Adjuvant Therapy in pancreatic cancer

1. Adjuvant Therapy in Pancreatic
Cancer – An outlook
20-07-2018

2. Introduction
• Pancreatic cancer is the third leading cause of cancer-related death
• 43,090 estimated deaths projected for 2017 in the USA alone
• Worldwide incidence of pancreatic cancer is close to 338,000
• If the mortality rate continues on its current trajectory, pancreatic cancer would become the second leading
cause of deaths from cancer by the year 2030
• 5-year survival rate for pancreatic cancer remains below 10%
• Over the course of 30 years, the 5-year survival rate among all stages of pancreatic cancer has only increased
from 3% in 1975 to 8.9% in 2009
• Surgical resection remains the only chance for cure, but despite this and standard chemotherapy, the 5-year
survival rate for resected disease is less than 30%

3. • Pancreatic cancer is classified by stage and the ability to surgically
resect tumor based on proximity to vital structures
• In resectable disease, the standard of care has been surgery followed
by adjuvant gemcitabine ± chemoradiation
• With recent progress driven by clinical trials, however, there are now
multiple regimens that are data supported
• Systemic therapy is used in all stages of pancreatic cancer including
neoadjuvant (resectable or borderline resectable), adjuvant, locally
advanced, and metastatic disease

6. • Randomized prospective trial conducted between 1974 and 1982
• 14 institutes participated in the study including 43 patients
• Compared observation after surgery
Vs
• Adjuvant 5-fluorouracil (5-FU)-based radiation after surgery, followed by weekly 5-FU for
2 years or until recurrence
• RT consisted of a split course of 40 Gy—two courses of 20 Gy with an interval of 2 weeks.
5-FU was given concomitantly during the first week of radiotherapy and during 2 years
thereafter
• Median survival in observation (n = 23) – 11 months
• Median survival in 5 FU RT(n = 21) – 20 months
• A substantial difference in favour of chemoradiotherapy

8. • RCT
• Between 1987 and 1995
• Included
• T1- 2N0-1aM0 pancreatic head cancer
• T1-3N0-1aM0 periampullary cancer.
• Exluded –
• Stage T3 pancreatic head cancer
• Stage T4 periampullary cancer - excluded because of limited prognosis
• Patients with complications resulting in a prolonged hospital stay were not randomized
• 29 European institutes participated in the study
• Patients were randomized when the definitive pathology report was available and
the patient had recovered from surgery
• The treatment should start within 8 weeks after surgery

9. • 5-FU was given during the periods of radiotherapy, not thereafter
• Given as a continuous infusion instead of a bolus injection
• Radiotherapy was given using a 3 or 4 field technique, starting 2 to 8 weeks
after surgery
• Daily dose RT was 2 Gy, 5 fractions a week, during 2 weeks
• After an interval of 2 weeks, the treatment was repeated to a total
absorbed dose of 40 Gy
• Chemotherapy was started on the same day before radiotherapy and
consisted of a 5-FU dose of 25 mg/kg per 24 hours, with a maximal daily
dose of 1500 mg.

10. • 218 patients were randomized - 108 patients in the observation group and
110 patients in the treatment group
• 114 patients (55%) had pancreatic cancer (54 in the observation group and
60 in the treatment group)
• In the treatment arm, 21 patients (20%) received no treatment because of
postoperative complications or patient refusal
• In the treatment group, only minor toxicity was observed
• The median duration of survival
• 19.0 months for the observation group and 24.5 months in the treatment group
• 2-year survival estimates were 41% (observation group) and 51% (treatment group)

11. • The results when stratifying for tumor location
• Pancreatic head cancer
• 2-year survival rate of 26% in the observation group and 34% in the treatment
group (log-rank, p 5 0.099)
• Periampullary cancer
• the 2-year survival rate was 63% in the observation group and 67% in the
treatment group (log-rank, p 5 0.737)
• No reduction of locoregional recurrence rates was apparent in the
groups

12. • Conclusions of EORTC trial
• Adjuvant radiotherapy in combination with 5-fluorouracil is safe and well
tolerated
• However, the benefit in the study was small
• Routine use of adjuvant chemoradiotherapy is not warranted as standard
treatment in cancer of the head of the pancreas or periampullary region

14. ESPAC 1 Trial

15. • A multicenter trial using a two-by-two factorial design
• A total of 289 patients from 53 hospitals in 11 European countries underwent randomization between
February 1994 and June 2000
• After resection of the pancreatic ductal adenocarcinoma
• Each patient was randomly assigned to receive chemoradiotherapy or chemotherapy, neither treatment, or
both treatments
• Patients were followed up at three-month intervals until death
• Chemoradiotherapy
• 20-Gy dose in 10 daily fractions over a two-week period plus an intravenous bolus of fluorouracil (500 mg per square meter of body-surface
area on each of the first three days of radiotherapy and again after a planned break of two weeks).
• Chemotherapy
• IV bolus of leucovorin (20 mg per square meter), followed by an IV bolus of fluorouracil (425 mg per square meter) on each of 5 consecutive
days every 28 days for six cycles
• Combination therapy consisted of chemoradiotherapy followed by chemotherapy, both administered as described above.

17. • The analysis was based on 237 deaths among the 289 patients (82
percent) and a median follow-up of 47 months (interquartile range,
33 to 62).
• The estimated five-year survival rate
• 10 percent - chemoradiotherapy
• 20 percent - did not receive chemoradiotherapy (P=0.05)
• The five-year survival rate
• 21 percent - who received chemotherapy
• 8 percent - who did not receive chemotherapy (P=0.009)
• The benefit of chemotherapy persisted after adjustment for major
prognostic factors

18. • Conclusions of ESPAC 1
• Adjuvant chemotherapy has a significant survival benefit in patients
with resected pancreatic cancer, whereas adjuvant
chemoradiotherapy has a deleterious effect on survival

19. CONKO 001

20. • Open, multicenter, randomized controlled phase 3 trial with
stratification for resection, tumor, and node status
• Conducted from July 1998 to December 2004 in the outpatient
setting at 88 academic and community-based oncology centers in
Germany and Austria
• A total of 368 patients with gross complete (R0 or R1) resection of
pancreatic cancer and no prior radiation or chemotherapy were
enrolled into 2 groups

21. • Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1,
8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175)
• Results
• More than 80% of patients had R0 resection
• The median number of chemotherapy cycles in the gemcitabine group was 6
(range, 0-6)
• Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by
Spitzer index) between groups
• During median follow-up of 53 months
• 133 patients (74%) in the gemcitabine group
• 161 patients (92%) in the control group developed recurrent disease

22. • Median disease-free survival
• 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3)
• 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank)
• Estimated disease-free survival at 3 and 5 years
• 23.5% and 16.5% in the gemcitabine group
• 7.5% and 5.5% in the control group
• Subgroup analyses showed that the effect of gemcitabine on disease-free
survival was significant in patients with either R0 or R1 resection
• There was no difference in overall survival between
• Gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8;
estimated survival, 34% at 3 years and 22.5% at 5 years)
• Control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated
survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank).

23. • Conclusions CONKO 001 Postoperative gemcitabine significantly
delayed the development of recurrent disease after complete
resection of pancreatic cancer compared with observation alone.
These results support the use of gemcitabine as adjuvant
chemotherapy in resectable carcinoma of the pancreas.

24. ESPAC 3

25. • Background
• Patients with periampullary adenocarcinomas undergo the same
resectional surgery as that of patients with pancreatic ductal
adenocarcinoma
• Although adjuvant chemotherapy has been shown to have a survival
benefit for pancreatic cancer, there have been no randomized trials for
periampullary adenocarcinomas
• Open-label, phase 3, randomized controlled trial ( July 2000- May 2008) in
100 centers in Europe, Australia, Japan, and Canada
• 428 patients included in the primary analysis
• 297 had ampullary, 96 had bile duct, and 35 had other cancers.

26. • Interventions
• 144 patients were assigned to the observation group
• 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus
injection followed by 425 mg/m2 of fluorouracil via intravenous bolus
injection administered 1 to 5 days every 28 days
• 141 patients to receive 1000 mg/m2 of intravenous infusion of
gemcitabine once a week for 3 of every 4 weeks for 6 months

27. • Results
• 88 patients (61%) in the observation group
• 83 (58%) in the fluorouracil plus folinic acid group
• 73 (52%) in the gemcitabine group died
• Median survival
• 35.2 months (95%% CI, 27.2-43.0 months) observational group
• 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86;
(95% CI, 0.66-1.11; 2=1.33; P=.25).

28. • After adjusting for independent prognostic variables of age, bile duct
cancer, poor tumor differentiation, and positive lymph nodes and after
conducting multiple regression analysis
• Hazard ratio for chemotherapy compared with observation was 0.75 (95%
CI, 0.57-0.98; Wald 2=4.53, P=.03)
• Gemcitabine had less severe toxicity than 5 FU
• Conclusions of ESPAC 3
• Among patients with resected periampullary adenocarcinoma, adjuvant
chemotherapy, compared with observation, was not associated with a
significant survival benefit in the primary analysis
• Multivariable analysis adjusting for prognostic variables demonstrated a
statistically significant survival benefit associated with adjuvant
chemotherapy

30. • Determine the efficacy and safety of gemcitabine and capecitabine
compared with gemcitabine monotherapy for resected pancreatic
cancer
• ESPAC 4 – Phase 3, two-group, open-label, multicentre, randomised
clinical trial at 92 hospitals in England, Scotland, Wales, Germany,
France, and Sweden
• Elligible patients were aged 18 years or older and had undergone
complete macroscopic resection for ductal adenocarcinoma of the
pancreas (R0 or R1 resection).
• Randomly assigned patients (1:1) within 12 weeks of surgery

31. • Six cycles of either 1000 mg/m² gemcitabine alone administered once
a week for three of every 4 weeks (one cycle) or with 1660 mg/m²
oral capecitabine administered for 21 days followed by 7 days’ rest
(one cycle).
• Randomisation was based on a minimisation routine, and country
was used as a stratification factor.
• The primary endpoint was overall survival, measured as the time from
randomisation until death from any cause, and assessed in the
intention-to-treat population.
• Toxicity was analysed in all patients who received trial treatment.

32. • Findings
• 730 were included in the final analysis
• 366 were randomly assigned to receive gemcitabine
• 364 to gemcitabine plus capecitabine
• The Independent Data and Safety Monitoring Committee requested
reporting of the results after there were 458 (95%) of a target of 480
deaths.

33. • The median overall survival for patients
• Gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5)
• Gemcitabine group - 25·5 months (22·7–27·9) (hazard ratio 0·82 [95% CI 0·68–0·98],
p=0·032).
• Grade 3–4 adverse events were reported by
• 226 of 359 patients in the gemcitabine plus capecitabine group
• 196 of 366 patients in the gemcitabine group
• Interpretation
• The adjuvant combination of gemcitabine and capecitabine should be the new
standard of care following resection for pancreatic ductal adenocarcinoma

36. Adjuvant Therapy - NCCN Recommendation
• CONKO 001 trial
• Demonstrated significant improvements in disease-free survival and overall
survival with use of postoperative gemcitabine as adjuvant chemotherapy
versus observation in resectable pancreatic adenocarcinoma
• ESPAC-3 study
• Results showed no significant difference in overall survival between 5-
FU/leucovorin versus gemcitabine following surgery.
• When the groups receiving adjuvant 5-FU/leucovorin and adjuvant
gemcitabine were compared, median survival was 23.0 months and 23.6
months, respectively.

37. • ESPAC-4 study
• Support the use of gemcitabine combined with capecitabine (1,660
mg/m2/d d1–21 q 4 weeks) with superiority demonstrated compared to
gemcitabine alone (HR, 0.82; 95% CI, 0.68, 0.98; P = .032).
• No significant differences were observed in the RTOG 97-04 study
comparing pre- and post-chemoradiation 5-FU with pre- and
postchemoradiation gemcitabine for postoperative adjuvant treatment
• Recommended adjuvant therapy options apply to patients who did not
receive prior neoadjuvant therapy.
• For those who received prior neoadjuvant therapy, the adjuvant therapy
options are dependent on the response to neoadjuvant therapy and other
clinical considerations

38. • Gemcitabine (category 1)
• 5-FU/leucovorin (category 1)
• Gemcitabine + capecitabine (category 1)
• Continuous infusion 5-FU (CI 5-FU)
• Capecitabine (category 2B)
• Induction chemotherapy (gemcitabine, 5-FU/leucovorin, or CI 5-FU)
followed by chemoradiation*
• Induction chemotherapy (gemcitabine, 5-FU/leucovorin, or CI 5-FU)
followed by chemoradiation* followed by subsequent chemotherapy:4
• ◊ Gemcitabine followed by chemoradiation* followed by gemcitabine
• ◊ Bolus 5-FU/leucovorin followed by chemoradiation* followed by bolus 5-
FU/leucovorin
• ◊ CI 5-FU followed by chemoradiation* followed by CI 5-FU

39. •Thank You !!!