ABSTRACT: The prognosis of patients with biliary cancers is poor. Although surgery is potentially curative in selected patients, local recurrence is a common pattern of failure. Adjuvant or neoadjuvant radiation therapy improves local control and possibly survival. In locally advanced patients, radiation therapy provides palliation and may prolong survival. Concurrently administered chemotherapy may further enhance these results. Newer radiation therapy techniques, including intraluminal transcatheter brachytherapy, intraoperative radiation therapy, intensity-modulated radiation therapy, and three- and four-dimensional treatment planning, permit radiation dose escalation without significant increases in normal tissue toxicity, thereby increasing the effective radiation dose. Preliminary results of studies employing hepatic transplantation with radiation therapy are encouraging. Although these new approaches hold promise, the prognosis in patients with biliary cancers remains poor, and the integration of novel therapeutic strategies is indicated.
Carcinomas of the gallbladder and biliary system are rare, with an estimated 8,570 cases occurring in the United States in 2006. Because the majority of patients with biliary cancers present with unresectable or metastatic disease, the overall 5-year survival rate is less than 10%.[2,3] Surgery is the only potentially curative treatment for patients with biliary carcinoma; however, only 10% to 35% of patients are potential candidates for surgery at presentation.[4-6] In resected patients, outcome is closely associated with the pathologic findings of depth of tumor penetration and nodal metastases.
For patients resected for cure, the prognosis remains poor with high local failure rates and associated morbidity and mortality.[7,8] Given these poor outcomes, further therapy should be considered in management. However, the role of adjuvant radiation therapy and chemotherapy in resected patients is poorly defined given the rarity of this malignancy, low resection rates, and physician's therapeutic nihilism.
Importance of Local Tumor Control
Surgery is the only curative treatment modality in the management of patients with primary carcinoma of the gallbladder and bile duct cancer. Unfortunately, this subset constitutes only 10% to 35% of patients, with the overwhelming majority of patients presenting with locally advanced or metastatic disease. In patients undergoing "curative" resection, approximately half will experience local recurrence, resulting in death from biliary obstruction, sepsis, and/or liver failure. Therefore, patients with gallbladder and biliary carcinomas are frequently treated palliatively. Survival rates are poor, ranging from 2 to 3 months in patients receiving medical management alone, 6 to 12 months for those undergoing surgical palliation, and 12 to 22 months for resected patients. Overall 5-year survival remains dismal at less than 10%.
The optimal radiation dose and schedule in the adjuvant and "definitive" treatment of biliary malignancies is unknown. Current practice guidelines are derived from nonrandomized and single-institution experiences, with selection bias favoring high-dose treatment in good performance patients.[11,12]
Investigators from Hospital Lyon in France reported that patients receiving doses ≥ 40 Gy experienced median survivals of 22 months vs 10 months in patients receiving ≤ 35 Gy. Similarly, University of Pittsburgh investigators found that patients receiving radiation doses ≥ 45 Gy had improved median survival compared to those receiving < 45 Gy (11 vs 4.4 months). Similar data were reported from Thomas Jefferson University investigators who retrospectively stratified patients by total radiation dose ≤ 55 Gy or > 55 Gy. In this study, patients received combined external-beam radiation therapy (EBRT) as well as iridium (Ir)-192 brachytherapy. For patients receiving ≤ 55 Gy, median survival was 6 months and the 2-year survival rate was 0%, whereas for patients treated to > 55 Gy, these figures were 24 months and 48%. Median survival increased with escalating doses.
In contrast, investigators from the University of Amsterdam showed no benefit to doses > 55 Gy compared to patients receiving ≤ 55 Gy. Interpretation of these study results are complicated by heterogeneous disease stages, patient performance status, and variety of radiation therapy techniques and doses.
The role of radiation therapy for patients with resected cholangiocarcinoma is controversial. Pattern-of-failure analyses suggest that local failure following resection is common and the use of adjuvant radiation therapy is rational. Single-institution studies have attempted to clarify the role of adjuvant EBRT in resected patients and are discussed below.
An early study from the Massachusetts General Hospital reported the results of 13 patients following resection with curative intent. Patients receiving radiation therapy after surgery experienced a longer median survival (32 months) vs the nontreated cohort (13 months). Duke University investigators recently analyzed the outcome of 22 patients with localized gallbladder carcinoma undergoing resection and adjuvant radiation therapy. Patients undergoing radical resection had improved survival compared to patients undergoing a simple cholecystectomy. Estimated 5-year survival for the entire cohort was 37%, which compared favorably to reported surgery alone results for similar patients.
An EORTC (European Organization for Research and Treatment of Cancer) series retrospectively reviewed 112 patients with Klatskin tumors (tumors arising at the common hepatic duct bifurcation) and found a statistically improved survival in patients treated with resection and postoperative radiotherapy vs those with resection only (median survival: 19 vs 8.3 months; 3-year survival: 31% vs 10%).
Investigators from Johns Hopkins Hospital described 96 patients with proximal cholangiocarcinoma treated surgically (41% curative resection, 14% noncurative resection, 45% palliative stenting). Overall, 66% of patients received postoperative EBRT. Patients undergoing gross total or subtotal resection had improved survival vs patients undergoing stenting only. The 1-, 3-, and 5-year survival rates in the resection group were 66%, 21%, and 8%, respectively, compared to 27%, 6%, and 0%, respectively, in the stenting-alone group. Improved 2-year survival was observed in stented patients receiving EBRT vs patients treated with stent only (10% vs 0%). Additionally, 5-year survival in resected patients receiving adjuvant radiotherapy was 16% vs 0% with resection alone.
In a report from the University of Amsterdam, 112 patients underwent resection of hilar cholangiocarcinoma. Of the 91 patients surviving postoperatively, 20 patients had no additional treatment, 30 patients EBRT only, and 41 patients combined EBRT and intraluminal brachytherapy. Patients receiving adjuvant radiotherapy experienced an improved median survival compared to those receiving no additional treatment (24 vs 8 months). The authors concluded that radiotherapy following resection of hilar cholangiocarcinoma improved survival, although there was no apparent benefit of intraluminal brachytherapy.
Investigators from the University of California at San Francisco described the outcome of 129 patients who underwent resection for bile duct carcinoma. Forty-five received EBRT and 22 received charged-particle radiation therapy. Median survival for surgery alone, surgery/EBRT and surgery/particle therapy was 6.5, 11, and 14 months, respectively.
In contrast to previous reports, a follow-up study from Johns Hopkins investigators detailed a prospective, nonrandomized analysis of patients with perihilar cholangiocarcinoma. Fifty patients underwent resection or palliative decompression for localized disease. Radiotherapy was delivered as EBRT alone or EBRT with intraluminal brachytherapy. For patients undergoing curative resection, no difference in median survival was seen whether or not patients received radiotherapy (20 months in both groups). Additionally, no significant difference in median survival was seen with the addition of radiation therapy in patients undergoing palliative surgery (8 vs 12.5 months). The authors concluded that postoperative radiation therapy did not improve survival.
However, a more recent report from John Hopkins described 34 patients with distal common bile duct cholangiocarcinoma treated with pancreaticoduodenectomy followed by adjuvant radiation therapy with concurrent and maintenance fluorouracil(Drug information on fluorouracil) (5-FU)-based chemotherapy. Median survival was 37 months, with a 5-year survival rate of 35%. When compared to historical controls from the same institution treated with pancreaticoduodenectomy only (prior to the routine practice of adjuvant chemoradiation), patients receiving adjuvant therapy had a significantly longer survival (37 vs 22 months, P < .05).
No definitive conclusions as to the efficacy of postoperative radiotherapy can be drawn from these studies, although these and other data suggest improved local control and survival may be achieved with its use. A summary of postoperative EBRT studies is shown in Table 1.[1-23]
Even with the addition of radiation therapy and chemotherapy to surgery, the risk of local recurrence in cholangiocarcinomas remains high. This experience has prompted investigation of novel treatment approaches to enhance local control and survival. Although there is limited experience with neoadjuvant treatment in biliary carcinoma, this strategy has potential advantages. By postponing surgical resection until completion of chemoradiation, patients with malignancy that is rapidly progressive may avoid unnecessary surgery with potential morbidity. Secondly, preoperative therapy may facilitate tumor downstaging and potentially convert an unresectable tumor to resectable status. Theoretically, preoperative therapy may reduce the risk of tumor seeding and dissemination at the time of resection, as well as allow delivery of treatment to disease with an intact vasculature. This may improve the therapeutic effect of both chemotherapy and radiotherapy via improved drug delivery and better tumor oxygenation, which renders cells more sensitive to radiation. Additionally, the morbidity and delayed recovery time associated with extensive surgical procedures may preclude the timely delivery of postoperative therapy in a high percentage of patients.[24,25]
A report from M.D. Anderson Cancer Center described nine patients (five hilar and four distal common duct cholangiocarcinoma) treated with preoperative chemoradiation therapy. Patients received continuous-infusion 5-FU (300 mg/m2/d) during EBRT. No residual carcinoma was seen in the surgical specimens in three of nine patients, whereas the tumors of the remaining six patients showed a range of histologic responses. The margin-negative resection rate was 100% for the preoperative chemoradiation group, compared with 54% for the surgery-alone group (P < .01). Patients receiving preoperative treatment did not experience significant treatment-related complications.
Gerhards et al described 21 patients with proximal cholangiocarcinoma receiving low-dose preoperative irradiation of 10.5 Gy given over three fractions. None of these patients developed wound implantation, in contrast to a 20% rate of wound implantation in similar patients not receiving preoperative chemoradiation. At Duke University Medical Center, marginally resectable and selected resectable patients with extra-hepatic biliary ductal cancers have received preoperative chemoradiotherapy (EBRT and 5-FU via continuous infusion or capecitabine(Drug information on capecitabine) [Xeloda]), followed by laparotomy and resection when feasible.