRLM. The demographic and tumor characteristics are displayed in Table 1. Treatment details The most common operations for the primary tumor were low anterior resection (n = 12, 26%), left colectomy (n = 12, 26%), right
Table 1 Demographic and tumor characteristics for patients undergoing ALPPS and having ≥6-month follow-up. Characteristic Age, y Mean ± SD Sex, n (%) Male Female Primary tumor location, n (%) Colon Rectum Timing of liver metastases, n (%) Synchronous Metachronous No. of liver lesions, n Median (IQR) Largest lesion size, mm Median (IQR) FLR prior to stage 1, % Mean ± SD FLR prior to stage 2, % Mean ± SD Time between stages, d Median (IQR)
Of the total cohort including those without a 6-month followup (n = 58), and no patients experienced in-hospital mortality. Twelve patients (21%) had a severe complication, Clavien-Dindo ≥3b during either stage of ALPPS, while 9 patients (16%) had complications graded Clavien-Dindo 3a. Of those who had severe complications, 4 had a severe complication after stage 1, and 8 after stage 2. Thirtyseven patients (79%) received adjuvant chemotherapy. Survival and recurrence The median duration of follow-up was 35 months. OS was 93% (standard error: ± 4%) at 1-year, 66% (±8%) at 2-years, and 50% (±9 %) at 3-years. Median overall OS was 36 months. DFS was 50% (±8%) at 1-year, 16% (±6%) at 2-years, and 13% (±6%) at 3-years. Median DFS was 12 months. The Kaplan-Meier curves for OS and DFS are shown in Figs 1 and 2, respectively. A total of 37 patients (79%) experienced tumor recurrence during the follow-up period. The location of first recurrence was most commonly in the liver alone (n = 14, 38%), lung alone (n = 7, 19%), liver and lung synchronously (n = 7, 19%), liver and peritoneum synchronously (n = 2, 5%), lung and peritoneum synchronously (n = 2, 5%), adrenal gland alone (n = 2, 5%), peritoneum alone (n = 1, 3%), liver and local recurrence at rectal anastomosis (n = 1, 3%), and bone alone (n = 1, 3%).
Value
QoL 57 ± 12 34 (72%) 13 (28%) 35 (74%) 12 (26%) 39 (83%) 8 (17%) 8 (4–12) 40 (35–45) 22 ± 5.3
Responses to the EORTC QLQ-C30 survey are displayed in Fig 3 with comparison to population reference values. Responses were obtained from 23 of the 26 surviving patients (88% response rate). The median time from ALPPS stage 2 to administration of the survey was 29 months (IQR: 19–41 months). In general, patients who underwent ALPPS reported high median global health status and functional scale scores with low symptom scale scores. Multivariable regression analysis did not identify any significant impact of age, sex, receipt of adjuvant chemotherapy, presence of recurrence, or duration of time from surgery on the QoL summary score (Table 2). Discussion
42 ± 9.6 8 (7–11)
We report the outcomes of a moderately sized cohort of patients who underwent ALPPS for initially unresectable CRLM with
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS 4
K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
Fig. 1. Kaplan-Meier survival curve for DFS.
Fig. 2. Kaplan-Meier survival curve for OS.
a median follow-up of 3 years. In addition to low perioperative morbidity and no perioperative mortality, our findings identify a median OS of 3 years from completion of ALPPS, with QoL comparable with that of the general population. As expected, in patients with
advanced CRLM, most patients experience early and typically hepatic disease recurrence; however, the low perioperative risk, good overall survival, and excellent QoL of this cohort support the role of ALPPS in select patients.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
5
Quality of life scores 100 90 80 70 60 50 40 30 20 10 0
ALPPS patients
General population reference values
Fig. 3. QoL scores obtained via administration of a telephone survey (the European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire (ALPPS) compared to scores of the general population scores (general population reference values). High scores in functional scales indicate better outcomes, while high scores in symptom scales indicate worse outcomes. Median scores are displayed, with IQR illustrated with error bars.
Table 2 Multiple regression analysis model with quality of life summary score as dependant variable. Characteristic for patients who responded to survey Age, y Mean ± SD Sex, n (%) Male Adjuvant treatment, n (%) Received Presence of recurrence, n (%) Yes Time from surgery to survey, mo Median (IQR)
Value
β
57 ± 11
−0.189
0.319
.561
16 (70%)
4.18
7.77
.597
20 (87%)
9.39
15 (65%)
−9.97
29 (19–41)
0.141
Standard error
10.5
Adjusted P value
.384
7.16
.182
0.254
.587
Categorical variables are presented as n (% of population who responded to survey).
Two-staged hepatectomy was first reported 2 decades ago and has facilitated curative resection in patients with initially unresectable colorectal cancer liver metastases.25,26 The conventional approach to TSH is limited by the need for a prolonged waiting period between stages during which FLR hypertrophy occurs. The completion of the second stage is often not feasible (in ≈30% of patients) due to inadequate FLR hypertrophy and/or short-interval disease progression.17,18 ALPPS has grown in popularity recently as a variation of the conventional TSH technique, because of the accelerated FLR hypertrophy due to liver partition during the first stage, which has expanded the feasibility of TSH.6,14,27 The major drawback of ALPPS is high morbidity and mortality, which has been reported in single-institution cases series as well as international registry studies.4-6,28 Considering these reports, it is nor surprising that in meta-analyses of published studies, ALPPS trended toward having a greater perioperative mortality compared with conventional TSH.13,16 Our initial published experiences with ALPPS have presented an alternate perspective and, at our intuitions, we have demonstrated improved perioperative outcomes due to assiduous patient selection.8,10 Beyond perioperative outcomes, doubts have also been raised about the oncologic outcomes after ALPPS, and some have suggested
that conventional TSH allows patients with poor tumor biology manifested by short-interval disease progression to be spared the need for futile completion hepatectomy. 29 Due to the relative paucity of data on long-term outcomes after ALPPS, the validity of this hypothesis has not been established adequately.30,31 In this study, we demonstrate a 50% 3-year rate of OS calculated from completion of the ALPPS in patients with advanced CRLM. This survival compares favorably to reported rates of 3-year survival after conventional TSH ranging from 28–84%, with median survival of 24–44 months.17 Likewise, the DFS of 13% at 3-years in our cohort of patients was similar to the results reported after the more classic TSH (6–27%),17 and, not unpredictably, poorer than the 5-year DFS rates for patients with a lesser tumor burden which border on 30%.32-34 It is not surprising that these patients with advanced oligometastatic colorectal cancer had early recurrence despite aggressive treatment. The results of our study, however, suggest that complete resection of metastatic disease likely contributes to the improved OS. In those patients who did experience recurrence, the liver was the most common site of relapse, although, many patients had synchronous recurrence in the liver as well as a second site. Despite the high tumor load and recurrence rates posttreatment, a small number of patients remain disease-free at intermediate-term follow-up, suggesting that perhaps some might be cured. We also present the first data on QoL after TSH to our knowledge. Surgeons who performed ALPPS were not involved in conducting the QoL survey to mitigate the risk of response bias. Our results demonstrate that despite having highly advanced disease requiring aggressive hepatic resection, patients report few functional limitations or symptoms. The reported QoL in our series is similar to median values from a large dataset of general population reference values.22 This finding is consistent with and expands on other studies, which have shown that patients who have undergone liver resection for CRLM experience a transient and marginal deterioration in QoL, but with rapid recovery of baseline health.35-37 Patients who experienced recurrence may be expected to experience deterioration in QoL,38 but despite many patients in our cohort having recurrence, no association between recurrence and patient-reported outcomes was observed.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS 6
K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
Several centers including ours have reported previously poor oncologic and survival outcomes after ALPPS using data compiled in the International ALPPS Registry.39,40 There is substantial variability in the criteria used at various institutions to determine application of ALPPS. Furthermore, operative techniques diverge considerably among international centers.41 Our present cohort is bi-institutionally constructed, benefiting from similar selection criteria and operative technique at both centers. The outcomes observed in this specific population may therefore, not be generalizable widely; however, further standardization of operative approaches and experience with the ALPPS technique is likely to improve overall international results. A learning curve has been suggested for ALPPS, with evidence of improved perioperative outcomes due to improvements in patient selection and a decrease in inter-stage complications.42 A trend in selection toward younger patients and those with CRLMs, which have been the cornerstone of our selection criteria since the adoption of ALPPS at our centers, has been shown to result in decreased early morbidity and mortality. There is now a need to understand the intermediate and long-term oncologic outcomes, as well as the QoL of those undergoing ALPPS. Our data provides early insight into these integral endpoints and will encourage publication hopefully of similar data from other centers. Our study has a number of notable limitations. We analyzed retrospectively a cohort of highly selected patients with comparison to values from prior publications. In the absence of a randomized trial of conventional TSH versus ALPPS, it is difficult to compare these variations directly, because some surgeons perform one but not the other type of hepatectomy, and at centers where both procedures are performed, selection criteria may vary for the two approaches. In this context, the patient populations are likely not exchangeable and unadjusted factors may bias any comparative analysis. Even longer-term follow up data must be published before ALPPS can be compared conclusively with conventional TSH, since 5 to 10-year survival data has been reported for the latter. Further research is necessary to define the role of ALPPS in the management of patients with advanced, initially unresectable, bilobar CRLM. We were unable to evaluate the change in patient-reported outcomes during treatment, because the retrospective nature of the study limited us to measuring QoL after completion of the ALPPS. Several variables may impact QoL after a TSH, and our sample size is likely underpowered to identify significant independent associations. Additionally, a QoL survey may not be the best tool for assessing long-term, patient-reported outcomes after complex oncologic treatment, but until further qualitative and quantitative QoL data regarding ALPPS are available, the QLQ-C30 represents a wellvalidated, practical option. In patients with heavy tumor burden, few patients will be expected to achieve durable disease-free response to any operative procedure. Both conventional TSH and ALPPS may cure select patients with oncologically favorable characteristics, and ALPPS seems to expand the feasibility of resection to a greater proportion of patients.2 Ultimately, the treatment of advanced cancer should emphasize increasing the duration of survival while maintaining QoL. In this perspective, ALPPS seems to reset the oncological “clock” by extending overall survival in patients who would compared have died of disease progression earlier in the course of palliative treatment. In experienced hepatobiliary centers and in well selected patients, ALPPS can be performed with low perioperative morbidity and minimal-to-no mortality, resulting in good intermediateterm survival and excellent QoL. Many patients may benefit from the improvement in 2-stage hepatectomy completion rates achieved using ALPPS.
Acknowledgments We would like to thank Chadia Elkhatib at Western University for administrating the telephone survey. References 1. Ratti F, Cipriani F, Gagliano A, Catena M, Paganelli M, Aldrighetti L. Defining indications to ALPPS procedure: technical aspects and open issues. Updates Surg 2013;66:41-9. 2. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg 2014;38:1510-9. 3. Nadalin S, Capobianco I, Li J, Girotti P, Königsrainer I, Königsrainer A. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons learned from 15 cases at a single centre. Z Gastroenterol 2014;52:35-42. 4. Torres OJM, Fernandes Ede SM, Oliveira CVC, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): the Brazilian experience. Arq Bras Cir Dig 2013;26:40-3. 5. Li J, Girotti P, Königsrainer I, Ladurner R, Königsrainer A, Nadalin S. ALPPS in right trisectionectomy: a safe procedure to avoid postoperative liver failure? J Gastrointest Surg 2013;17:956-61. 6. 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;255:405-14. 7. Knoefel WT, Gabor I, Rehders A, et al. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013;100:388-94. 8. 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 (ALPPS) procedure in the management of colorectal liver metastases? Surgery 2015;157:194-201. 9. Sala S, Ardiles V, Ulla M, Alvarez F, Pekolj J, de Santibañes E. Our initial experience with ALPPS technique: encouraging results. Updates Surg 2012;64:167-72. 10. Alvarez FA, Ardiles V, de Santibañes M, Pekolj J, de Santibañes 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;261:723-32. 11. Alvarez FA, Ardiles V, Claria RS, Pekolj J, de Santibañes E. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): tips and tricks. J Gastrointest Surg 2012;17:814-21. 12. 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 2013;38:1504-9. 13. Eshmuminov D, Raptis DA, Linecker M, Wirsching A, Lesurtel M, Clavien P-A. Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy: ALPPS versus portal vein occlusion for staged hepatectomy. Br J Surg 2016;103:1768-82. 14. Croome KP, Hernandez-Alejandro R, Parker M, Heimbach J, Rosen C, Nagorney DM. Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. HPB (Oxford) 2015;17:477-84. 15. Bertens KA, Hawel J, Lung K, Buac S, Pineda-Solis K, Hernandez-Alejandro R. ALPPS: challenging the concept of unresectability—a systematic review. Int J Surg 2015;13:280-7. 16. Schadde E, Schnitzbauer AA, Tschuor C, Raptis DA, Bechstein WO, Clavien P-A. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. Ann Surg Oncol 2015;22:3109-20. 17. Lam VWT, Laurence JM, Johnston E, Hollands MJ, Pleass HCC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013;15:48-91. 18. Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver metastases: two-stage resection of CLM. J Surg Oncol 2013;107:211-6. 19. Aloia TA, Vauthey J-N. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is gained and what is lost? Ann Surg 2012;256:e9. 20. 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;240:205-13. 21. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: EORTC; 2001. 22. Scott NW, Fayers PM, Aaronson NK, et al. EORTC QLQ-C30 Reference Values. Brussels: EORTC Quality of Life Group Publications; 2008. 23. Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol 2016;69:79-88. 24. Gundy CM, Aaronson NK. Effects of mode of administration (MOA) on the measurement properties of the EORTC QLQ-C30: a randomized study. Health Qual Life Outcomes 2010;8:35.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
25. Bismuth H, Adam R, Lévi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;224: 509-20. 26. Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg 2000;232: 777-85. 27. 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: 839-47. 28. 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;260:82938. 29. Shindoh J, Vauthey J-N, Zimmitti G, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg 2013;217:126-33. 30. Lang SA, Loss M, Benseler V, Glockzin G, Schlitt HJ. Long-term results after in-situ split (ISS) liver resection. Langenbecks Arch Surg 2015;400: 361-9. 31. Björnsson B, Sparrelid E, Røsok B, et al. Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases—intermediate oncological results. Eur J Surg Oncol 2016;42: 531-7. 32. Wei AC, Greig PD, Grant D, Taylor B, Langer B, Gallinger S. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006;13:668-76.
7
33. House MG, Ito H, Gönen M, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg 2010;210:744-52. 34. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multiinstitutional analysis of 1669 patients. Ann Surg 2009;250:440-8. 35. Rees JR, Blazeby JM, Fayers P, et al. Patient-reported outcomes after hepatic resection of colorectal cancer metastases. J Clin Oncol 2012;30:1364-70. 36. Langenhoff BS, Krabbe PFM, Peerenboom L, Wobbes T, Ruers TJM. Quality of life after surgical treatment of colorectal liver metastases. Br J Surg 2006;93:1007-14. 37. Rees JR, Blazeby JM, Brookes ST, John T, Welsh FK, Rees M. Patient-reported outcomes in long-term survivors of metastatic colorectal cancer needing liver resection. Br J Surg 2014;101:1468-74. 38. Wiering B, Oyen WJG, Adang EMM, et al. Long-term global quality of life in patients treated for colorectal liver metastases. Br J Surg 2011;98:565-71. 39. Olthof PB, Huiskens J, Wicherts DA, et al. Survival after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for advanced colorectal liver metastases: a case-matched comparison with palliative systemic therapy. Surgery 2017;161:909-19. 40. Wanis KN, Buac S, Linecker M, et al. Patient survival after simultaneous ALPPS and colorectal resection. World J Surg 2017;41:1119-25. 41. Buac S, Schadde E, Schnitzbauer AA, Vogt K, Hernandez-Alejandro R. The many faces of ALPPS: surgical indications and techniques among surgeons collaborating in the international registry. HPB (Oxford) 2016;18:442-8. 42. Linecker M, Bjornsson B, Stavrou GA, et al. Risk adjustment in ALPPS is associated with a dramatic decrease in early mortality and morbidity. Ann Surg 2017;266:779-86.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
Contents lists available at ScienceDirect
Surgery j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y m s y
Original Communications
Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy Kerollos Nashat Wanis a, Victoria Ardiles b, Fernando A. Alvarez b, Mauro Enrique Tun-Abraham a, David Linehan c, Eduardo de Santibañes b, and Roberto Hernandez-Alejandro d,* a
Department of Surgery, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Buenos Aires, Argentina c Department of Surgery, University of Rochester, Rochester, NY d Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, Rochester, NY b
A R T I C L E
I N F O
Article history: Accepted 13 September 2017
A B S T R A C T
Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is an innovative, 2-staged hepatectomy which has elicited controversy within the international hepatobiliary community. Uptake of ALPPS has been limited due to concerns related to evidence of high morbidity and mortality and scant oncologic and quality of life outcome data and quality of life (Ool). Demonstrating reasonable long-term benefits with a short-term risk is necessary to support more widespread endorsement of ALPPS. Our aim was to describe the intermediate-term survival and patient-reported quality of life outcomes after an ALPPS. Methods. Prospectively collected data from 2 high-volume ALPPS centers, who were pioneers with the technique, were combined and analyzed for disease-free and overall survival from date of the ALLPS. Only patients treated for colorectal liver metastases with >6 month postoperative follow-up were included. All patients had bilateral colorectal liver metastases with an initially unresectable tumor load, and received preoperative chemotherapy. Information concerning the demographics of the patients, characteristics of the tumor, and treatment were analyzed. The well-validated European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire version 3.0 questionnaire was used to assess patient quality of life. Results. A total of 58 patients underwent ALPPS for colorectal liver metastases, and 47 patients met our inclusion criteria. There were no perioperative mortalities, and the rate of severe complications was 21%. At 3 years post-ALPPS, the overall survival was 50%, while the disease-free survival was 13%. The commonest site of first recurrence was the liver alone (38%). Patient-reported quality of life after ALPPS was similar to reference values for general population. Conclusion. In select patients operated at experienced centers, ALPPS results in low perioperative risk, satisfactory overall survival, and excellent quality of life. Hepatic recurrence and not systemic recurrence is the most common site of relapse after ALPPS. (Surgery 2017;160:XXX-XXX.) © 2017 Elsevier Inc. All rights reserved.
During the past few years, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an innovative modification on classic 2-staged hepatectomy (TSH) with portal vein embolization, the goal of ALLPS has been to increase resectability. As with other innovations in their infancy, ALPPS has inspired considerable controversy. This controversy has not been
* Corresponding author. University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. E-mail address: [email protected] (R. Hernandez-Alejandro).
without merit, because many of the earlier publications reported relatively high rates of morbidity and mortality.1-7 Others, however, have managed to perform ALPPS and its subsequent modifications with acceptable perioperative risk.8-12 As this technique continues to gain momentum within the international hepatobiliary community, further evidence is necessary to corroborate its safety. The main advantage of ALPPS is its ability to generate extensive and accelerated hypertrophy of the future liver remnant (FLR), achieving adequate volume for completion of the second stage of the ALPPS in as short as 1 week.13-16 This possibility allows ALPPS to address the major flaw of classic TSH, which is that a substantial
https://doi.org/10.1016/j.surg.2017.09.044 0039-6060/© 2017 Elsevier Inc. All rights reserved.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
2
proportion (≈30%) of patients are unable to complete the second stage due to inadequate FLR growth and short-interval progression of the disease.17,18 Some groups have proposed that shortinterval disease progression represents a manifestation of a true tumor true biology, and that inter-stage drop-out in classic TSH is an oncologic selection process, identifying those patients who would not benefit from major liver resection.19 This hypothesis, however, has not been proven, and many patients who would fail to complete the second stage of classic TSH may derive oncologic benefit from complete metastasectomy. Although it has been >5 years since the first publications describing ALPPS with ≈1,000 cases now documented in the International ALPPS Registry, it remains unknown whether improving the feasibility of 2-stage hepatectomy using the ALPPS approach results in clinically and oncologically acceptable long-term outcomes, and whether patients are able to resume ordinary life after such an extensive operation. Demonstrating reasonable long-term benefits with acceptable short-term risk would support more widespread endorsement of the approach. As early-adopters of the ALPPS approach, the authors present primary data on intermediate-term outcomes at 3 years post ALPPS for patients with colorectal liver metastases (CRLM). We also describe the first patient reported quality of life (QoL) results after an ALPPS. Methods Study design Prospectively collected data from a cohort of patients who underwent ALPPS for CRLM at 2, early-adopting ALPPS centers was analyzed. A telephone survey was conducted to determine patientreported QoL for survivors. The study was approved by the Western University Office of Research Ethics and the Hospital Italiano University Ethics Committee. Patients and data We analyzed the data on all patients undergoing ALPPS for initially unresectable CRLM at London Health Sciences Centre and Hospital Italiano de Buenos Aires between June 2011 and June 2016. Patients undergoing ALPPS for non-CRLM indications were excluded from this study. Both centers were early adopters of the ALPPS technique, and surgeons at both institutions share similar attitudes regarding patient selection and perioperative management of patients with advanced CRLM undergoing ALPPS. Pilot studies have been published from both of our institutions detailing our initial experience with ALPPS.8-10 After these pilot experiences identifying a low perioperative risk and greater feasibility of completion of the 2-staged hepatectomy with ALPPS, our centers adopted the ALPPS technique primarily for patients with extensive, bilobar CRLM and a small FLR. While PVE continued to be used over the study period, it was reserved for patients whose FLR did not require extensive hypertrophy, and in patients who typically did not require a 2-staged resection. In our ongoing experience with ALPPS, we have continued to observe and confirm a near 100% feasibility of secondstage completion, in contrast to the historically reported rate of ≈70% for classic TSH with PVE. All patients in this study who underwent ALPPS had a FLR ≤30% of total liver volume. Patients were considered for ALPPS only if they had resectable metastases in the FLR, a resectable (or already removed) primary tumor, and absence of unresectable extrahepatic metastases. Other important selection criteria included morphologic response to chemotherapy or lack of tumor progression on chemotherapy, excellent performance status, absence of major medical comorbidities, extensive bilobar or central metastases
necessitating extended hepatectomy, and technical feasibility of R0 resection. All patients were discussed at a multidisciplinary tumor board prior to resection with input from radiologists, colorectal surgeons, hepatobiliary surgeons, medical oncologists, and radiation oncologists. Prior to ALPPS, induction chemotherapy was given in all cases at both centers. Only patients with ≥6-month follow-up were included. Data on patient demographics, primary and secondary tumor characteristics, FLR hypertrophy, chemotherapy and radiation treatments, operative details, perioperative outcomes, follow-up, recurrence, and survival were recorded. Outcomes The primary outcomes were overall survival (OS) and patientreported QoL. The secondary outcomes were disease-free survival (DFS) and pattern of recurrence. OS was defined as the time from the date of the second stage of ALPPS to the date of death. DFS was defined as the time from the date of the second stage of ALPPS to the date of disease recurrence. Patients who died without recurrence, were lost to follow-up without evidence of recurrence, or were alive at the end of the study were censored on the date of death or date of last follow-up. The anatomic location(s) of recurrence were identified on the first imaging test to demonstrate evidence of recurrent disease. Morbidity in the perioperative period was graded using the Clavien-Dindo classification.20 Severe complications and major but not severe complications were defined as those classified as ClavienDindo ≥3b and Clavien-Dindo = 3a, respectively. In-hospital mortality was calculated. Survey We conducted a survey of patient-reported QoL after completion of ALPPS. The European Organization for Research and Treatment for Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) version 3.0 was used to assess QoL.21 The QLQ-C30 is comprised of a 2-item, global health scale, 5 multi-item functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 3 multi-item symptom scales (fatigue, nausea and vomiting, and pain), and 6, single-item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The questionnaire assesses QoL during the 1-week time period prior to assessment. Responses are elicited on a 4-point range (“not at all,” “a little,” “quite a bit,” and “very much”), except for the global health scale which is reported on a 7-point range from very poor to excellent. Scores in each scale are converted to values on a range from 0 to 100. High scores in the global health status and functional scales indicate better QoL. Conversely, higher scores in the symptom scales suggest worse QoL. QoL scores from our population of patients who underwent ALPPS were compared to reference values of the general population reported in an aggregate sample of individuals from Germany, Norway, Austria, Denmark, and the United States.22 To reduce the risk of type I error, a single summary score was used to assess whether any variables had an impact on QoL. The summary score used was derived from the model validated by Giesinger et al23 and is the mean score of 13 of the 15 scales, excluding the global health scale and financial difficulties scale. All surveys were conducted via telephone using a standardized script. Telephone administration of the EORTC QLQ-C30 has been validated with no impact of mode of administration on reliability or scores.24 The QLQ-C30 survey has been translated and validated in several languages, and the survey was administered in the primary language of the patient (English or Spanish). Surgeons who performed ALPPS were not involved in conducting the survey to
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
decrease the risk of response bias. All surveys were conducted in October and November of 2016. Statistical analysis Continuous variables were expressed as means with standard deviations (SD) for normally distributed data and as medians with inter-quartile ranges (IQR) for non-normally distributed data. Categorical variables were expressed as percentages. OS and DFS probabilities were calculated using the Kaplan-Meier method and were reported at 1-year, 2-years, and 3-years with standard errors. A multivariable linear regression was performed to identify whether any variables were independent predictors of worse QoL after ALPPS. Variables were selected a priori, because a number of factors may be expected to impact QoL. The selected variables included age, sex, receipt of adjuvant chemotherapy, presence of recurrence, and duration of time from operation. All statistical analysis was performed using IBM SPSS Statistics for Windows, version 23 (IBM Corp., Armonk, NY).
3
colectomy (n = 11, 23%), and sigmoidectomy (n = 7, 15%). Only a few patients had abdominoperineal resection (n = 2, 4%), subtotal colectomy (n = 2, 4%), or segmental colectomy (n = 1, 2%). All patients received induction chemotherapy prior to ALPPS with a median of 6 (IQR: 5–7) cycles. Most patients received oxaliplatin-based induction chemotherapy (FOLFOX+bevacizumab [n = 17, 36%], FOLFOX [n = 12, 26%], FOLFOX+cetuximab [n = 6, 13%], CapeOx+bevacizumab [n = 3, 6%], CapeOx [n = 1, 2%], TOMOX [n = 1, 2%]). Others received irinotecan-based therapy (FOLFIRI [n = 3, 6%], FOLFIRI+bevacizumab [n = 1, 2%]) or 5-fluorouracil only (capecitabine [n = 2, 4%], 5-fluorouracil [n = 1, 2%]). The type of ALPPS performed was right trisectionectomy (n = 32, 68%), right hepatectomy (n = 12, 26%), left trisectionectomy (n = 1, 2%), or left hepatectomy (n = 2, 4%). Forty (85%) patients required tumor clearance from the FLR (median number of lesions: 2 [IQR: 1–3]) during stage 1. Of the patients with synchronous liver metastases (n = 37), 17 (46%) had colorectal resection during stage 1 of ALPPS. Patients experienced a median inter-stage period of 8 days (IQR: 7–11) prior to stage 2. After stage 2 ALPPS, 36 (77%) patients received adjuvant chemotherapy.
Results Perioperative outcomes Cohort characteristics ALPPS was performed for 58 patients with initially unresectable CRLM during the study period. One additional patient underwent stage one of ALPPS, but had partial thrombosis of the left portal vein resulting in inadequate hypertrophy of the left lateral sector and inability to proceed with stage 2; this patient had a metastasis abutting the left portal vein requiring dissection and manipulation of the vein using an energy device, which were the likely factors resulting in postoperative thrombosis. The patient received palliative chemotherapy. No other patients at either center failed to complete both stages of the ALPPS since our adoption of the technique. A total of 47 patients met the inclusion criteria, having ≥6month follow-up after the ALPPS for CRLM. The demographic and tumor characteristics are displayed in Table 1. Treatment details The most common operations for the primary tumor were low anterior resection (n = 12, 26%), left colectomy (n = 12, 26%), right
Table 1 Demographic and tumor characteristics for patients undergoing ALPPS and having ≥6-month follow-up. Characteristic Age, y Mean ± SD Sex, n (%) Male Female Primary tumor location, n (%) Colon Rectum Timing of liver metastases, n (%) Synchronous Metachronous No. of liver lesions, n Median (IQR) Largest lesion size, mm Median (IQR) FLR prior to stage 1, % Mean ± SD FLR prior to stage 2, % Mean ± SD Time between stages, d Median (IQR)
Of the total cohort including those without a 6-month followup (n = 58), and no patients experienced in-hospital mortality. Twelve patients (21%) had a severe complication, Clavien-Dindo ≥3b during either stage of ALPPS, while 9 patients (16%) had complications graded Clavien-Dindo 3a. Of those who had severe complications, 4 had a severe complication after stage 1, and 8 after stage 2. Thirtyseven patients (79%) received adjuvant chemotherapy. Survival and recurrence The median duration of follow-up was 35 months. OS was 93% (standard error: ± 4%) at 1-year, 66% (±8%) at 2-years, and 50% (±9 %) at 3-years. Median overall OS was 36 months. DFS was 50% (±8%) at 1-year, 16% (±6%) at 2-years, and 13% (±6%) at 3-years. Median DFS was 12 months. The Kaplan-Meier curves for OS and DFS are shown in Figs 1 and 2, respectively. A total of 37 patients (79%) experienced tumor recurrence during the follow-up period. The location of first recurrence was most commonly in the liver alone (n = 14, 38%), lung alone (n = 7, 19%), liver and lung synchronously (n = 7, 19%), liver and peritoneum synchronously (n = 2, 5%), lung and peritoneum synchronously (n = 2, 5%), adrenal gland alone (n = 2, 5%), peritoneum alone (n = 1, 3%), liver and local recurrence at rectal anastomosis (n = 1, 3%), and bone alone (n = 1, 3%).
Value
QoL 57 ± 12 34 (72%) 13 (28%) 35 (74%) 12 (26%) 39 (83%) 8 (17%) 8 (4–12) 40 (35–45) 22 ± 5.3
Responses to the EORTC QLQ-C30 survey are displayed in Fig 3 with comparison to population reference values. Responses were obtained from 23 of the 26 surviving patients (88% response rate). The median time from ALPPS stage 2 to administration of the survey was 29 months (IQR: 19–41 months). In general, patients who underwent ALPPS reported high median global health status and functional scale scores with low symptom scale scores. Multivariable regression analysis did not identify any significant impact of age, sex, receipt of adjuvant chemotherapy, presence of recurrence, or duration of time from surgery on the QoL summary score (Table 2). Discussion
42 ± 9.6 8 (7–11)
We report the outcomes of a moderately sized cohort of patients who underwent ALPPS for initially unresectable CRLM with
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS 4
K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
Fig. 1. Kaplan-Meier survival curve for DFS.
Fig. 2. Kaplan-Meier survival curve for OS.
a median follow-up of 3 years. In addition to low perioperative morbidity and no perioperative mortality, our findings identify a median OS of 3 years from completion of ALPPS, with QoL comparable with that of the general population. As expected, in patients with
advanced CRLM, most patients experience early and typically hepatic disease recurrence; however, the low perioperative risk, good overall survival, and excellent QoL of this cohort support the role of ALPPS in select patients.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
5
Quality of life scores 100 90 80 70 60 50 40 30 20 10 0
ALPPS patients
General population reference values
Fig. 3. QoL scores obtained via administration of a telephone survey (the European Organization for Research and Treatment for Cancer Quality of Life Core Questionnaire (ALPPS) compared to scores of the general population scores (general population reference values). High scores in functional scales indicate better outcomes, while high scores in symptom scales indicate worse outcomes. Median scores are displayed, with IQR illustrated with error bars.
Table 2 Multiple regression analysis model with quality of life summary score as dependant variable. Characteristic for patients who responded to survey Age, y Mean ± SD Sex, n (%) Male Adjuvant treatment, n (%) Received Presence of recurrence, n (%) Yes Time from surgery to survey, mo Median (IQR)
Value
β
57 ± 11
−0.189
0.319
.561
16 (70%)
4.18
7.77
.597
20 (87%)
9.39
15 (65%)
−9.97
29 (19–41)
0.141
Standard error
10.5
Adjusted P value
.384
7.16
.182
0.254
.587
Categorical variables are presented as n (% of population who responded to survey).
Two-staged hepatectomy was first reported 2 decades ago and has facilitated curative resection in patients with initially unresectable colorectal cancer liver metastases.25,26 The conventional approach to TSH is limited by the need for a prolonged waiting period between stages during which FLR hypertrophy occurs. The completion of the second stage is often not feasible (in ≈30% of patients) due to inadequate FLR hypertrophy and/or short-interval disease progression.17,18 ALPPS has grown in popularity recently as a variation of the conventional TSH technique, because of the accelerated FLR hypertrophy due to liver partition during the first stage, which has expanded the feasibility of TSH.6,14,27 The major drawback of ALPPS is high morbidity and mortality, which has been reported in single-institution cases series as well as international registry studies.4-6,28 Considering these reports, it is nor surprising that in meta-analyses of published studies, ALPPS trended toward having a greater perioperative mortality compared with conventional TSH.13,16 Our initial published experiences with ALPPS have presented an alternate perspective and, at our intuitions, we have demonstrated improved perioperative outcomes due to assiduous patient selection.8,10 Beyond perioperative outcomes, doubts have also been raised about the oncologic outcomes after ALPPS, and some have suggested
that conventional TSH allows patients with poor tumor biology manifested by short-interval disease progression to be spared the need for futile completion hepatectomy. 29 Due to the relative paucity of data on long-term outcomes after ALPPS, the validity of this hypothesis has not been established adequately.30,31 In this study, we demonstrate a 50% 3-year rate of OS calculated from completion of the ALPPS in patients with advanced CRLM. This survival compares favorably to reported rates of 3-year survival after conventional TSH ranging from 28–84%, with median survival of 24–44 months.17 Likewise, the DFS of 13% at 3-years in our cohort of patients was similar to the results reported after the more classic TSH (6–27%),17 and, not unpredictably, poorer than the 5-year DFS rates for patients with a lesser tumor burden which border on 30%.32-34 It is not surprising that these patients with advanced oligometastatic colorectal cancer had early recurrence despite aggressive treatment. The results of our study, however, suggest that complete resection of metastatic disease likely contributes to the improved OS. In those patients who did experience recurrence, the liver was the most common site of relapse, although, many patients had synchronous recurrence in the liver as well as a second site. Despite the high tumor load and recurrence rates posttreatment, a small number of patients remain disease-free at intermediate-term follow-up, suggesting that perhaps some might be cured. We also present the first data on QoL after TSH to our knowledge. Surgeons who performed ALPPS were not involved in conducting the QoL survey to mitigate the risk of response bias. Our results demonstrate that despite having highly advanced disease requiring aggressive hepatic resection, patients report few functional limitations or symptoms. The reported QoL in our series is similar to median values from a large dataset of general population reference values.22 This finding is consistent with and expands on other studies, which have shown that patients who have undergone liver resection for CRLM experience a transient and marginal deterioration in QoL, but with rapid recovery of baseline health.35-37 Patients who experienced recurrence may be expected to experience deterioration in QoL,38 but despite many patients in our cohort having recurrence, no association between recurrence and patient-reported outcomes was observed.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS 6
K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
Several centers including ours have reported previously poor oncologic and survival outcomes after ALPPS using data compiled in the International ALPPS Registry.39,40 There is substantial variability in the criteria used at various institutions to determine application of ALPPS. Furthermore, operative techniques diverge considerably among international centers.41 Our present cohort is bi-institutionally constructed, benefiting from similar selection criteria and operative technique at both centers. The outcomes observed in this specific population may therefore, not be generalizable widely; however, further standardization of operative approaches and experience with the ALPPS technique is likely to improve overall international results. A learning curve has been suggested for ALPPS, with evidence of improved perioperative outcomes due to improvements in patient selection and a decrease in inter-stage complications.42 A trend in selection toward younger patients and those with CRLMs, which have been the cornerstone of our selection criteria since the adoption of ALPPS at our centers, has been shown to result in decreased early morbidity and mortality. There is now a need to understand the intermediate and long-term oncologic outcomes, as well as the QoL of those undergoing ALPPS. Our data provides early insight into these integral endpoints and will encourage publication hopefully of similar data from other centers. Our study has a number of notable limitations. We analyzed retrospectively a cohort of highly selected patients with comparison to values from prior publications. In the absence of a randomized trial of conventional TSH versus ALPPS, it is difficult to compare these variations directly, because some surgeons perform one but not the other type of hepatectomy, and at centers where both procedures are performed, selection criteria may vary for the two approaches. In this context, the patient populations are likely not exchangeable and unadjusted factors may bias any comparative analysis. Even longer-term follow up data must be published before ALPPS can be compared conclusively with conventional TSH, since 5 to 10-year survival data has been reported for the latter. Further research is necessary to define the role of ALPPS in the management of patients with advanced, initially unresectable, bilobar CRLM. We were unable to evaluate the change in patient-reported outcomes during treatment, because the retrospective nature of the study limited us to measuring QoL after completion of the ALPPS. Several variables may impact QoL after a TSH, and our sample size is likely underpowered to identify significant independent associations. Additionally, a QoL survey may not be the best tool for assessing long-term, patient-reported outcomes after complex oncologic treatment, but until further qualitative and quantitative QoL data regarding ALPPS are available, the QLQ-C30 represents a wellvalidated, practical option. In patients with heavy tumor burden, few patients will be expected to achieve durable disease-free response to any operative procedure. Both conventional TSH and ALPPS may cure select patients with oncologically favorable characteristics, and ALPPS seems to expand the feasibility of resection to a greater proportion of patients.2 Ultimately, the treatment of advanced cancer should emphasize increasing the duration of survival while maintaining QoL. In this perspective, ALPPS seems to reset the oncological “clock” by extending overall survival in patients who would compared have died of disease progression earlier in the course of palliative treatment. In experienced hepatobiliary centers and in well selected patients, ALPPS can be performed with low perioperative morbidity and minimal-to-no mortality, resulting in good intermediateterm survival and excellent QoL. Many patients may benefit from the improvement in 2-stage hepatectomy completion rates achieved using ALPPS.
Acknowledgments We would like to thank Chadia Elkhatib at Western University for administrating the telephone survey. References 1. Ratti F, Cipriani F, Gagliano A, Catena M, Paganelli M, Aldrighetti L. Defining indications to ALPPS procedure: technical aspects and open issues. Updates Surg 2013;66:41-9. 2. Schadde E, Ardiles V, Slankamenac K, et al. ALPPS offers a better chance of complete resection in patients with primarily unresectable liver tumors compared with conventional-staged hepatectomies: results of a multicenter analysis. World J Surg 2014;38:1510-9. 3. Nadalin S, Capobianco I, Li J, Girotti P, Königsrainer I, Königsrainer A. Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons learned from 15 cases at a single centre. Z Gastroenterol 2014;52:35-42. 4. Torres OJM, Fernandes Ede SM, Oliveira CVC, et al. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): the Brazilian experience. Arq Bras Cir Dig 2013;26:40-3. 5. Li J, Girotti P, Königsrainer I, Ladurner R, Königsrainer A, Nadalin S. ALPPS in right trisectionectomy: a safe procedure to avoid postoperative liver failure? J Gastrointest Surg 2013;17:956-61. 6. 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;255:405-14. 7. Knoefel WT, Gabor I, Rehders A, et al. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013;100:388-94. 8. 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 (ALPPS) procedure in the management of colorectal liver metastases? Surgery 2015;157:194-201. 9. Sala S, Ardiles V, Ulla M, Alvarez F, Pekolj J, de Santibañes E. Our initial experience with ALPPS technique: encouraging results. Updates Surg 2012;64:167-72. 10. Alvarez FA, Ardiles V, de Santibañes M, Pekolj J, de Santibañes 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;261:723-32. 11. Alvarez FA, Ardiles V, Claria RS, Pekolj J, de Santibañes E. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): tips and tricks. J Gastrointest Surg 2012;17:814-21. 12. 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 2013;38:1504-9. 13. Eshmuminov D, Raptis DA, Linecker M, Wirsching A, Lesurtel M, Clavien P-A. Meta-analysis of associating liver partition with portal vein ligation and portal vein occlusion for two-stage hepatectomy: ALPPS versus portal vein occlusion for staged hepatectomy. Br J Surg 2016;103:1768-82. 14. Croome KP, Hernandez-Alejandro R, Parker M, Heimbach J, Rosen C, Nagorney DM. Is the liver kinetic growth rate in ALPPS unprecedented when compared with PVE and living donor liver transplant? A multicentre analysis. HPB (Oxford) 2015;17:477-84. 15. Bertens KA, Hawel J, Lung K, Buac S, Pineda-Solis K, Hernandez-Alejandro R. ALPPS: challenging the concept of unresectability—a systematic review. Int J Surg 2015;13:280-7. 16. Schadde E, Schnitzbauer AA, Tschuor C, Raptis DA, Bechstein WO, Clavien P-A. Systematic review and meta-analysis of feasibility, safety, and efficacy of a novel procedure: associating liver partition and portal vein ligation for staged hepatectomy. Ann Surg Oncol 2015;22:3109-20. 17. Lam VWT, Laurence JM, Johnston E, Hollands MJ, Pleass HCC, Richardson AJ. A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. HPB (Oxford) 2013;15:48-91. 18. Chua TC, Liauw W, Chu F, Morris DL. Summary outcomes of two-stage resection for advanced colorectal liver metastases: two-stage resection of CLM. J Surg Oncol 2013;107:211-6. 19. Aloia TA, Vauthey J-N. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS): what is gained and what is lost? Ann Surg 2012;256:e9. 20. 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;240:205-13. 21. Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A. EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels: EORTC; 2001. 22. Scott NW, Fayers PM, Aaronson NK, et al. EORTC QLQ-C30 Reference Values. Brussels: EORTC Quality of Life Group Publications; 2008. 23. Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol 2016;69:79-88. 24. Gundy CM, Aaronson NK. Effects of mode of administration (MOA) on the measurement properties of the EORTC QLQ-C30: a randomized study. Health Qual Life Outcomes 2010;8:35.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044
ARTICLE IN PRESS K.N. Wanis et al. / Surgery ■■ (2017) ■■–■■
25. Bismuth H, Adam R, Lévi F, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 1996;224: 509-20. 26. Adam R, Laurent A, Azoulay D, Castaing D, Bismuth H. Two-stage hepatectomy: a planned strategy to treat irresectable liver tumors. Ann Surg 2000;232: 777-85. 27. 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: 839-47. 28. 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;260:82938. 29. Shindoh J, Vauthey J-N, Zimmitti G, et al. Analysis of the efficacy of portal vein embolization for patients with extensive liver malignancy and very low future liver remnant volume, including a comparison with the associating liver partition with portal vein ligation for staged hepatectomy approach. J Am Coll Surg 2013;217:126-33. 30. Lang SA, Loss M, Benseler V, Glockzin G, Schlitt HJ. Long-term results after in-situ split (ISS) liver resection. Langenbecks Arch Surg 2015;400: 361-9. 31. Björnsson B, Sparrelid E, Røsok B, et al. Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases—intermediate oncological results. Eur J Surg Oncol 2016;42: 531-7. 32. Wei AC, Greig PD, Grant D, Taylor B, Langer B, Gallinger S. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006;13:668-76.
7
33. House MG, Ito H, Gönen M, et al. Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg 2010;210:744-52. 34. de Jong MC, Pulitano C, Ribero D, et al. Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multiinstitutional analysis of 1669 patients. Ann Surg 2009;250:440-8. 35. Rees JR, Blazeby JM, Fayers P, et al. Patient-reported outcomes after hepatic resection of colorectal cancer metastases. J Clin Oncol 2012;30:1364-70. 36. Langenhoff BS, Krabbe PFM, Peerenboom L, Wobbes T, Ruers TJM. Quality of life after surgical treatment of colorectal liver metastases. Br J Surg 2006;93:1007-14. 37. Rees JR, Blazeby JM, Brookes ST, John T, Welsh FK, Rees M. Patient-reported outcomes in long-term survivors of metastatic colorectal cancer needing liver resection. Br J Surg 2014;101:1468-74. 38. Wiering B, Oyen WJG, Adang EMM, et al. Long-term global quality of life in patients treated for colorectal liver metastases. Br J Surg 2011;98:565-71. 39. Olthof PB, Huiskens J, Wicherts DA, et al. Survival after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for advanced colorectal liver metastases: a case-matched comparison with palliative systemic therapy. Surgery 2017;161:909-19. 40. Wanis KN, Buac S, Linecker M, et al. Patient survival after simultaneous ALPPS and colorectal resection. World J Surg 2017;41:1119-25. 41. Buac S, Schadde E, Schnitzbauer AA, Vogt K, Hernandez-Alejandro R. The many faces of ALPPS: surgical indications and techniques among surgeons collaborating in the international registry. HPB (Oxford) 2016;18:442-8. 42. Linecker M, Bjornsson B, Stavrou GA, et al. Risk adjustment in ALPPS is associated with a dramatic decrease in early mortality and morbidity. Ann Surg 2017;266:779-86.
Please cite this article in press as: Kerollos Nashat Wanis, et al., Intermediate-term survival and quality of life outcomes in patients with advanced colorectal liver metastases undergoing associating liver partition and portal vein ligation for staged hepatectomy, Surgery (2017), doi: 10.1016/j.surg.2017.09.044