1. Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study Atul Sharma, Amit Dutt Dwary, Bidhu Kalyan Mohanti, Surya V. Deo, Sujoy Pal.Vishnu Sreenivas,Vinod Raina, Nootan Kumar Shukla, Sanjay Thulkar, Pramod Garg, and Surendra Pal Chaudhary JOURNAL OF CLINICAL ONCOLOGY ; VOLUME 28 NUMBER 30 OCTOBER 20 2010 R1 정명화 / Prof. 김시영

2. Gall bladder cancer (GBC) 10% of patients are suitable for surgery There is no standard chemotherapy for GBC No study has compared chemotherapy to best supportive care (BSC) to determine whether chemotherapy improves survival in unresectable GBC. Chemotherapeutic agents (with or without fluorouracil [FU]) response rates were reported in 0% to 36% of patients. BACK GOUND 1

3. Gemcitabine and oxaliplatin as single agents or in combination (GEMOX) with other drugs have shown activity in adenocarcinoma of pancreas, gall bladder, and biliary tracts. However, biliary tract cancer includes cholangiocarcinoma, GBCs, and ampullary tumors. Median survival reported for GBC : 4 to 11 months cholangiocarcinoma :15 to 16 months -> different biology and clinical course BACK GROUND 2

4. Gemcitabine is for the treatment of biliary tract cancer. reponse rate: 36% Combinations Gemcitabine and cisplatin : somewhat higher response rates. GEMOX ( Gemcitabine and Oxaliplatin): alternative to gem+ cisplatin The dose and schedule of GEMOX used by us in this study different from that used by Andre et al  modified GEMOX (mGEMOX). One of the largest trials of patients with GBC alone treated with chemotherapy compared with BSC. BACK GROUND 3

5. PATIENT & METHODS - Trial Design This was a randomized, controlled, open-label, single- center study At Dr BRA Institute Rotary Cancer Hospital of All India Institute of Medical Sciences, New Delhi. This study was designed in 2006. Period : June 2006 ~ October 2008. 4

6. PATIENT & METHODS - Trial Design 1. Patients who had biopsy or fine needle aspiration -> cytology–proven unresectable or metastatic of GBC 2. Age 18 years or older 3. Adequate organ and bone marrow function Hb > 10 g/dL, ANC > 1500 /uL, Platelets >100000/uL Cr < 1.8, bilirubin < 3, LFT < x 3 4.ECOG performance status < 3 5.Prior adjuvant chemotherapy and/or radiotherapy, if given, should have been completed 6 months before enrollment. - INCLUSION CRITERIA 5

7. PATIENT & METHODS Statistical Analyses The 2 test and Fisher’s exact test, Kruskal-Wallis test : comparison of baseline characteristics, response rates, and toxicity among the three treatment groups. Quantitative characteristics, such as age. The Kaplan-Meier method, log-rank test. : Survival rate was calculated using the Kaplan-Meier method, P value of.05 or lower was considered statistically significant. End Points Primary end points: Overall Survival mesurement Secondary end point : Progression-free survival 6

8. PATIENT & METHODS- Treatment Group A BSC ( Best Surportive Care) B 5-FU425mg/m2 + folinic acid 20mg/m2,30 weeks (FUFA) C Gemcitabine 900 mg/m2 + oxaliplatin 80 mg/m2 (mGEMOX) on days 1 and 8 every 3 weeks ( max: six cycles )  After 3 cycles, if progressive disease -> Stop & F/U survival data  BSC( analgesics, blood TF, symptomatic treatment ): to all the patients  If, grade 3 or 4 toxicity -> delayed until resolution of toxicity or lower than grade 2.  If, Neutropenia (grade 4), thrombocytopenia -> CTx dose reduced by 25%  If, Delayedfor longer than 3 weeks -> taken off protocol & F/U survival data  Cross-over from one arm to another was not allowed. 7

9. Response Evaluation 1. Response Evaluation Criteria in Solid Tumors (RECIST) : CR, PR, stable disease, and progressive disease 2. period: 6 cycles in the mGEMOX (group C) 15 and 30 weeks in theBSC and FUFA (group A & B) 3. CT scan : every 3 months for 1 year -> every 6 months until 3 years after completion oftreatment. Toxicity National Cancer Institute Common Toxicity Criteria (version 3.0) PATIENT & METHODS 8

10. RESULTS 9

11. 10

12. 11

13. 26(96%) : PD 4(14.3%) :PR 1 (3%) : SD 0 (0%) : PR 1(7.1%) :SD 23(82%) : PD 12

14. 8(30.7%) : PD 10 (38.5%) : SD 6 +2 (30.7 %) : PR + CR 13

15. (7.7%) (38.5%) (7.1%) (11%) (15%) 14

16. ★ Overall survival BSC : 4.5 month FUFA : 4.6 month mGEMOX :9.5 month 18% 56% ★ Progression Free BSC : 2.8 month FUFA : 3.5 month mGEMOX :8.5 month 28% 72% 15

17. Discussion 1. The major difference in this trial : only GBC -> worse OS 2. One patients with PR on CT scan -> taken up for radical cholecystectomy. GEMOX-based therapy, may be used as neoadjuvant therapy in borderline resectable disease. 3. If, Achievement of pathologic CR (3%) with this combination into saving about 30 lives/1,000 patients with GBC each year possible that one patient with pathologic CR here may have different genetic profile and therefore responded well -> needed more study 16

18. Conclusion Palliative chemotherapy is superior to BSC GEMOX maybe a better choice for response rates, OS, and PFS. (GEMOX-based chemotherapy is superior not only to BSC but also FUFA ) 17