68Ga-Prostate-Specific Membrane Antigen PET/CT in Cholangiocarcinoma: A Potential Biomarker for Targeted Radioligand Therapy?

Ga-PSMA is a promising tracer for both staging and detection of biochemical recurrence in prostate cancer. Prostate-specific membrane antigen is also expressed in the endothelium of neovasculature of various solid malignancies possibly due to tumor-associated angiogenic factors and endothelial cell sprouting. We report a case of 75-year-old man with metastatic cholangiocarcinoma to liver and lymph nodes progressing on chemotherapy. Ga-PSMA PET/CT was performed to assess PSMA expression and showed additional bone and hepatic lesions compared with F-FDG PET/CT. Ga-PSMA expression in the metastatic cholangiocarcinoma potentially guides radionuclide legend therapy with α/ß-emitters especially after enervation of all approved therapeutic options.

SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma.

PURPOSE: The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. PATIENTS AND METHODS: Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. RESULTS: A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. CONCLUSION: This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers.

BACKGROUND: Extrahepatic biliary duct cancers (EBDC) are uncommon malignancies characterized by a poor prognosis with high rate of loco-regional recurrence. The purpose of the present study is to assess the feasibility and the potential impact of adjuvant radiotherapy (RT) in a series of patients treated in one institution. METHODS: Twenty three patients with non-metastatic bile duct cancer treated surgically with curative intent (4 gallbladder, 7 ampullary and 12 cholangiocarcinoma) received 3D conformal external beam RT to a median total dose of 50.4 Gy. Concurrent chemotherapy based on 5-FU was delivered to 21 patients (91%). Surgical margins were negative in 11 patients (48%), narrow in 2 (9%), and microscopically involved in 8 (35%). Eleven patients (55%) had metastatic nodal involvement. The average follow-up time for all patients was 30 months (ranging from 3-98). RESULTS: Acute gastrointestinal grade 2 toxicity (RTOG scale) was recorded in 2 patients (9%). Nausea or vomiting grade 1 and 2 was observed in 8 (35%) and 2 patients (9%) respectively. Only one patient developed a major late radiation-induced toxicity. The main pattern of recurrence was both loco-regional and distant (liver, peritoneum and/or lung). No difference was observed in loco-regional control according to the tumor location. The 5-year actuarial loco-regional control rate was 48.3% (67% and 30% for patients operated on with negative and positive/narrow/unknown margins respectively, p=0.04). The 5-year actuarial overall survival was of 35.9% for the entire group (61.4% in case of negative margins and 16.7% in case of positive/narrow/unknown margins, p=0.07). CONCLUSIONS: Postoperative RT with 50-60 Gy is feasible with acceptable acute and late toxicities. The potential benefit observed in our series may support the use of adjuvant RT in patients with locally advanced disease. Prospective randomized trials are warranted to confirm definitively the role of RT in this tumor location.

Gamma knife-treated hepatoma: case of obstructive jaundice and management.

Gamma knife therapy is becoming more frequently applied in solid tumor treatment. This article reports a unique case of severe obstructive jaundice arising as a complication of treatment of hepatoma at the hepatic hilum using a gamma knife.While planning an intervention, some images seem to promise success but actually lead to failure. Radiation damage to specific organs is difficult to predict because of several variables. Radiation-induced fibrosis and necrosis are the most common long-term adverse effects of radiotherapy; they are usually considered irreversible and result in induration and firmness of the tissue.To minimize radiation fibrosis, accurate patient positioning and tumor relocalization are essential for gamma knife use in the liver and other extracranial sites. Even when practiced frequently, any intervention must be delivered with caution if the liver has been treated with radiation. Otherwise, even with much experience, the unwary doctor can be trapped by deceptive images.

Role of liver transplantation in the treatment of cholangiocarcinoma.

Cholangiocarcinoma is a rare malignancy arising from the bile duct epithelium with a grim prognosis. Although complete resection may be curative, it is feasible only in a minority of cases owing to local extension of the tumor. Early experiences with liver transplantation were discouraging, given the high rates of tumor recurrence and poor patient survival. Trials with aggressive transplantation methods and adjuvant chemotherapy did not yield significantly better outcomes. Recently, stringent patient selection and neoadjuvant chemoradiation have yielded promising results with 5-year survival rates as high as 76%. Factors associated with recurrence after transplantation include advanced age, history of cholecystectomy, elevated serum glycoprotein cancer antigen 19-9 level, a discreet mass on imaging and an interval from enrollment to transplant greater than 100 days.

Arterial chemotherapy and conformal radiation abolish malignant biliary obstruction.

Malignant biliary obstruction has been a challenge to clinical practitioners, especially when it is serious and complete. Chemotherapy or radiation alone is often unsuccessful. In this study, the authors report a 59-year-old patient with complete common bile duct obstruction caused by cholangiocarcinoma who was treated with arterial chemotherapy followed by 3-dimensional conformal radiation, which resulted in a good clinical outcome.

[Palliative locoregional therapy for hilar cholangiocarcinoma: photodynamic therapy and brachytherapy]. / Palliative lokoregionäre Therapie des hilären Gallengangskarzinoms: photodynamische Therapie und Brachytherapie.

In hilar cholangiocarcinoma, only 20-30% of the patients are candidates for curative surgical resection, leaving the majority with merely palliative treatment options. Since the natural history of hilar cholangiocarcinoma is dominated by local complications rather than metastatic disease, local palliative treatment seems a reasonable option. Here, endoluminal photodynamic therapy has emerged as a promising treatment with several prospective observational studies and 2 prospective randomised studies published which included nearly 200 patients. With low complication rate and morbidity, PDT achieves an increased median survival as well as an increased quality of life even in patients with reduced performance status. Radiotherapy is an alternative local treatment option applied as brachytherapy, external beam radiotherapy or combined modality treatment. To date, however, sufficient data from controlled clinical trials are lacking, thus palliative radiotherapy has to be considered an experimental treatment option.

Effects of the anti-epidermal growth factor receptor antibody cetuximab on cholangiocarcinoma of the liver.

BACKGROUND: Cholangiocarcinoma is a malignant neoplasm arising from the biliary epithelium. The disease is notoriously difficult to diagnose and is usually fatal because of its late clinical presentation and the lack of effective nonsurgical therapeutic modalities. The overall survival rate, including in patients who underwent tumor resections, is poor, with less than 5% surviving more than 5 years. Over the past 5 years, several important studies have yielded new insight into the molecular mechanisms involved in the development and growth of these tumors. The tumor cells of the cholangiocarcinoma express an epidermal growth factor receptor which plays an important role in the pathogenesis of these tumors. CASE REPORT: A 49-year-old woman with cholangiocarcinoma of the liver developed spinal metastases. The antiepidermal growth factor receptor (anti-EGFR) antibody was used successfully in combination with radiotherapy. The response to treatment was assessed by magnetic resonance imaging and positron-emission tomography. CONCLUSION: The patient with cholangiocarcinoma had a response to cetuximab-based therapies. This may lead to another option for the treatment of hepatic cholangiocarcinoma.

Limitations of conventional doses of chemoradiation for unresectable biliary cancer.

PURPOSE: To determine, in a retrospective review, the limitations of definitive chemoradiation in the treatment of patients with unresectable extrahepatic cholangiocarcinoma and generate testable hypotheses for future prospective clinical trials. METHODS AND MATERIALS: Between 1957 and 2000, 52 patients with localized, unresectable cholangiocarcinoma were treated with radiotherapy (RT) with or without concurrent chemotherapy. Unresectable disease was defined, by evidence on imaging studies or at surgical exploration, as localized tumor abutting or involving the main portal vein, tumor involvement of secondary biliary radicals, or evidence of nodal metastases. Patients were grouped according to the RT dose: 27 patients received a total dose of 30 Gy (Group 1), 14 patients received 36-50.4 Gy (Group 2), and 11 patients received 54-85 Gy (Group 3). 192Ir intracavitary boosts (median 20 Gy) were delivered in 3 patients, and an intraoperative boost (20 Gy) was used in 1 patient. Of the 52 patients, 38 (73%) received concomitant protracted venous infusion of 5-fluorouracil (200-300 mg/m2 daily, Monday through Friday). Kaplan-Meier analysis was used to calculate the actuarial 1-year and median overall survival (OS), radiographic local progression, symptomatic progression, and distant failure. Treatment-related variables and prognostic factors were evaluated using the log-rank test. RESULTS: The first site of disease progression was local in 72% of cases. The actuarial local progression rate at 12 months for all patients was 59%. The median time to radiographic local progression was 9, 11, and 15 months in Groups 1, 2, and 3, respectively (p = 0.48). Fifteen percent of all patients developed metastatic disease (1-year OS rate 18%). The median survival rate for all patients was 10 months (1-year OS rate 44%). The RT dose, use of concurrent chemotherapy, histologic grade, initial extent of liver involvement, and extent of vascular involvement had no influence on radiographic local progression or OS. Grade 3 or greater toxicity was similar in all dose groups (22% vs. 14% vs. 27%, p = 0.718). CONCLUSION: The primary limitation of definitive chemoradiation was local progression. Although the small patient numbers limited the statistical power of this study, a suggestion of improved local control was found with the use of higher RT doses. To address this pattern of failure, future prospective investigation using high-dose conformal RT with novel cytotoxic and/or biologic agents with radiosensitizing properties is warranted.

Adjuvant chemoradiotherapy for "unfavorable" carcinoma of the ampulla of Vater: preliminary report.

HYPOTHESES: Adjuvant chemoradiotherapy decreases the risk of local recurrence in patients with adenocarcinoma of the ampulla of Vater and high-risk features. Adjuvant chemoradiotherapy for this population can be administered safely and without much morbidity. DESIGN: Controlled, prospective, single-arm study. SETTING: Tertiary care referral hospital. PATIENTS: From June 1995 to March 1999, 12 patients (7 men and 5 women; median age, 66 years; age range, 38-78 years) with "unfavorable" ampullary carcinoma were treated with adjuvant chemoradiotherapy. All patients underwent pancreaticoduodenectomy, and all pathologic findings were confirmed at Stanford University Medical Center, Stanford, Calif. Unfavorable features were defined as involved lymph nodes (n = 10), involved surgical margins (n = 1), poorly differentiated histological features (n = 3), tumor size greater than 2 cm (n = 6), or the presence of neurovascular invasion (n = 4). INTERVENTIONS: Four to 6 weeks after undergoing pylorus-preserving pancreaticoduodenectomy with regional lymphadenectomy, patients began adjuvant chemoradiotherapy consisting of concurrent radiotherapy (45 Gy) and fluorouracil by protracted venous infusion (225-250 mg/m(2) per day, 7 days per week) for 5 weeks. MAIN OUTCOME MEASURES: Local recurrence, distant recurrence, overall survival rate, and treatment-related toxic effects. RESULTS: All patients completed the prescribed treatment course. Toxic effects were assessed twice a week during treatment and graded according to the National Cancer Institute Common Toxicity Criteria Scale. One patient required a treatment interruption of 1 week for grade III nausea/vomiting. No grade IV or V toxic effects were observed. At median follow-up of 24 months (range, 13-50 months), 8 of 12 patients were alive and disease free. One patient was alive but had disease recurrence. Three patients died of this disease (liver metastases). Actuarial overall survival at 2 years was 89%, and median survival was 34 months. One surviving patient developed a local recurrence and a lung lesion. Actuarial overall survival and median survival were better than in a parallel cohort with resected high-risk pancreatic cancer (n = 26) treated with the same adjuvant chemoradiotherapy regimen (median survival, 34 vs 14 months; P<.004). CONCLUSIONS: Adjuvant chemoradiotherapy for carcinoma of the ampulla of Vater is well tolerated and might improve control of this disease in patients with unfavorable features.

Selective radionuclide localisation in primary liver tumours (pilot study).

The therapeutic potential of 131I-Lipiodol was investigated in 8 patients with cholangiocarcinoma (CCA) and 15 patients with hepatocellular carcinoma (HCC). Patients received one or two doses of 131I-Lipiodol via hepatic arterial injection. The mean total administered activity was 668 (SD 325) MBq in CCA and 953 (SD 477) MBq in HCC. One patient with CCA retained 131I-Lipiodol. The cumulative radiation dose was 9.6 Gy to tumour, 6.4 Gy to liver and 1.5 Gy to lung. The patient remained asymptomatic with no evidence of tumour 30 months from the start of treatment, whereas the remaining 7 patients exhibited tumour progression. The mean survival in CCA was 11.6 (SD 14.5) months. All 15 patients with HCC retained 131I with tumour: liver ratios of up to 30:1. The mean cumulative radiation dose was 34.7 (SD 32.4) Gy to tumour, 3.3 (SD 1.5) Gy to liver and 4.4 (SD 2.3) Gy to lung. The mean dose per administered activity was 3.8 (SD 4.1) cGy/MBq. Partial response (reduction in tumour size > 50%) was observed in 6 patients (40%). The mean survival was 7.1 (SD 6.0) months. 131I-Lipiodol can deliver highly selective internal irradiation to foci of HCC with evidence of objective response and may be the treatment of choice for patients with cirrhosis and a small tumour.