This document summarizes the evolution of adjuvant therapy trials for pancreatic cancer. It discusses several major trials including ESPAC-1 which established 5FU + leucovorin as standard adjuvant therapy, CONKO-001 which showed gemcitabine was beneficial, ESPAC-3 which found similar survival for 5FU vs gemcitabine, ESPAC-4 which found gemcitabine + capecitabine improved survival, the PRODIGE/UNICANCER trial which showed modified FOLFIRINOX significantly improved survival over gemcitabine, and the APACT trial which found nab-paclitaxel + gemcitabine did not significantly improve DFS over gemcitabine alone.

1. Evolution of adjuvant therapy in pancreatic cancer
DR SUJAN SHRESTHA
MCh, RESIDENT
TUTH, IOM

3. ESPAC 1
February 1994 and June 2000.

4. 53 hospitals in 11 European countries
underwent randomization between
February 1994 and June 2000.

5. • Chemoradiotherapy consisted of a 20-Gy dose to the tumor given in
10 daily fractions over a two-week period plus an intravenous bolus of
fluorouracil
• Chemotherapy (leucovorin and fluorouracil for six cycles)
• Combination therapy consisted of
chemoradiotherapy(preoperatively) followed by
chemotherapy(adjuvant)
• Observation : no therapy given
Four categories
Multicentric , phase 3 , RCT
METHOD

6. • The primary outcome measure was the two-year survival rate
• Secondary outcomes were the incidence of adverse effects and
recurrence and measures of the quality of life.
The analysis of survival was based on 237 deaths
among the 289 patients (82 percent).
METHOD

7. The median survival was 15.9
months for chemoradiotherapy
and 17.9 for without
chemoradiotherapy
Two-year and five-year survival
estimates were
• 29 percent and 10 percent,
respectively for CR group
• 41 percent and 20 percent,
respectively for no CR group
RESULT

8. The median survival was
• 20.1 months for chemotherapy
• 15.5 months for no
chemotherapy
• Two-year and five-year
survival estimates were 40
percent and 21 percent,
respectively for chemotherapy
30 percent and 8 percent,
respectively for no
chemotherapy
RESULT

9. • Standard care for patients with resectable pancreatic cancer should
consist of curative surgery followed by adjuvant systemic
chemotherapy. (YES) (5FU + LEUCOVORIN)
• Adjuvant chemoradiotherapy not only fails to benefit patients but
also reduces survival when it is given before chemotherapy. (NO)
CONCLUSION

10. July 1998 and December 2004
PURELY GERMAN STUDY

11. Stage T1-4N0-1M0, histologically proven, macroscopically completely
resected pancreatic cancer were eligible.
• Active treatment group 6 cycles of gemcitabine
• Control group (observation with a similar follow-up schedule)
The primary objective of disease-free survival
Secondary objectives included treatment safety and overall
survival
METHOD
Multicentric , phase 3 , RCT

13. The median disease-
free survival was 13.4
months in the treatment
group compared with 6.7
months in the observation
group
RESULT

14. At 5 and 10 years, the rates of
disease-free survival were 16.6% and
14.3% respectively, in the gemcitabine
group and 7.0% and 5.8% in the
observation group
RESULT

15. Adjuvant gemcitabine for 6 months compared with
observation resulted in increased overall survival as
well as disease-free survival. These findings support
the use of gemcitabine in this setting.
CONCLUSION

16. ESPAC 1 = 5FU AND LEUCOVORIN IS GOOD
CONKO1 = GEMCITABINE IS GOOD
ESPAC 3 = OK LET'S COMPARE BOTH

17. 2003 to 2007
ESPAC 3

18. The ESPAC-3 trial was initially introduced as a 3-group study designed to
compare the survival benefit of resection alone (observation) with either
adjuvant fluorouracil plus folinic acid or gemcitabine.
Version 1
Version 2
The trial design of ESPAC-3 (version 2) therefore necessitated removal
of the control group from the original ESPAC-3 (version 1) trial design.
Result of ESPAC 1
ESPAC-3 (version 2) is thus a 2-group, international, open-label, RCT
OBVIOUS BENEFIT OF ADJUVANT THERAPY
METHOD

19. Patients were eligible if they had undergone complete macroscopic (R0
or R1) resection for ductal adenocarcinoma of the pancreas.
Performance score of less than or equal to 2
• Folinic acid and fluorouracil 6 cycles (24 weeks).
• Gemcitabine once a week for 3 out of every 4 weeks (1 cycle) for 6
cycles (24 weeks)
Toxicity was assessed using the National Cancer Institute Common Toxicity
Criteria for Adverse Events (version 2)
• Primary endpoint overall length of
survival
• Secondary end points were
progression-free survival, toxicity, and
quality of life.
METHOD

21. Overall Survival
Median survival for patients treated with fluorouracil
plus folinic acid was 23.0 months and for patients
treated with gemcitabine was 23.6 months
The median progression-free survival for patients
treated with fluorouracil plus folinic acid was 14.1 months
and 14.3 months for patients treated with gemcitabine
RESULT

22. • Patients receiving fluorouracil plus folinic acid had
significantly increased grade 3/4 stomatitis and diarrhea
• Patients receiving gemcitabine reported significantly
increased grade 3/4 hematologic toxicity
(14%) receiving
fluorouracil plus folinic acid
reported serious adverse
events, compared with
(7.5%) receiving
gemcitabine
RESULT

23. Adjuvant gemcitabine was recommended as the
treatment of choice in pancreatic cancer patients
following upfront resection.
CONCLUSION

24. Nov 10, 2008, and Sept 11, 2014
ESPAC 4

25. Phase 3, two-group, open-label, multicentre, randomised clinical
trial
• Complete macroscopic resection for ductal adenocarcinoma of the pancreas
(R0 or R1 resection)
• WHO performance score of two or less
• Creatinine clearance of at least 50 mL/min,
• Life expectancy of more than 3 months.
• Gemcitabine for six cycles (24 weeks).
• Capecitabine was administered orally for
21 days followed by 7 days’ rest (one
cycle) for six cycles (24 weeks)
• The primary endpoint was overall survival
• Secondary endpoints
 Survival estimates at 24 months,
 5 year survival, and
 Relapse-free survival.
Toxicity was graded according to the National
Cancer Institute common toxicity criteria,
version 4.03
METHOD

27. The median overall survival time was 25·5 months
in the gemcitabine group and 28·0 months in the
gemcitabine plus capecitabine favouring the
gemcitabine plus capecitabine group
Overall survival was 80·5 at 12 months and 52·1%
at 24 months in the gemcitabine group and 84·1% at
12 months and 53·8% at 24 months in the
gemcitabine plus capecitabine group.
RESULT

28. RESULT

29. No statistically significant grade 3 or 4 toxicity differences

30. ESPAC-4 indicate that adjuvant gemcitabine plus
capecitabine is the new standard of care.
CONCLUSION

31. France and Canada
April 2012 through October 2016

32. • Pancreatic ductal adenocarcinoma, who had undergone complete macroscopic
resection
• World Health Organization (WHO) performance-status score of 0 or 1
• Adequate hematologic function
• Liver function
• Renal function
Multicenter, randomized, open-label, phase 3 trial
Gemcitabine
The modified FOLFIRINOX regimen consisted of oxaliplatin, leucovorin,
irinotecan fluorouracil.
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for
Adverse Events, version 4.0.
• The primary end point was disease-free survival.
• Secondary end points were overall survival, metastasis-free survival, cancer-
specific survival, and safety.
METHOD

34. The median disease-free survival was 21.6 months in the
modified-FOLFIRINOX group, as compared with 12.8 months in the
gemcitabine group
RESULT

35. The median overall survival was 54.4 months in the modified- FOLFIRINOX group,
as compared with 35.0 in the gemcitabine group
RESULT

36. Adverse events of grade 3 or 4 were
reported (75.9%) in the modified- FOLFIRINOX
group and (52.9%) in the gemcitabine group, and
grade 4 events were reported in (12.2%) and
patients (12.0%), respectively
RESULT

37. Modified FOLFIRINOX regimen led to significantly longer
disease-free survival and overall survival than adjuvant
chemotherapy with gemcitabine. The incidence of toxic effects
was higher with the modified FOLFIRINOX regimen than with
gemcitabine therapy.
CONCLUSION

38. Treatment (tx)-naive patients (pts) with histologically
confirmed PC, macroscopic complete resection,
ECOG PS 0/1, & CA19-9 < 100 U/mL were eligible.
Primary endpoint was disease-free survival (DFS)
Secondary endpoints were OS & safety
866 pts were randomized
• Median IR-assessed DFS (439 events) was 19.4 mo (nab-P/G) vs
18.8 mo (G)
• Interim OS (427 events) was 40.5 mo (nab-P/G) vs 36.2 mo
• Grade ≥ 3 TEAEs were reported in 86% vs 68% of pts with nab-P/G vs G.
IR DFS with nab-P/G was not significantly longer vs G
interim OS were improved with nab-P/G vs G
Adjuvant nab-P/G may be an option for pts who are ineligible for FOLFIRINOX

40. Espac 1
Conko 001 trial
Espac 3 (version 1 and 2)(more toxicity with 5fu )
Espac 4
Unicancer gi and prodige trial (maximum median survival of 54 months)
Apact trial

41. Thank you