Neoadjuvant Chemoradiotherapy Followed by Liver Transplantation for Hilar CCA
Julie Heimbach, MD, FACS
Associate Professor of Surgery, Surgical Director of Liver Transplantation, Mayo Clinic, Rochester, MN
There is no effective systemic chemotherapy for hilar cholangiocarcinoma (CCA). Radiation may provide palliation and in exceptional cases, prolong survival. Therefore, the primary therapy for hilar CCA is resection. Outcomes for resection of hilar CCA are limited by the challenge of obtaining a timely and accurate diagnosis. Many patients present with unresectable lesions due to extension into the liver and/or hilar blood vessels; such patients have very few options. Due to the limitations of pre-operative diagnosis and staging (CCA is a desmoplastic lesion, making it difficult to obtain cytology and visualize the lesion on pre-operative imaging), a complete resection is possible in only 70 percent to 80 percent of attempted resections. In most series, five-year survival is approximately 25 percent to 30 percent.
Recent resection data for CCA have included techniques such as vascular reconstruction and pre-operative portal vein embolization of the affected lobe to induce hypertrophy in the segment that the therapeutic team is planning to retain after resection. Such treatments have led to survival rates of 35 percent to 45 percent for patients with resectable lesions.1-7
An option for those with unresectable hilar CCA
Liver transplantation was initially proposed as the ideal treatment for patients with hilar CCA that could not be resected, either due to underlying primary sclerosing cholangitis (PSC) or involvement of bilateral hilar structures that precluded complete removal of the tumor. The outcome with liver transplantation alone was uniformly disappointing due to a high incidence of disease recurrence and subsequent mortality.8-11 Currently, patients with hilar CCA are generally considered to be ineligible for liver transplantation.
A protocol for treatment of unresectable hilar CCA combining neoadjuvant external beam radiation therapy (EBRT) with 5-FU chemo-sensitization, followed by brachytherapy, staging laparotomy and subsequent liver transplantation, was undertaken at Mayo Clinic (figure 1).12 A similar protocol employing higher dose brachytherapy without EBRT was performed at the University of Nebraska.13 Following brachytherapy, patients receive oral capecitabine (2,000 mg/m2 per day, two out of every three weeks) as tolerated until transplantation. The rationale for this aggressive approach is that high-dose neoadjuvant therapy is used to devitalize the tumor and decrease the likelihood of tumor spread while awaiting transplantation. Complete hepatectomy followed by transplantation removes any residual tumor and addresses any liver injury resulting from radiation and/or the antecedent PSC.
Outcomes of neoadjuvant therapy and liver transplantation
The most recently published survival data on neoadjuvant therapy followed by orthotopic liver transplantation (OLT) for CCA report outcomes on 111 patients through September 2008; survival is 72 percent at five years.14 Survival data through May 2009, including 119 patients, are similar and are shown in figure 2. These results are slightly superior to the most recent overall expected five-year patient survival following liver transplantation for all indications, reported by the Scientific Registry of Transplant Recipients (67.6 percent), and are similar to unadjusted five-year survival for patients with cholestatic liver disease (74.3 percent).15 For patients with essentially no other treatment options, these results are excellent.
Though patient survival following the combined protocol for treatment of hilar CCA is similar to that for other indications for liver transplantation, the toxicity of the treatment is significant. Early effects of neoadjuvant therapy include cholangitis, sepsis, duodenal ulceration and impaired gastric motility. The intra-operative challenges attributable to the neoadjuvant therapy include severe inflammatory changes and dense fibrosis leading to difficulty identifying and separating hilar structures. Late effects include vascular strictures secondary to radiation injury, which can be managed either by use of arterial interposition grafts in all cases of deceased donor transplant to avoid the radiated artery, or by endovascular treatments for strictures of the portal vein (and non-replaced arteries, as in the case of a living donor transplant).16 Despite aggressive neoadjuvant treatment, disease recurrence following transplant occurs in ~15 percent.17
Comparing outcomes for patients who undergo a liver transplantation protocol for hilar CCA versus those who undergo resection is imperfect because the OLT protocol has been restricted to patients with unresectable primary lesions with negative lymph nodes, while data from patients undergoing surgical resection involves resectable primary lesions including some with positive lymph nodes. Rea, et al. compared outcomes of 38 patients undergoing OLT for unresectable hilar CCA from 1993 to 2002 versus all patients who underwent resection of hilar CCA at the same institution during the same period. Five-year survivals were 82 percent after transplantation versus 21 percent five-year survival after resection.18 A significant survival benefit for transplantation versus resection was seen in patients with PSC and de novo CCA.
Limitations of the transplant protocol (neoadjuvant therapy plus OLT)
The current data demonstrate excellent outcomes for neoadjuvant therapy followed by OLT in highly selected patients at experienced centers. However, each component of this statement must be carefully considered:
1. Neoadjuvant therapy is associated with toxicities, including recurrent cholangitis, gastric and duodenal ulceration, decompensation of underlying liver disease, and failure to thrive during a prolonged wait to transplantation.
2. Liver transplantation is a major operation performed at a transplant center, requires life-long immunosuppression and long-term follow-up, and requires a donor organ.
3. Selected patients: it is still unknown whether resection of regional lymph nodes at the time of OLT provides benefit, particularly in the setting of immunosuppression required after transplantation. Given the severe donor organ shortage, liver transplantation should only be offered in a setting where outcomes are expected to be excellent. More efficacious systemic therapy is greatly needed.
4. Experienced centers: the current outcomes originate from a few centers that have applied a rigorous approach. Transplantation alone provides little benefit, and there is concern that, as the protocol is more widely used, some centers may apply a less rigorous approach such as less aggressive neoadjuvant regimen, inadequate staging or application for lesions which are intra-hepatic or in the distal bile duct. Outcomes may be inferior to current data.
Conclusions
The neoadjuvant chemoradiotherapy followed by OLT protocol offers hope and the possibility of excellent long-term outcomes for patients with unresectable hilar CCA who previously had essentially no other options. Timely diagnosis remains a key challenge regardless of whether the patient undergoes resection or transplantation. Given the severe donor organ shortage, continued analysis of outcomes is essential in order to identify patients not likely to gain benefit from this aggressive protocol. As the chemoradiotherapy-OLT protocol is introduced in other centers, the key principles to achieve successful outcomes are the multi-disciplinary approach involving neoadjuvant therapy, pre-transplant staging and inclusion of patients with hilar CCA without metastases. |
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