Patients with locally advanced, unresectable gallbladder carcinoma may
present with symptoms of jaundice, pain, and bowel obstruction. These
patients have a limited life expectancy, on the order of months,
especially in the setting of liver and/or peritoneal dissemination.
Different palliative treatment aimed at relief of pain,jaundice,
intestinal obstruction, and prolongation of life, has been discussed:
Sunday, June 22, 2008
Cancer gallbladder; treatment of advance and unresectable disease.
Patients with locally advanced, unresectable gallbladder carcinoma may present
with symptoms of jaundice, pain, and bowel obstruction. These patients have a
limited life expectancy, on the order of months, especially in the setting of
liver and/or peritoneal dissemination.
* The treatment of locally advanced, unresectable gallbladder carcinoma is
palliation aimed at relief of pain, jaundice, and bowel obstruction, along with
prolongation of life.
* Patients who have pain from local growth may benefit from radiation
therapy with or without concomitant chemotherapy.
* Although biliary or intestinal bypass can be considered, a percutaneous
or endoscopic approach may be preferred, given the limited median survival in
patients with advanced disease (generally, less than six months).
Recurrence
In a recent retrospective review of the patterns of initial disease recurrence
after potentially curative surgical resection, Jarnagin et al. followed 80
patients with gallbladder carcinoma and compared them to 76 patients with hilar
cholangiocarcinoma.
* The median time to disease recurrence was shorter for gallbladder
carcinoma patients (11.5 months) compared to patients with hilar
cholangiocarcinoma (20.3 months).
* At a median follow-up of 24 months, 68% of patients with hilar
cholangiocarcinoma and 66% of patients with gallbladder carcinoma suffered
disease recurrence.
* The site of initial disease recurrence was locoregional in only 15% of
patients with gallbladder carcinoma compared to 59% of patients with hilar
cholangiocarcinoma.
* In contrast, 85% of patients with gallbladder carcinoma had a distant
(+/−locoregional) site as their initial site of failure compared to 41%
of patients with hilar cholangiocarcinoma.
* This study provides considerable insight into the clinical behavior of
these malignancies and suggests that in the case of gallbladder carcinoma,
improvements in survival are most likely to be achieved with more effective
systemic therapies as opposed to adjuvant treatment such as radiation therapy
designed to achieve better locoregional control.
Radiation therapy
External beam radiation(EBRT) may be considered for palliative management of
patients with locally advanced disease, particularly if there is no evidence of
metastatic disease, and patients are symptomatic. At the time of exploration,
the margins of unresectable and/or residual disease are often marked with
radiopaque clips to facilitate treatment planning.
* Hanna and Rider reported on 51 patients with gallbladder carcinoma from
the Princess Margaret Hospital, 35 of whom underwent a potentially curative
surgical resection and EBRT.
o There was a survival advantage for those patients who received
adjuvant EBRT in addition to surgery compared with those who had surgery alone.
* Several other small, retrospective series consisting of heterogeneous
groups of patients with diverse treatment schema and follow up criteria have
been published, making definitive conclusions about the potential benefits of
adjuvant EBRT difficult.
* Most recently, Kresl et al. published their retrospective analysis of
adjuvant EBRT with concurrent 5-FU after curative surgical resection in 21
patients with gallbladder cancer treated at the Mayo Clinic from 1985 through
1997. Patients with a margin-negative (R0) resection followed by adjuvant EBRT
plus 5-FU had a favorable 5-year survival rate of 64%.
* However, similar to the findings of Jarnagin et al. [58], 67% of the
patients suffered distant failure, emphasizing the need for more effective
adjuvant chemotherapy for this disease.
Intraoperative radiation therapy (IORT) has been advocated as a means to
deliver high-dose, small-field therapy directly to the tumor bed without the
dose limitations associated with EBRT. Todoroki et al. have reported the most
substantial experience with IORT in 85 patients with AJCC stage IV gallbladder
cancer who underwent aggressive surgical resection with or without IORT at a
mean dose of 21 Gy.
* Fortyseven patients in total received some form of radiation therapy
(EBRT and/or IORT).
* The local control rate was significantly higher after adjuvant
radiotherapy (59%) than after resection alone (36%).
* Moreover, the 5-year survival rate was significantly higher after
adjuvant radiotherapy (9%) than after resection alone (3%), with the most
pronounced improvement in 5-year survival rate (17%) in patients with only
microscopic residual disease (R1 resection).
The role of radiation therapy for the palliation of symptoms such as jaundice,
pain, and pruritus in patients with unresectable disease is difficult to
ascertain as published studies consist of small numbers of patients with the
significant confounding variable that most patients also underwent a biliary
drainage procedure.
Chemotherapy
Most published studies concerning the role of chemotherapy in patients with
locally advanced or metastatic gallbladder carcinoma are limited by the small
numbers of patients and by the inclusion of patients with biliary tract cancers.
* Unfortunately, no single chemotherapeutic agent or combination of agents
has been identified to be effective in the treatment of this disease .
* Though overall response rates range as high as 64%, complete responses
are rare and median overall survival rates range from only 20 weeks to 15
months.
* 5-fluoruracil (5-FU), administered either alone or in combination, is the
most extensively studied chemotherapeutic agent for this disease.
* In a prospective, randomized study of 53 patients with advanced
gallbladder cancer treated with oral 5-FU alone or in combinationwith either
streptozocin or methyl-CCNU, objective response rates ranged from 5 to 12% in
the three treatment arms.
* 5-FU administered in combination with doxorubicin and mitomycin C (FAM)
or in combination with cisplatin and epirubicin (CEF) has yielded response
rates of 8% and 33%, respectively.
* Better response rates have been published in patients treated with
combinations of 5-FU with hydroxyurea (30%) or interferon alpha-2b (34%).
Other chemotherapeutic agents have exhibited variable success in the treatment
of advanced gallbladder cancer. Cisplatin, mitomycin C, paclitaxel, and CPT-11
have produced response rates of 10% or less as single agents.
* In contrast, four of eight patients with gallbladder carcinoma treated
with single-agent oral capecitabine had either a complete (n =2) or partial (n
=2) response.
* Several case reports have shown that gemcitabine is active in the
treatment of patients with gallbladder carcinoma.
* Accordingly, several phase II studies of gemcitabine in combination with
other agents have subsequently been reported.
* Gemcitabine in combination with cisplatin has yielded response rates of
36 to 64%; in combination with docetaxel yielded a response rate of only 9%;
and in combination with 5-FU has produced response rates of 9 to 33%.
* Based on these studies, it appears that gemcitabine is an important
component of the systemic therapy of gallbladder carcinoma, but additional
studies of gemcitabine in combination with other agents are warranted, as the
survival benefit with existing regimens is modest at best.
Hepatic arterial infusion chemotherapy has been studied in a few patients with
locally unresectable gallbladder cancer.
* Partial response rates of up to 60% have been reported, but the median
duration of response was only 3 months and all patients developed progressive
disease.
* The median overall survival rates of 12 to 14 months in these studies is
comparable to that achieved with intravenous chemotherapy, providing little
impetus to recommend this more complicated mode of drug delivery.
Targeted therapy
Early data suggest possible benefit from blockade of the epidermal growth
factor receptor (EGFR) by the oral tyrosine kinase inhibitor erlotinib.
* In one study, 42 patients with advanced biliary cancer (not stratified
according to primary site), 57 percent of whom had received prior chemotherapy,
received erlotinib (150 mg daily).
* There were three partial responses (two with documented expression of
EGFR) and seven additional patients remained progression-free at six months.
* All responding patients had mile (grade 1 or 2) skin toxicity.
* Further experience with this drug is needed, particularly combined with
cytotoxic chemotherapy.
Palliative surgery
For patients with unresectable disease detected radiographically or
laparoscopically, biliary drainage is best achieved by endoscopic or
percutaneous means.
* If unresectable disease is discovered at the time of laparotomy, a
biliary bypass (hepaticojejunostomy or segment III bypass) can be performed.
* However, in a prospective study of 21 consecutive patients with
unresectable gallbladder cancer who underwent a segment III bypass, six (29%)
suffered complications; three (14.3%) patients had bile leaks, and three
patients died as a result of the procedure.
* The median survival of these 21 patients was only 20 weeks, and all but
three patients died within 32 weeks of the surgery.
* Given this limited life expectancy, patients with unresectable
gallbladder cancer and biliary obstruction are best palliated by percutaneous
or endoscopic stenting.
Intestinal bypass offers durable relief of intestinal obstruction, though there
are reports of excellent palliation of malignant duodenal obstruction by the
endoscopic placement of expandable metal Wallstents.
Posted by jitendraagrawal2000 at 10:06 PM
Dr. Jitendra Agrawal, Kanpur, India.
