COMMENTARY ON TECHNIQUE/CASE REPORT The RAPID Concept—Novel Idea or a Bridge Too Far?
S
urgical resection is the mainstay of curative treatment of colorectal liver metastases (CLMs). Today, 5-year cancer-free survival rates of 55% to 67% are achievable.1 Surgical approaches are often restricted, however, because of unfavorable distribution of tumor deposits or tumor burden in the liver that precludes resection of all disease without compromising the viability and volume of liver left behind. That limitation can be overcome by total hepatectomy and liver transplantation as reported in this Journal 2 years ago by Hagness and colleagues2 from Norway. After orthotopic whole-sized liver grafting for otherwise incurable bilobar CLMs, cancer recurred in 90% of the recipients after a median of 6 months. With aggressive treatment of recurrent disease, the overall 5-year actuarial survival was 60%. That number may excite oncologists, especially those who routinely treat patients with pancreatic, esophageal, and lung cancers, but allocating deceased donor livers for this indication is not regarded as justifiable when survival after transplantation for nonmalignant disease and early-stage hepatocellular carcinoma is superior and so many patients are dying on waiting lists for lack of donated organs. In this issue of Annals of Surgery, Line and colleagues3 from the same Norwegian center report a novel approach that addresses the criticism of an unacceptable use of deceased donor grafts for this indication. Their proposal combines partial orthotopic liver transplantation and staged hepatic resection to treat patients with otherwise unresectable CLMs. They have embarked on a pilot study in which just the left lateral sector of the deceased donor organ (segments 2 and 3) is used for the cancer recipient with the extended right lobe (segments 1, 4–8) allocated to an appropriately size-matched (and presumably priority-listed) recipient. The protocol requires that no suitable child in the Norwegian system would be a potential candidate for the smaller split graft. Thus, no patient on the waiting list is denied a transplant because of their protocol. Briefly, the donor left lateral sector is implanted replacing the resected cancerous recipient left lateral sector, followed by ligation of the right portal vein. After ade-
Disclosure: The authors declare no conflicts of interest. C 2015 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/15/26201-e0010 DOI: 10.1097/SLA.0000000000001269
e10 | www.annalsofsurgery.com
quate hypertrophy of the graft in 2 to 4 weeks, in a second-stage surgery, the deportalized cancerous liver is removed. The authors have named their approach the RAPID (Resection And Partial LIver segment 2/3 transplantation with Delayed total hepatectomy) concept. Their operation has features similar to the recently described ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) procedure to treat patients with bilobar CLMs.4 Hepatic parenchyma is transected along the falciform ligament, and the future liver remnant segments 2 and 3 are cleared from tumors with partial resections as needed. The right portal vein is ligated to stimulate and accelerate liver regeneration. In a second operation 1 or 2 weeks later, the deportalized liver is removed when an acceptable volume of the future liver remnant is achieved.5 The pronounced and quick hypertrophy of the left lateral sector seen in the RAPID concept is similar to what has been documented in the ALPPS procedure.6,7 In both procedures, insufficient size of the left lateral segment at the time of the first operation is thus overcome. It is assumed that the liver injury in combination with portal flow manipulation and the patient’s metabolic demands activate growth factors that play a key role in hepatic regeneration.8 The 1- and 2-year actuarial diseasefree survival (DFS) in the ALPPS registry for patients with CLMs is 59% and 41%, respectively, with a median DFS of 14 months.6 This DFS may be a better comparison for the RAPID concept than for the results of palliative chemotherapy. Presumably, candidates for the RAPID protocol would not be suitable for an ALPPS procedure because of the extent of tumor involvement of the left lateral sector. The single patient described in the RAPID report is not the ideal index case. His rectal primary was locally advanced (he received neoadjuvant chemoradiation), and 2 metastatic lung nodules were already present, which presumably were going to be resected after he recovered from the liver operations. The authors previously reported that the largest tumor diameter and a low carcinoembryonic antigen level were predictors of better survival.2 Curiously, they do not provide those details on this patient. But if we put that aside for the moment and accept that at least theoretically more ideal candidates could be chosen, that is, disease confined to the liver after confident extirpation of the primary, low carcinoembryonic antigen level, etc, then the authors have demonstrated the feasibility of their approach from a purely anatomic and physiologic standpoint. Clearly there are many complexities to the RAPID treatment. The surgery is technically challenging, the commitment of resources is
extensive, and the entire concept is dependent upon the uncertain and unpredictable availability of a deceased donor graft. Acknowledging those concerns, the essential question then is what will be the survival of the patients who participate in this RAPID pilot project. It is not logical to expect that it will any better than what the authors previously reported with whole grafts for CLMs. Indeed, it could be worse because, as the authors point out, administering immunosuppression during those several weeks between the staged hepatectomy in a recipient with a high tumor burden could increases the risk of tumor growth and spread. This could prove to be a fatal flaw in the RAPID concept. Simultaneous adjuvant chemotherapy would not be practical during this period, and it would still be tricky later in the immunocompromised patient. The protocol includes switching from tacrolimus to rapamycin after the first month because of its antineoplastic effect, but there are no certainties there. If given the option of receiving palliative chemotherapy for 12 to 18 months or having an elaborate procedure that would provide the opportunity of surviving for 5 years, even if the chance of cure was remote, many patients would opt for the latter. This then becomes the argument for “properly selected” patients. The recruitment of suitable candidates to this pilot study would be enhanced if the protocol could be tightened as in an oncologic trial. For example, using a defined course of neoadjuvant chemotherapy with strict objectives of response in the absence of extra hepatic disease, followed by timely surgery. The last point is perhaps the reason that the authors warn against the thought of using living donors in the RAPID study. Emergency surgery would become elective surgery. There would be ample time for preoperative imaging and adoption of scientifically sound neoadjuvant chemotherapy. Undoubtedly, donors would come forward to donate, especially when they would be donating “just” the left lateral sector. Notwithstanding all the practical advantages that living donors would provide, the authors correctly emphasize that it would not be appropriate to consider them for this pilot study. Line and colleagues have proposed a treatment option for patients with incurable cancer that combines anatomy, physiology, and biology in a unique human experiment. Is it a brave new world that they have introduced to us, one in which victims of cancer may be given hope of meaningful survival? Or, is their proposal a bridge too far, too unrealistic, and destined to fail? There are so many controversial aspects to this concept that it is tempting to discard it outright, were it not for the fact that thousands of patients with CLMs would conceivably be candidates for it. The
Annals of Surgery r Volume 262, Number 1, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 1, July 2015
end point of their study surely has to be DFS. A 90% cancer recurrence rate at 6 months will not convince the transplant community to embrace the RAPID concept. As the authors have stated, their center alone should accrue an experience that will provide data that will be used to judge this innovative approach. Until then, it would be unwise for other centers to adopt the RAPID concept, and it would be wrong to subject living donors to this undertaking. Roberto Hernandez-Alejandro, MD, FRCS(C) Department of Surgery & Oncology Western University, Canada London Health Sciences Centre London, Ontario, Canada [email protected]
Commentary
William J. Wall, MD, FRCS(C) Department of Surgery Western University, Canada London, Ontario, Canada
REFERENCES 1. Andreou A, Aloia TA, Vauthey JN, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257:1079–1088. 2. Hagness M, Foss A, Line P-D, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg. 2013;257:800–806. 3. Line P-D, Hagness M, Berstad A, et al. A novel concept for partial liver transplantation in nonresectable colorectal liver metastases: the RAPID concept. Ann Surg. 2015;262:e5–e9. 4. De Santiba˜nes E, Clavien P-A. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012;255:415–417.
C 2015 Wolters Kluwer Health, Inc. All rights reserved.
5. 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;255:405–414. 6. Schadde E, Ardiles V, Hernandez-Alejandro R, et al. Early survival and safety of ALPPS: first report of the International ALPPS registry. Ann Surg. 2014;260:829–836. 7. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, et al. 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. 8. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–846.
www.annalsofsurgery.com | e11
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
S
urgical resection is the mainstay of curative treatment of colorectal liver metastases (CLMs). Today, 5-year cancer-free survival rates of 55% to 67% are achievable.1 Surgical approaches are often restricted, however, because of unfavorable distribution of tumor deposits or tumor burden in the liver that precludes resection of all disease without compromising the viability and volume of liver left behind. That limitation can be overcome by total hepatectomy and liver transplantation as reported in this Journal 2 years ago by Hagness and colleagues2 from Norway. After orthotopic whole-sized liver grafting for otherwise incurable bilobar CLMs, cancer recurred in 90% of the recipients after a median of 6 months. With aggressive treatment of recurrent disease, the overall 5-year actuarial survival was 60%. That number may excite oncologists, especially those who routinely treat patients with pancreatic, esophageal, and lung cancers, but allocating deceased donor livers for this indication is not regarded as justifiable when survival after transplantation for nonmalignant disease and early-stage hepatocellular carcinoma is superior and so many patients are dying on waiting lists for lack of donated organs. In this issue of Annals of Surgery, Line and colleagues3 from the same Norwegian center report a novel approach that addresses the criticism of an unacceptable use of deceased donor grafts for this indication. Their proposal combines partial orthotopic liver transplantation and staged hepatic resection to treat patients with otherwise unresectable CLMs. They have embarked on a pilot study in which just the left lateral sector of the deceased donor organ (segments 2 and 3) is used for the cancer recipient with the extended right lobe (segments 1, 4–8) allocated to an appropriately size-matched (and presumably priority-listed) recipient. The protocol requires that no suitable child in the Norwegian system would be a potential candidate for the smaller split graft. Thus, no patient on the waiting list is denied a transplant because of their protocol. Briefly, the donor left lateral sector is implanted replacing the resected cancerous recipient left lateral sector, followed by ligation of the right portal vein. After ade-
Disclosure: The authors declare no conflicts of interest. C 2015 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/15/26201-e0010 DOI: 10.1097/SLA.0000000000001269
e10 | www.annalsofsurgery.com
quate hypertrophy of the graft in 2 to 4 weeks, in a second-stage surgery, the deportalized cancerous liver is removed. The authors have named their approach the RAPID (Resection And Partial LIver segment 2/3 transplantation with Delayed total hepatectomy) concept. Their operation has features similar to the recently described ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) procedure to treat patients with bilobar CLMs.4 Hepatic parenchyma is transected along the falciform ligament, and the future liver remnant segments 2 and 3 are cleared from tumors with partial resections as needed. The right portal vein is ligated to stimulate and accelerate liver regeneration. In a second operation 1 or 2 weeks later, the deportalized liver is removed when an acceptable volume of the future liver remnant is achieved.5 The pronounced and quick hypertrophy of the left lateral sector seen in the RAPID concept is similar to what has been documented in the ALPPS procedure.6,7 In both procedures, insufficient size of the left lateral segment at the time of the first operation is thus overcome. It is assumed that the liver injury in combination with portal flow manipulation and the patient’s metabolic demands activate growth factors that play a key role in hepatic regeneration.8 The 1- and 2-year actuarial diseasefree survival (DFS) in the ALPPS registry for patients with CLMs is 59% and 41%, respectively, with a median DFS of 14 months.6 This DFS may be a better comparison for the RAPID concept than for the results of palliative chemotherapy. Presumably, candidates for the RAPID protocol would not be suitable for an ALPPS procedure because of the extent of tumor involvement of the left lateral sector. The single patient described in the RAPID report is not the ideal index case. His rectal primary was locally advanced (he received neoadjuvant chemoradiation), and 2 metastatic lung nodules were already present, which presumably were going to be resected after he recovered from the liver operations. The authors previously reported that the largest tumor diameter and a low carcinoembryonic antigen level were predictors of better survival.2 Curiously, they do not provide those details on this patient. But if we put that aside for the moment and accept that at least theoretically more ideal candidates could be chosen, that is, disease confined to the liver after confident extirpation of the primary, low carcinoembryonic antigen level, etc, then the authors have demonstrated the feasibility of their approach from a purely anatomic and physiologic standpoint. Clearly there are many complexities to the RAPID treatment. The surgery is technically challenging, the commitment of resources is
extensive, and the entire concept is dependent upon the uncertain and unpredictable availability of a deceased donor graft. Acknowledging those concerns, the essential question then is what will be the survival of the patients who participate in this RAPID pilot project. It is not logical to expect that it will any better than what the authors previously reported with whole grafts for CLMs. Indeed, it could be worse because, as the authors point out, administering immunosuppression during those several weeks between the staged hepatectomy in a recipient with a high tumor burden could increases the risk of tumor growth and spread. This could prove to be a fatal flaw in the RAPID concept. Simultaneous adjuvant chemotherapy would not be practical during this period, and it would still be tricky later in the immunocompromised patient. The protocol includes switching from tacrolimus to rapamycin after the first month because of its antineoplastic effect, but there are no certainties there. If given the option of receiving palliative chemotherapy for 12 to 18 months or having an elaborate procedure that would provide the opportunity of surviving for 5 years, even if the chance of cure was remote, many patients would opt for the latter. This then becomes the argument for “properly selected” patients. The recruitment of suitable candidates to this pilot study would be enhanced if the protocol could be tightened as in an oncologic trial. For example, using a defined course of neoadjuvant chemotherapy with strict objectives of response in the absence of extra hepatic disease, followed by timely surgery. The last point is perhaps the reason that the authors warn against the thought of using living donors in the RAPID study. Emergency surgery would become elective surgery. There would be ample time for preoperative imaging and adoption of scientifically sound neoadjuvant chemotherapy. Undoubtedly, donors would come forward to donate, especially when they would be donating “just” the left lateral sector. Notwithstanding all the practical advantages that living donors would provide, the authors correctly emphasize that it would not be appropriate to consider them for this pilot study. Line and colleagues have proposed a treatment option for patients with incurable cancer that combines anatomy, physiology, and biology in a unique human experiment. Is it a brave new world that they have introduced to us, one in which victims of cancer may be given hope of meaningful survival? Or, is their proposal a bridge too far, too unrealistic, and destined to fail? There are so many controversial aspects to this concept that it is tempting to discard it outright, were it not for the fact that thousands of patients with CLMs would conceivably be candidates for it. The
Annals of Surgery r Volume 262, Number 1, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 262, Number 1, July 2015
end point of their study surely has to be DFS. A 90% cancer recurrence rate at 6 months will not convince the transplant community to embrace the RAPID concept. As the authors have stated, their center alone should accrue an experience that will provide data that will be used to judge this innovative approach. Until then, it would be unwise for other centers to adopt the RAPID concept, and it would be wrong to subject living donors to this undertaking. Roberto Hernandez-Alejandro, MD, FRCS(C) Department of Surgery & Oncology Western University, Canada London Health Sciences Centre London, Ontario, Canada [email protected]
Commentary
William J. Wall, MD, FRCS(C) Department of Surgery Western University, Canada London, Ontario, Canada
REFERENCES 1. Andreou A, Aloia TA, Vauthey JN, et al. Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy. Ann Surg. 2013;257:1079–1088. 2. Hagness M, Foss A, Line P-D, et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg. 2013;257:800–806. 3. Line P-D, Hagness M, Berstad A, et al. A novel concept for partial liver transplantation in nonresectable colorectal liver metastases: the RAPID concept. Ann Surg. 2015;262:e5–e9. 4. De Santiba˜nes E, Clavien P-A. Playing Play-Doh to prevent postoperative liver failure: the “ALPPS” approach. Ann Surg. 2012;255:415–417.
C 2015 Wolters Kluwer Health, Inc. All rights reserved.
5. 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;255:405–414. 6. Schadde E, Ardiles V, Hernandez-Alejandro R, et al. Early survival and safety of ALPPS: first report of the International ALPPS registry. Ann Surg. 2014;260:829–836. 7. Hernandez-Alejandro R, Bertens KA, Pineda-Solis K, et al. 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. 8. Schlegel A, Lesurtel M, Melloul E, et al. ALPPS: from human to mice highlighting accelerated and novel mechanisms of liver regeneration. Ann Surg. 2014;260:839–846.
www.annalsofsurgery.com | e11
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
