The treatment of patients with unresectable cholangiocarcinoma (CCA) presents exceptional and challenging problems to the hepatologist and hepatobiliary surgeon alike. Unlike hepatocellular carcinoma (HCC), effective screening does not exist for CCA. Because of the often advanced nature at presentation, the majority of patients must contend with the inevitable consequences of biliary obstruction, cholangitis, and death soon after diagnosis. With the lack of effective chemotherapy regimens, many clinicians have historically taken a nihilistic approach to the treatment of unresectable hilar CCAs, and survival in patients has typically been measured on the order of months. Most therapies have been palliative in nature with results often discouraging. Not to be excluded is the historical experience with liver transplantation. The University of Pittsburgh was the first to report a disappointing 3-year survival (20%) and prohibitive recurrence (57%) in patients with CCA undergoing transplantation (1), an experience that was echoed by Meyer and Penn in their report from the Cincinnati Transplant Tumor Registry (2). Studies as recent as 2004 are strikingly similar, with a Scandinavian report detailing a 30% 5-year survival for patients transplanted for early CCA arising in the setting of PSC (3).
In 2005, Rea et al. (4) published a follow-up to two earlier studies examining the results of an innovative treatment protocol for patients with stage I and II hilar CCAs (5, 6). In an experience spanning over 10 years, this study examined outcomes in the patients with CCA treated with orthotopic liver transplant (OLT) preceded by neoadjuvant chemoradiation and was the first of its kind to include a contemporary resection group for comparison. Designed to limit the likelihood of local recurrence and tumor dissemination at the time of transplant, the protocol mentioned in the study by Rea et al. achieved 1, 3, and 5 year patient survival rates of 92%, 82%, and 82%, respectively. These results are difficult to ignore, especially in light of historical comparisons. By setting forth criteria by which CCA could be transplanted successfully, the impact of this report can be similar to the study by Mazzaferro et al. (7) in 1996 detailing transplant outcomes in patients with small HCCs.
Although retrospective, the study by Rea et al. includes a meaningful comparison cohort of patients who underwent standard resection, thereby providing a perspective by which to view their results. There are, of course, inherent difficulties in comparing outcomes between unresectable (transplant cohort) and resectable patients. Still, not only was there significant improvement in survival at all time points in patients receiving a transplant, but also the average time to cancer recurrence was significantly longer in the transplant group when compared with the resection group (4). Attempts at direct comparisons between patients treated with resection versus transplantation are further complicated by the lack of neoadjuvant therapy in the resection cohort, the younger age of the transplant group, and the fact that all transplant patients had node negative disease removed by R0 resection (8). Some authors would point to the higher rate of PSC in the transplant group as a potential selection bias (8), despite the fact that transplantation for de novo CCA still demonstrated a clear survival benefit.
These concerns are warranted, but other reports tend to corroborate the Mayo data. Recently, Becker et al. (9) used the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network database to identify 280 patients with CCA treated with OLT over an 18-year period. Although the UNOS/Organ Procurement and Transplantation Network database lacks details regarding the use of neoadjuvant therapy, the authors noted overall 1- and 5-year patient survival rates of 74% and 38%, but also improvements in outcomes over time, such that the 3-year survival rate in patients transplanted after 2000 was 68% (9). Because CCA is currently a contraindication to transplantation in the absence of neoadjuvant therapy, it is most likely that the majority of these patients received such treatment. Interestingly, patients with an incidental finding of CCA, and presumably earlier disease, had significantly worse outcomes. Implicit in this finding is the impact of neoadjuvant protocols, as the 5-year survival for patients with known (and potentially more advanced) CCA was 68% (9). Added to this is the 2002 report by Sudan et al. (10) examining the experience at Nebraska, which also demonstrates a survival benefit. In contradistinction, Robles et al. (11) examined the recent Spanish experience in the absence of neoadjuvant therapy. With a 5-year survival rate of only 30%, results were on par with historical comparators lacking the neoadjuvant component (11). Taken together, these studies provide strong evidence that selected CCA patients treated with OLT experience a survival benefit (9, 10). Furthermore, they underscore the inclusion of neoadjuvant therapy as a major determinant in achieving optimal outcomes (9–11). Indeed, without appropriate neoadjuvant therapy, liver transplantation for CCA should be contraindicated.
The unexpected success of these combined results astonished many in the liver transplant community. They were greeted with cautious optimism by others familiar with early transplant outcomes for this disease, many of whom remain engaged in valiant, but disheartening attempts to render treatment to patients who carry this diagnosis. The results of these contemporary studies certainly invoke the possibility that CCA, especially if detected early, may not always foreshadow a dismal outcome. Just as Mazzaferro’s study ultimately effected a change in organ allocation policy by providing criteria for successful outcomes in patients with HCC (7), the availability of contemporary outcomes data on CCA affords us a unique opportunity to develop guidelines by which this malignancy may evolve as a universally accepted indication for liver transplantation.
Accordingly, criteria for model for end-stage liver disease (MELD) exception for liver transplant candidates with CCA was first proposed in 2006 by Gores et al. (12). In an attempt to establish uniformity for centers seeking MELD exceptions for their patients, diagnostic criteria for hilar CCA were based on tumor size less than 3 cm, the findings of a malignant-appearing stricture confirmed by biopsy or cytology, an elevated CA 19–9 level more than 100 U/mL, or evidence of aneuploidy (12). Unresectability was predicated on technical considerations or the presence of intrinsic liver disease (12). Exclusion of regional lymph node and peritoneal involvement was required by operative staging after completion of neoadjuvant therapy (12). Finally, and perhaps most importantly, centers were required to submit a written summary, detailing their diagnostic, treatment, and selection protocols to the UNOS Liver and Intestinal Committee before seeking a MELD exception (12). From this, it was proposed that patients meeting established criteria be granted a MELD score exception equivalent to 10% mortality at 3 months, increased by a 10% mortality equivalent at 3-month intervals (12).
Guidelines such as these provide an interesting point of departure for discussion of trends in organ allocation policy as they pertain to CCA, where, at the national level, only 2 of 11 UNOS regions have standardized their criteria to accept patients for transplantation (13). Because of regional referral patterns within the Intermountain West, the University of Utah’s Huntsman Cancer Center currently sees ∼25 patients a year with hilar CCA, many of which are unresectable. The existence of this population along with the increasing number of patients with primary sclerosing cholangitis seen in our gastroenterology and hepatology practices served as the impetus for protocol development at our institution to facilitate liver transplantation in patients with hilar CCA. Based on the Mayo algorithm, ours became one of only a handful of programs in the country offering potentially curative treatment to this patient population previously devoid of hope.
At the present time, a variance implemented in March 2006, within UNOS Region 5 permits patients harboring a diagnosis of hilar CCA to petition the Regional Review Board for an upgraded MELD score of 22 providing an IRB-approved neoadjuvant protocol has been established at their listing institution. Patients falling within strictly defined criteria (stages I and II) are eligible for quarterly 10% upgrades similar to those granted to patients with HCC falling within Milan criteria. Currently, a similar policy exists within UNOS region 4. An agreement within UNOS region 7 limits patients to an initial MELD upgrade of 20 and subsequent upgrades every 6 months. The region 5 variance provides more initial points and a shorter interval for MELD upgrades. However, the existence of 20 liver transplant centers in a region home to one sixth of the U.S. population tends to mitigate many of the benefits seen with this more liberal policy.
Our protocol began in March of 2007 after an extended period of scrutiny by our institutional review board. Since its inception, our program has transplanted four individuals (three adults, one adolescent). All four have received neoadjuvant chemoradiation. At the conclusion of the neoadjuvant therapy, the adults underwent staging laparotomy to rule out the presence of N2 disease. After the first 2 enrollees, PET scanning was added as part of the initial evaluation and the staging laparotomy was timed to coincide with the transplant operation itself. The first adult was transplanted after a wait-list time of 307 days, the second after one full calendar year. Although not reaching statistical significance, Heimbach et al. (14) recently demonstrated in their follow-up to the initial Mayo series, a trend toward increasing risk of recurrence after transplantation coinciding with increasing interval from staging to transplant (>100 days). To place this in the proper perspective, patients in Region 5 as of this writing are transplanted at an average MELD of 29.5 (15) and a patient with a MELD of 22 can expect a median wait time of 489 days (16), the current Region 5 variance may ultimately compromise attempts to influence the course of this disease by allowing a protracted interval during which disease could progress.
Increasingly, it is becoming apparent that to impact the course of this disease, patients and will be forced to accept transplantation with a marginal deceased donor liver or resort to the use of a living donor as a consensus on the use of deceased donor livers remains elusive. This is due, at least in part, to the well-documented history in which patients with CCA failed to benefit from OLT. Early experiences with transplantation for this disease must be acknowledged. However, most failed to discriminate between intrahepatic and hilar CCAs (17–22). More importantly, the emerging evidence in well-selected patients strongly suggests that outcomes may improve in OLT when preceded by neoadjuvant chemoradiation (4).
Some may conclude that the rigorous selection process contributed to the excellent results seen in the Mayo study, where 38 of 71 patients entering the neoadjuvant protocol eventually underwent transplant (4). However, 9 patents died before staging due to complications of therapy and 10 additional patients were awaiting transplant at the time of the report, making such assertions difficult to substantiate. In transplanted cases, pathological examination failed to detect residual disease in 16 of the 38 explants (1), perhaps inferring propitious outcomes merely reflected strict inclusion criteria favoring those with early stage disease. Even so, when neoadjuvant therapy is used to treat epithelial malignancies, the lack of measurable disease in the resection specimen is a regular occurrence (23–26) regardless of stage. Rather than suggesting a negative connotation, the lack of measurable disease is likely indicative of the efficacy and potency of the chemoradiation used, often portending a more favorable prognosis (23–26).
Despite the difficulties with retrospective reviews, the survival data dealing with OLT and CCA are compelling. Although existing studies have largely defined the toxicity and feasibility of the neoadjuvant approach to these tumors (4), the desire for more robust data is understandable. Unfortunately, most single-institution studies will fail to accrue adequate patient numbers for a robust phase III trial. Similarly, multicenter data may be difficult to acquire and even more difficult to interpret given the variability of drug type and dose, duration of treatment, fractionation of radiation, and methods of delivery of the brachytherapy boost among various programs. We know that many of these neoadjuvant therapies are effective in eradicating tumor, but the frequent lack of residual disease diminishes our capacity to measure tumor response. The only objective endpoints that can be validated are disease-free and overall survival. Survival results must then, in turn, be compared with standard of care. Studies involving surgical resection for hilar CCA exist in relative abundance (19, 20, 27–36) with modern studies demonstrating improved long-term survival, due in part to enhanced patient selection (27, 37). However, these results continue to fall short of those obtained with OLT (4) and only one third of patients presenting with hilar CCA are actually eligible for an attempt at surgical resection (27). Likewise, many patients with CCA are simply not standard resection candidates due to their intrinsic liver disease. Finally, the concept of a randomized trial involving early non-resectable hilar CCA (neoadjuvant therapy+transplantation vs. palliation) seems unproductive and somewhat nonsensical.
So, how do we continue to move the field forward? First, we must recognize that HCC and CCA are not equivalent. The same ablative techniques and local-regional therapies that are effective for HCC do not exist for the CCA patient. Second, we need to follow outcomes prospectively for those treated as standard of care, perhaps through the creation of a centralized data registry. Next, we must decide whether a second single institution series like the one published by Rea et al. is necessary and sufficient to effect a change in nationwide organ allocation policy or whether a multi-institutional trial will be needed. If the latter is chosen, those interested in the field should standardize treatment approaches and move forward with multi-institutional phase II and III studies orchestrated from a central location.
The Mayo protocol represents the first significant advance in cancer therapy for what many consider a uniformly fatal disease, and we believe that additional research should be pursued aggressively. In the meantime, as we contemplate expanding the indications for OLT in the setting of a severe organ shortage, it is important that we not overlook a potentially effective form of therapy for a previously untreatable disease. Offering hope to patients without available standard treatment is part of what fulfills our mission as transplant physicians. In this regard, liver transplantation for CCA should continue–in the context of an allocation system that reflects patient disease factors, regional MELD scores, and waiting times.
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