PRODIGE 12-ACCORD 18: trial | Bending the Curve: Trial by Trial

PRODIGE 12-ACCORD 18

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study

Phase 3N = 196NCT01313377

Population

Patients with a localised biliary tract cancer after R0 or R1 resection; 196 included.

Design

Multicentre, open-label randomised phase III trial in 33 centres. Patients were randomly assigned 1:1 within 3 months after complete (R0) or microscopically incomplete (R1) resection of a localised biliary tract cancer to gemcitabine plus oxaliplatin (GEMOX: gemcitabine 1000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or to surveillance (standard arm B). Primary end points were relapse-free survival and health-related quality of life. 196 patients were included between July 2009 and February 2014; after a median follow-up of 46.5 months (95% CI 42.6 to 49.3), 126 relapse-free survival events and 82 deaths were recorded. ClinicalTrials.gov NCT01313377 (registered under the PRODIGE-12 and ACCORD-18 identifiers) lists enrolment 190; the paper reports 196.

Primary endpoint

RFS

Arms

Surveillance (control): Surveillance after resection (standard arm B)
Gemcitabine plus oxaliplatin (experimental): Gemcitabine 1000 mg/m2 on day 1 plus oxaliplatin 85 mg/m2 on day 2 of a 2-week cycle, 12 cycles (experimental arm A)

People

Edeline J, UNICANCER GI

RFSHR 0.88 (95% CI 0.62–1.25)Δ median RFS+11.9 monthsOSHR 1.08 (95% CI 0.70–1.66)Δ median OS+25 monthsTime to definitive deterioration of global health-related quality of lifeHR 1.28 (95% CI 0.73–2.26)Δ median Time to definitive deterioration of global health-related quality of life−0.3 months

Show the numbers

Results reported for PRODIGE 12-ACCORD 18
Endpoint	Analysis	Gemcitabine plus oxaliplatin	Surveillance	Effect
RFSRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 30.4 months	median 18.5 months	HR 0.88 (95% CI 0.62–1.25)P=0.48No significant difference in relapse-free survival (a primary endpoint). Maximal adverse events were grade 3 in 62% (gemcitabine plus oxaliplatin) versus 18% (surveillance) and grade 4 in 11% versus 3% (P < .001).
OSRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 75.8 months	median 50.8 months	HR 1.08 (95% CI 0.70–1.66)P=0.74Overall survival was not a primary endpoint; the abstract reports no difference (log-rank P = .74) after 82 deaths. The medians numerically favour the gemcitabine-oxaliplatin arm while the hazard ratio is above 1; the abstract gives no confidence intervals for the medians.
Time to definitive deterioration of global health-related quality of lifeRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 31.8 months	median 32.1 months	HR 1.28 (95% CI 0.73–2.26)P=0.39Health-related quality of life was a co-primary endpoint; no difference in time to definitive deterioration of global quality of life (log-rank P = .39).

Results reported for PRODIGE 12-ACCORD 18
Endpoint	Analysis	Gemcitabine plus oxaliplatin	Surveillance	Effect
RFSRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 30.4 months	median 18.5 months	HR 0.88 (95% CI 0.62–1.25)P=0.48No significant difference in relapse-free survival (a primary endpoint). Maximal adverse events were grade 3 in 62% (gemcitabine plus oxaliplatin) versus 18% (surveillance) and grade 4 in 11% versus 3% (P < .001).
OSRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 75.8 months	median 50.8 months	HR 1.08 (95% CI 0.70–1.66)P=0.74Overall survival was not a primary endpoint; the abstract reports no difference (log-rank P = .74) after 82 deaths. The medians numerically favour the gemcitabine-oxaliplatin arm while the hazard ratio is above 1; the abstract gives no confidence intervals for the medians.
Time to definitive deterioration of global health-related quality of lifeRandomised patients (analysis population not stated in the abstract)	primarymedian follow-up 46.5 monthsEdeline 2019	median 31.8 months	median 32.1 months	HR 1.28 (95% CI 0.73–2.26)P=0.39Health-related quality of life was a co-primary endpoint; no difference in time to definitive deterioration of global quality of life (log-rank P = .39).

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
RFS	0.88	0.62–1.25
OS	1.08	0.7–1.66
Time to definitive deterioration of global health-related quality of life	1.28	0.73–2.26

Illustrative — modelled from reported values, not trial data. RFS, primary.

Show curves

Gemcitabine plus oxaliplatin (experimental)
Surveillance (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Gemcitabine plus oxaliplatin	Surveillance
0	100.0%	100.0%
19	64.8%	49.1%
38	42.0%	24.1%
57	27.3%	11.8%
76	17.7%	5.8%

Illustrative — modelled from reported values, not trial data. OS, primary.

Show curves

Gemcitabine plus oxaliplatin (experimental)
Surveillance (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)

Months	Gemcitabine plus oxaliplatin	Surveillance
0	100.0%	100.0%
47	65.1%	52.7%
95	41.9%	27.4%
142	27.3%	14.4%
190	17.6%	7.5%

Appears in

2018 BCAT, PRODIGE 12: adjuvant gemcitabine trials, no significant benefit

Sources

Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019;37(8):658-667.
PubMed DOI