Concurrent versus sequential neoadjuvant chemo-radiotherapy followed by surgery in operable carcinoma gallbladder patients: A pilot study

Carcinoma of the Gall Bladder is the most common malignancy of the biliary tract and the fifth most common neoplasm of the digestive tract. The highest gallbladder cancer incidence rates worldwide were reported for women in Delhi, India (21.5/100,000), South Karachi, Pakistan (13.8/100,000) and Quito, Ecuador (12.9/100,000). High incidence was found in Korea and Japan and some central and eastern European countries. Female-to-male incidence ratios were generally around 3, but ranged from 1 in Far East Asia to over 5 in Spain and Colombia. As per Delhi cancer registry2003, the crude incidence rate for GBC in females and males were 4.6 and 1.7 per 100,000 population respectively. xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /

Approximately 80% of GBCs are adenocarcinomas and is characterised by early spread to lymph tissues and blood stream giving rise to local invasion, extenve regional lymphnode metastasis, vascular encasement, and distant metastases. Because of lack of characteristic early symptoms, the tumor becomes symptomatic only with advanced growth, and three fourths of gallbladder tumors are unresectable at presentation. The overall 5-year survival is 13.7%. The median survival for patients with stage III tumors is 6 months and for those with stage IV is 1-3 months. A review of about 2500 patients with GBC from hospital cancer registries throughout U.S. showed tumour stage to be closely associated with survival; 5-year survival rates were 60%, 39%, 15%, 5% and 1% for patients with stage 0-stage IV disease respectively. Results from a recent retrospective single-centre analysis showed a 10.3 month median survival for the overall population of patients diagnosed with GBC. Median survival was 12 and 5.8 months for those with stage Ia-III and stage IV disease respectively.

In general, GBC is the most aggressive of the biliary cancerswith the shortest median survival duration. Complete surgicalresection offers the only chance for cure and achievement of R0 resection strongly correlates with long term survival; however, only 10%of patients present with early-stage disease and are consideredsurgical candidates. Among those patients who do undergo "curative"resection, recurrence rates are high. Even after a curative resection, the overall 5-year survival rate is only 5%.

 The main pattern of recurrence is loco regional as well as distant metastasis. In order to improve survival and outcomes in GBC, it is felt that surgery needs to be combined with other modalities like chemotherapy/radiotherapy (CT/RT) or chemoradiotherapy (CRT). Therefore, the therapeutic strategy in recent years combines the benefits of surgery with adjuvant CT/CRT. The oncological standpoint is to treat micrometastastic disease thereby reducing the high rates of loco regional recurrences and improve survival. The aim of neo-adjuvant therapy is to expand the benefits of adjuvant CRT/CT over surgery alone to patients in preoperative settings in order to increase resectability and to improve survival.

 GBC is an uncommon disease in U.S. and Europe, where the majority of cancer therapy studies are performed. As a result, management protocols for GBC are commonly extrapolated from studies that have included patients with all subsites of biliary tract cancers. However, biliary tract cancer includes cholangiocarcinoma (CC), GBCs, and ampullary tumors. These various tumors are likely to have a different biology and clinical course as evidenced by the fact that patients with CC have a better median survival than patients with GBC. Median survival reported for GBC in various studies is in the range of 4 to 11 months, compared with this, studies involving mainly CC have reported median survival of 15 to 16 months suggesting a difference in the biology of the two diseases.

The role of adjuvant chemotherapy in GBC has not been definitivelyevaluated in randomized trials. Most studies consist of small,heterogeneous groups of patients seen at a single institution.Several retrospective series and small phase II studies suggestsuperior outcomes for patients who receive postoperative CRT.Most of the experience in CT comes from trial evaluating CT for advanced GBC. There have been five trials exclusively enrolling GBC patients—oneevaluating gemcitabine alone, two gemcitabine–cisplatincombination studies and one gemcitabine carboplatin combination have shown some benefit. The fifth one is a recent randomised controlled study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC) and confirmed the efficacy of mGEMOX. There are not many studies evaluating NACRT in GBC. To date, there is only one phase II trial which tried to address the issue of neoadjuvant chemoradiotherapy (NACRT) in GBC.

 This study is a pilot study to evaluate efficacy and safety of NACRT in patients with operable GBC and aims to compare the outcomes following concurrent and sequential regimes.