Metastatic Gallbladder Cancer Research Articles

Infusion chemotherapy with cisplatinum and fluorouracil in the treatment of locally-advanced and metastatic gallbladder cancer

Gallbladder cancer (GBC) has a poor prognosis. Chemotherapy is traditionally considered to be ineffective. The goal of the current study was to evaluate the efficacy of infusional 5-fluorouracil (5-FU) and cisplatinum (CDDP) in patients with inoperable GBC. A total of 65 patients with inoperable GBC received palliative chemotherapy with CDDP and 5-FU. All the patients had clinically measurable disease as well as adequate bone marrow, hepatic, and renal function. Response was assessed after three cycles of chemotherapy. A total of 19 patients had locally advanced unresectable cancer and 46 patients had metastatic cancer. There were 39 females and 26 males, with a median age of 50 years. A total of 212 chemotherapy cycles were administered to the patients. Response evaluation after three cycles of chemotherapy revealed complete response in five patients [7.69%; 95% confidence interval (95% CI): 2.87-16.22], partial response in 17 patients (26.15%; 95% CI: 16.57-37.81), stabilization of disease in 9 patients (13.85%; 95% CI: 6.96-23.88), and progression in 21 patients (32.30%; 95% CI: 21.80-44.35). At 6 months 44.6% patients were alive and 18.5% patients were alive at 12 months. The median overall survival was 5.7 months and the median time to disease progression was 3.1 months. This chemotherapy combination was well tolerated. There were no chemotherapy-related deaths. Infusion chemotherapy with CDDP and 5-FU appears to have a fair amount of activity in patients of inoperable GBC, with acceptable toxicity. Tumor shrinkage following treatment with this regimen enabled surgical resection in two patients. We believe that this promising combination must be tested against gemcitabine-based combinations in patients with inoperable GBC.

Gemcitabine and carboplatin in the treatment of metastatic cholangiocarcinoma and gallbladder cancer

15102 Background: There is currently no standard therapy for patients with unresectable or metastatic biliary tract cancers. Gemcitabine has been shown to be active against these tumors with a 20–30% response in various phase II studies. Gemcitabine is also synergistic with platinum compounds. Aim: We conducted a Phase II study of gemcitabine plus carboplatin in patients with unresectable or metastatic choloangiocarcinoma or gallbladder cancer to assess the regimen’s safety and efficacy. Methods: Since 3/2002, 49 (48 evaluable) patients were treated with gemcitabine at 1000 mg/m2 IV over 30 minutes days 1 and 8 with carboplatin at AUC 5 IV on day 1 of a 21 day cycle. There were 34 women and 15 men enrolled. Ages ranged from 34 to 87 with a median age of 65 years. Results: Best radiologic responses - 5CR, 9 PR, 24 stable disease and 10 progression. CR+PR 14/48 (29.2%) and stable disease 24/48 (50%). Toxicity: Hematological toxicities: Grade 3 neutropenia 33%, febrile neutropenia 0.02%, anemia 12.5% and thrombocytopenia 14.6%. Grade 4 hematological toxicites were rare - neutropenia 0.04%, and thrombocytopenia 0.06%. Non-hematologic toxicities were generally mild (fatigue, edema, nausea, vomiting, elevated liver enzymes, electrolyte abnormalities). Except for one patient who had depression there were no grade 4 non-hematological toxicity. Grade 3 non- hematological toxicites were also rare occurring only in 1 to 3 patients. Conclusions: Gemcitabine and carboplatin is active against biliary cancer and is highly tolerable. This study is being supported by Eli Lilly & Co. No significant financial relationships to disclose.

SWOG 0514: A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas

4639 Background: There are no standard chemotherapeutic regimens for incurable biliary adenocarcinomas. Gemcitabine and fluoropyrimidine- based chemotherapy results in occasional responses and a median survival approaching 6 months. Given the presence of b- raf mutations and overexpression of VEGF in biliary cancers, we initiated a study to evaluate the efficacy of sorafenib, a multitargeted tyrosine kinase inhibitor of c and b-Raf, VEGFR-2/3 and PDGFR, in pts with metastatic biliary cancers. Methods: Pt eligibility included adequate organ function and no prior treatment for metastatic disease. The primary end-point was objective response rate (RR). Secondary endpoints were overall survival (OS) and progression free survival (PFS). A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one confirmed response occurred after the first 25 pts, another 25 were to be accrued. Sorafenib was administered at 400 mg PO BID continuously. A cycle was defined as 28 days of therapy, and radiological assessment was done every 2 cycles. Results: 36 pts were enrolled during the first stage of accrual. 5 pts were ineligible. 52% were female. Median age was 57.8 years (range 33.8–81.5). Adverse events: 1 pt died with grade 4 supraventricular tachycardia and venous thromboembolism. Grade 3/4 toxicities were noted in 20 pts (66.7%) and included hand-foot syndrome in 4 pts (13%), while thrombosis/embolism, elevated liver transaminases, and abdominal pain were each seen in 3 pts (10% for each). Reversible posterior leukoencephalopathy syndrome, GI perforation, and GI hemorrhage were each seen in 1 pt (3% for each). 2 pts (6%) had an unconfirmed partial response and 9 pts (29%) had stable disease. 27 pts have progressed. Median PFS was 2 months (95% CI: 2–4 months). 14 pts have died, with a median survival estimate of 6 months (95% CI: 4–10 months). Conclusions: Sorafenib did not result in a clinically significant objective RR in pts with gallbladder and cholangiocarcinoma but demonstrated an impact on survival that may be comparable to commonly used chemotherapy regimens. No significant financial relationships to disclose.

Phase II study of gemcitabine, oxaliplatin in combination with bevacizumab (GEMOX-B) in patients with unresectable or metastatic biliary tract and gallbladder cancers

4625 Background: Patients (Pts) with unresectable or metastatic biliary tract cancer (BTC) and gallbladder cancer (GBC) have a poor prognosis. Vascular endothelial growth factor (VEGF) expression has been detected in BTC and GBC. Increased angiogenesis has been correlated with advanced stage of disease and poor prognosis. Given reported activity of gemcitabine (GEM) and oxaliplatin (OX) in BTC/GBC and potential benefits of targeting the VEGF pathway with bevacizumab (B), we performed a study to examine the efficacy and tolerability of GEM, OX and B (GEMOX-B) in unresectable or metastatic BTC/GBC. Methods: Eligibility criteria included unresectable or metastatic measurable BTC/GBC, 0–1 prior chemotherapy regimens, performance status = 2, and adequate organ function. No clinically significant cardiovascular disease or history of active bleeding. Pts were treated with all 3 drugs intravenously on days 1 and 15 every 28 days (one cycle): B was given first at 10 mg/kg, followed by GEM at 1000 mg/m2 as dose rate infusion at 10 mg/m2/minute, and OX at 85 mg/m2. Whole body FDG-PET scan was obtained at baseline and after cycle 2. The primary endpoint of the study was progression-free survival (PFS). Results: 19 pts (10 BTC and 9 GBC) have been enrolled since May 17, 2006: median age = 69 (25–82), M/F = 13/6, ECOG 0/1/2 = 7/10/2. Treatment has been well tolerated with no grade 4–5 toxicities seen. Treatment related grade 3 toxicities included (number of pts): hypertension (2), neutropenia (1), transient SGPT elevation (1), proteinuria (1), neuropathy (1), and fatigue (1). Of 11 pts followed for at least 4 months, 3 had confirmed partial responses (PR), 5 had stable disease (SD) of at least 4 cycles, and 3 had progressive disease (PD) per RECIST criteria. Five pts had more than 50% decrease in CA19–9 levels. Of 16 PET studies analyzed, changes in SUV values from baseline to after 2 cycles of treatment were: 11 PRs, 4 SDs, 1 PD per EORTC criteria. Conclusions: GEMOX-B can be safely administered with tolerable safety profiles in patients with advanced BTC/GBC. Early evidence of antitumor activity was seen. A decreased SUV in FDG-PET following GEMOX-B treatment was observed in the majority of patients. No significant financial relationships to disclose.

Metastatic Gallbladder Cancer Diagnosed in a Hernia Sac

The presence of cancer in a hernia sac is uncommon. We report a case of a 77-year-old female who presented to emergency room with an incarcerated inguinal hernia. At inguinal hernia repair the sac appeared indurated with evidence of calcifications. Histological examination showed metastatic adenocarcinoma of gallbladder origin.

Combined chemotherapy and surgery for metastatic gallbladder cancer improve median survival

14136 Background: Metastatic gallbladder cancer (MGBC) is a rapidly progressive disease, orphan of treatment; its median survival is only 3 to 4 months. Since 1999 we had demonstrated that gemcitabine (Gem) and gemcitabine-cisplatin (Gem-plat) are active regimens against this disease, but median survival increases to only 8 months. We had seen some complete responses and cases with impressive partial responses, but all of them are transients, recurrence appears in all pts. The benefit of combining CHTx and surgery had not been tested in MGBC, but has demonstrated promising results in others GI cancers. Methods: A retrospective analysis was performed in data from 9 patients (pts) who had liver resection for MGBC. Gem o gem-plat was given to all patients. Between September 1999 and July 2005 we had included more than 70 pts in two trials and others 25 pts had been treated outside of clinical trials. Among then, 9 patients with metastases from MGBC who were treated with Gem ± plat, were sent for resection of residual tumors. All pts received radio-chemotherapy after resection The primary endpoint was overall survival. Safety was a secondary end point. Results: We report the results of the first 9 patients with at least 9 months follow-up post surgery. Median overall survival is 17 months (9+ - 24). Only one pt is free of recurrence, (at 9 months), all others died due to relapse. Liver was the most frequent site of recurrence (8/8), but also peritoneal cavity and duodenum. All pts presented recurrence distant to initial tumor site. Most possible explanation for recurrence in 3 cases was R1 resection. In the CHTx phase no one pts required a dose reduction. Grade ≥3 was rare, vomiting in 2.0%, febrile neutropenia in 1.3%. There was no toxic death. Surgical complications (within 30 days of surgery) were low, with no one requiring reoperation, and no deaths were observed. Conclusions: Chemotherapy with Gem ± cisplatin was safely administered. Surgical mortality and morbidity rates were low. Even though a high proportion of patients died due to relapse, and thus suggest that this approach in inconvenient, this combined therapy offer a double life expectancy compare to chemotherapy alone. No significant financial relationships to disclose.

SWOG S0202: A phase II trial of gemcitabine and capecitabine in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinoma

4134 Background: Pts with gallbladder cancer or cholangiocarcinoma usually present with advanced disease and limited treatment options. Based on data demonstrating effectiveness of gemcitabine in pancreatic carcinoma and the common embryologic origin of the exocrine pancreas and gallbladder, this trial was pursued. The primary objective of this study was to assess the response rate (confirmed complete and partial responses). Secondary objectives included overall survival and toxicities for gemcitabine and capecitabine. Methods: A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one response occurred after the first 20 pts, another 20 were to be accrued. The combination of gemcitabine 1,000 mg/m2 IV over 100 minutes days 1, 8 and capecitabine 650 mg/m2 BID PO days 1–14, was administered every 21 days. Results: The study accrued 57 pts from September 2003 until April 2005. Three patients were ineligible, and two others received no treatment. Characteristics of analyzable pts: 35 (73%) cholangiocarcinoma, 17 (32%) gallbladder cancer; PS 0 (18 pts), 1 (26 pts), 2 (8 pts); 26 (50%) male; median age 58.8 years (29.5–85.6). Among 51 pts evaluated for toxicity, 6 experienced grade 4 toxicities: 1 thrombosis/embolism and muscle pain, 1 fatigue and 4 neutropenia, one of whom also had grade 4 leukopenia and grade 4 anemia. Among 52 pts, there were 5 confirmed partial responses for a confirmed response probability of 10% (95% CI 3% to 21%). Four pts had an unconfirmed partial response for an overall response probability of 18% (95% CI 8% to 30%). Fourteen patients (27%) stable disease. The 6 month overall survival was 56% (95% CI 42%–70%) and median survival was 7.0 months. Conclusions: Gemcitabine and capecitabine is a well tolerated regimen with activity in pts with advanced gallbladder cancer and cholangiocarcinoma. Correlative analyses are ongoing. [Table: see text]

Treatment of unresectable or metastatic gallbladder cancer with single-agent gemcitabine or in combination with cisplatin

4211 Background: Gallbladder carcinomas (GC) are often diagnosed at an advanced/metastatic stage amenable only to palliative surgery. Published data on palliative CT for GC are quite scarce and frequently, erroneously mixed with others biliary tract cancers, their median survival is only around 8 to 12 weeks. Results of chemotherapy for advanced GC are extremely poor with traditional treatment based on 5-FU. Methods: Since 1997 we have been studying the effect of gemcitabine. We retrospectively reviewed data of two different protocol treatments, we made possible. In both trials pts had similar characteristics, they all pts had measurable locally or metastatic GC with histological or cytological proof, no prior chemotherapy or radiotherapy. The main endpoint was RR and secondary endpoints were treatment toxicity and overall survival. We reviewed pts data and outcomes. In first trial 26 pts with advanced GC were treated with GEM 1000 mg/m2 i.v. for 30 minutes weekly for 3 weeks out of every 4 until disease progression and/or toxicity. In second cohort, 44 pts received Gem 1200 mg/m2 and Cis 35 mg/m2 on d1and 8, every 21d for a total of 6 courses. RR was evaluated by abdominal CT scan. Pts were treated on an outpatient basis. Results: Twenty-five pts and 42 pts were, evaluated for response. There were 0/4 CRs and 9/16 PRs for gem vs gem + cispl. All pts were evaluated for toxicity. Four and 1 died due to disease progression, one pt. died due to renal toxicity in the arm gem +cispl. In one pt occurred hepatotoxicity grade 4 in arm gem alone. The main grade 3 hematology toxicities included thrombocytopenia (0% vs 2%), neutropenia (3.8% vs 23%) and anemia (3.8% vs 14%) in the group gem vs gem + cispl. Median survival time was 8.7 mos. vs 7 mos. for the entire population, 14.1 mos. vs 9 mos. for responders, and 6.1 mos. vs. 5 mos. for non-responders. Conclusions: GEM is active against advanced, unresectable recurrent and/or metastatic GC with a good tolerability. The low toxicity profile of GEM should be considered when a treatment choice is to be made for a patient with advanced GC. GEM combined cisplatin, resulting in an increased frequency and severity of side effects and not improved rates responses in comparison with gem alone No significant financial relationships to disclose.

Translational regulation of XIAP expression and cell survival during hypoxia in human cholangiocarcinoma

Tumor progression is promoted by the ability of tumor cells to resist adverse environmental conditions such as hypoxia. We have shown that translational dysregulation contributes to transformed cell growth in malignant cholangiocytes. Translational regulation of gene expression can contribute to an immediate and rapid response to environmental changes such as hypoxia. Thus, our aims were to assess translational mechanisms involved in cell survival during hypoxia and to identify specific translationally regulated proteins involved in the cellular response to hypoxia. Cell viability and apoptosis in response to hypoxia were assessed in human cholangiocarcinoma cells. Translational processes were deregulated by cycloheximide or rapamycin or by targeted deletion of eukaryotic initiation factor (eIF)-4E, a rate-limiting translational initiation factor using small interfering RNA (siRNA). A protein antibody microarray was used to screen for eIF-4E-dependent proteins expressed during hypoxia. Expression of the X-linked inhibitor of apoptosis (XIAP) was decreased using siRNA. Malignant cholangiocytes are resistant to hypoxia-induced apoptosis. Furthermore, cell survival during hypoxia required protein translation. eIF-4E was over expressed in malignant cholangiocytes. Reduction in eIF-4E expression by siRNA decreased tumor cell resistance to hypoxia, increased caspase-3 activation and apoptosis, and decreased cell survival compared with controls. XIAP was identified as a translationally regulated protein expressed during hypoxia. Modulation of XIAP expression by siRNA decreases cell death during hypoxia in vitro and in vivo. Human cholangiocarcinoma cells are highly resistant to hypoxia. Translational regulation of survival proteins such as XIAP is a mechanism mediating cholangiocarcinoma survival during hypoxia.

A case of metastatic gallbladder cancer from renal cell carcinoma

A case of metastatic gallbladder cancer from renal cell carcinoma

Preneoplastic lesions and gallbladder cancer: An estimate of the period required for progression

BACKGROUND & AIMS: Scarce biological information exists about the importance of preneoplastic lesions in gallbladder cancer. The aim of this study was to estimate the time required for the sequence of dysplasia (DY) to carcinoma of the gallbladder. METHODS: Eighty-four cases of DY, 60 cases of early carcinomas (ECs), 181 cases of advanced carcinomas (ACs), and 121 cases of metastatic (ME) gallbladder cancer were analyzed. Age was used as the main parameter. Statistical analysis was performed using analysis of variance and multiple regression analysis. RESULTS: Among all cases, the mean age of female patients was lower than the mean age of male patients (P = 0.001). A significant difference in mean age between sexes by specific type of lesion was also observed (P < 0.001). The mean age was 46.3 years (SD, 16) in the DY group, 57.5 years (SD, 16.7) in the EC group, 59 (SD, 13.7) in the AC group, and 61.1 (SD, 12.1) in the ME group. Multiple regression analysis showed statistically significant differences (r = 0.386; P < 0.001) in the mean age of patients with dysplastic lesions compared with the carcinoma group. CONCLUSIONS: According to these observations, the period required to progress from dysplasia to advanced gallbladder carcinoma would be around 15 years, observing a continuum in the progression of the lesions. (Gastroenterology 1996 Jul;111(1):232-6)