CONKO-001: Final Results of the Randomized, Prospective, Multicenter Phase III Trial of Adjuvant Chemotherapy with Gemcitabine vs. Observation in Patients with Resected Pancreatic Cancer (PC)

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 2, 2008

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Presenter: Neumann J.P.
Presenter's Affiliation: Charite School of Medicine, Berlin, Germany
Type of Session: Scientific

Background

  • Pancreatic cancer is the fourth leading cause of cancer death in the United States, and in 2007, over 37,000 cases were diagnosed, and over 33,000 deaths documented [Jemal, CA Cancer J Clin, 2007]. 
  • Surgery is the only curative treatment; however, most patients are unresectable at the time of diagnosis (~80%), and even in those who undergo complete resection, there are high rates of local recurrence (50-80%). 
  • Adjuvant therapy for resected pancreatic cancer remains suboptimal. Patients treated with 5-FU- based adjuvant therapy for pancreatic cancer have a median survival of 16-23 months, and 5-year overall survival remains poor at 10-20%.
  • The role of radiation in the post-operative setting remains controversial, with data both supporting its use (GITSG 9173; Kalser M.H. et al., Arch Surg, 1985) and refuting it (ESPAC-1; Neoptolemos J.P. et al., Lancet, 2001).
  • At present, it is unclear what the optimal postoperative treatment is in patients with pancreatic cancer.
  • A prior phase III study (Burris H.A., et al., JCO 1997) demonstrated that single agent gemcitabine significantly improved survival and clinical benefit compared with fluorouracil in the treatment of advanced pancreatic cancer.
  • Results from the present study have previously reported (Oettle H., et al. JAMA 2007) that the use of post-operative gemcitabine in patients with pancreatic cancer significantly delays the development of recurrent disease after complete resection and is generally well tolerated.  This presentation is an update of their previously published results.   

Materials and Methods

  • The present study is a Phase III, multicenter, prospective trial that was designed to evaluate the efficacy of gemcitabine versus placebo in the adjuvant setting in patients who had undergone an R0 or R1 resection for pancreatic cancer.
  • Inclusion criteria included: 
    • histologically proven pancreatic cancer
    • “standard surgery”
    • no measurable disease postoperatively
    • no prior chemotherapy or radiation
  • Patients were stratified by
    • T-stage (T1 and T2 versus T3 and T4)
    • Nodal status (node + versus node -)
    • Grade (grade 1 or 2 versus grade 3)
    • Resection (R1 versus R0)
  • Ultrasound was performed on weeks 8 and 16 to evaluate for disease, and CT scan was performed during week 32 to evaluate for disease. 
  • Patients were then randomized to either 6 months of adjuvant treatment with gemcitabine (arm A) or observation (arm B).
    • Gemcitabine was given at a dose of 1g/m2 on days 1, 8 and 15 every four weeks.
    • Patients in arm B received no specific anti-cancer treatment.
  • The primary endpoint for this study was disease-free survival (DFS)
  • The secondary endpoints for this study were overall survival (OS) and toxicity.
  • This study was powered to detect a significant difference in progression-free survival (PFS) with a power of 90% at a significance level of 0.05. All outcomes were calculated based on intent-to-treat (ITT) analysis.

Results

  • 368 patients were accrued between July 1998 and December 2004, and of these patients, 354 were eligible for ITT analysis. 186 patients were randomized to arm A of which 179 patients were evaluable. 182 patients were randomized to arm B, of which 175 were evaluable. The predominant reason patients were unevaluable was due to withdrawl of consent for both groups.
  • Analysis was performed in March of 2008
  • Patient demographics were similar in each of the two treatment arms.
o       Days to randomization were similar for the two arms (22 days for arm A as compared to 24 days for arm B). 
o       Age was also similar between the two groups (median age 62 yo in arm A as compared to 61 yo in arm B). 
o       The percent of male patients was also similar (59% male in arm A as compared to 56% in arm B).
  • PFS: Median PFS for patients in arm A was 13.4 months (95% CI=11.3-15.4 months) and for arm B was 6.9 months (5.2-7.5 months). 
  • Gemcitabine was beneficial across all subgroups
  • OS: Median OS was 22.8 months (18.5-27.2 months) in arm A versus 20.2 months (17.7-22.8 months) in arm B (p=0.005).
  •  The difference in OS between these two arms increased with time:

 
1 year
2 year
3 year
5 year
Arm A
72%
48.5%
36.5%
21.0%
Arm B
72.5%
40.0%
19.5%
9.0%

   
  • In patients with R0 resection, OS was 22.8 months for patients in arm A and 20.3 months for patients in arm B (p=0.018). For patients with R1 resection, OS was 22.1 in arm A and 14.1 months in arm B (p=0.088).

Author's Conclusions

  • Treatment with Gemcitabine resulted in improved OS and DFS compared with placebo.
    • Gemcitabine approximately doubled OS at 5 years.
  • Gemcitabine should be the standard of care for patients with pancreatic cancer in the post-operative setting.

Clinical/Scientific Implications

  • The optimal postoperative treatment for pancreatic cancer patients remains controversial. After the ESPAC-1 trial (Neoptolemos J.P. et al., Lancet, 2001), the use of radiation in this setting has largely been abandoned in Europe, and chemotherapy alone is considered the standard of care. The ESPAC-1 study suggested that there was a significant benefit to 5-FU based chemotherapy. Head-to-head comparison with 5-FU has suggested that gemcitibine is superior to 5-FU (Burris H.A., et al., JCO 1997). 
  • The CONKO study is the first large randomized study to suggest an advantage to postoperative gemcitabine. The findings from this study suggest that gemcitibine is safe and effective in the postoperative setting, and its use should be considered. It is important to keep in mind that the patient population enrolled in this study was a highly selected one, in that the postoperative CA 19-9 levels had to be less than 2.5 times the upper limit of normal. This is a requirement that might rule out many postoperative pancreatic cancer patients.
  • The optimal postoperative management regimen is currently being further investigated through ESPAC-3, which is designed to compare observation, 5-FU and gemcitabine in the postoperative setting. Given the abysmal outcomes in pancreatic cancer, a combination of multiple chemotherapeutic agents, or chemotherapy in combination with biological agents may prove more effective than single agent approaches.  Promising data from Virginia Mason (Picozzi V.J. et al., ACSO Annual Meeting 2003) regarding the use of multiple agents (alph interferon, cisplatin, 5-FU and radiation) further support this. 
  • Although radiation is controversial, there have been studies which suggest that it may be of benefit when used concurrently with gemcitibine (Loehrer P.J., ASCO Annual Meeting, 2008). There is now evidence to support the use of gemcitabine in the postoperative setting. However, based on currently available evidence, there is no clear standard of care in the postoperative setting. Ongoing studies comparing gemcitibine to 5-FU, and trials investigating the combined use of radiation and chemotherapy in the adjuvant setting, will hopefully further clarify the optimal postoperative treatment.   

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