Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.

Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic

cancer: a randomized controlled trial 

Oettle H, Post S, Neuhaus P et al.

JAMA, 2007, 297, 267-277

Exocrine pancreatic adenocarcinoma has a dismal prognosis with a mortality incidence ratio of 98%. Diagnosis is usually made when disease is already extended and no surgery with curative intent is feasible. Only 10-20% of patients will undergo surgery. An R0 surgical procedure is performed in two-thirds of these cases and most of these potentially cured patients will recur. Median survival is less than 2 years for this group of patients. Pancreatic cancer can be considered a systemic disease even at the early stages. This concept emphasises the need for effective adjuvant treatment strategies.

Gemcitabine has been the cornerstone of treatment in the advanced setting since 1997 when results from a trial comparing gemcitabine to 5-fluorouracil (5FU) were published [1]. Clinical benefit and 1-year survival were significantly improved (23.8% versus 4.5% and 18% versus 2%, respectively). Since then, gemcitabine doublets with cisplatin, oxaliplatin, irinotecan, pemetrexed, capecitabine and docetaxel have been tested. Only one Phase III trial demonstrated a significant advantage for the combination of gemcitabine and erlotinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), over gemcitabine alone with a median overall survival (OS) of 6.24 versus 5.91 months (hazard ratio, 0.82; P=0.038) and a 1-year survival of 23% versus 17% (P=0.023), respectively [2]. Two recent meta-analyses have shown a small but significant survival benefit for doublets of gemcitabine with either platinum compounds or capecitabine. The benefit was greater in the subgroup of patients with good performance status [3,4].

To date, an OS advantage has been established from postoperative treatment in resectable disease with bolus 5FU and leucovorin (LV) [5]. The 5-year survival rate was 21% among patients who received chemotherapy and 8% among those who did not (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. This trial [European Study Group for Pancreatic Cancer (ESPAC)-1) with 289 patients randomly assigned in a 2x2 factorial design (chemoradiotherapy versus chemotherapy versus chemoradiotherapy followed by chemotherapy versus observation) showed a deleterious effect of radiation therapy. The estimated 5-year survival rate was 10% among patients assigned to receive chemoradiotherapy and 20% among patients who did not receive chemoradiotherapy (P=0.05). Chemoradiotherapy has been accepted as the adjuvant standard in the USA and Canada, based on a small study of the Gastrointestinal Tumor Study Group, which randomly assigned patients to combined radiation and 5FU (21 patients) or observation (22 patients). Median survival for the treatment group (20 months) was significantly longer than that observed for the control group (11 months) [6].

Results from Radiation Therapy Oncology Group (RTOG) 9704 trial have shown that the addition of gemcitabine given over 3 weeks before and 12 weeks after postoperative adjuvant 5-FU chemoradiotherapy significantly improved median survival in patients with pancreatic head adenocarcinoma (n=380) (18.8 versus 16.7 months; P=0.047) when compared to infusional 5FU alone. When analysis included all patients (n=442), no significant difference in survival was found (P=0.20) [7].

The present trial by Oettle et al. clearly shows a significant advantage in terms of disease-free survival (DFS) for patients treated postoperatively with gemcitabine (1g/[m.sup.2] weekly for three weeks, every 4 weeks) for 6 months when compared with observation alone. A total of 368 patients were randomly assigned to gemcitabine post-operative treatment or observation, and stratified for prognostic factors: resection status (R0 versus R1), tumour status (T1/T2 versus T3/T4) and lymph node status (N0 versus N+). With a median follow-up of 53 months, the median DFS was 13.4 months in the gemcitabine group and 6.9 months in the control group (P=0.001).

Estimated DFS at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect on DFS of gemcitabine was significant in patients with either R0 or R1 resection, in those with large or small primary tumours, and in those with or without nodal involvement. There was no significant difference in OS between the gemcitabine group (median, 22.1 months; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P=0.06). Subgroup analyses showed a significant difference in median OS in favour of adjuvant gemcitabine for N0 patients in the intent-to-treat analysis (34 versus 27.6 months; P=0.04).

The ESPAC-3, three-arm trial with 1030 patients recruited, is comparing the efficacy of gemcitabine, bolus 5FU/LV and observation, in terms of OS, in patients with completely resected pancreatic cancer. Preliminary results are soon expected. In a direct comparison, gemcitabine may lead to significant improvements over 5FU/ LV in the adjuvant setting. It appears that gemcitabine doublets either with erlotinib, capecitabine or platinum compounds are slightly more active than gemcitabine alone in advanced disease and in the future these combinations may achieve an advantage over gemcitabine alone in the adjuvant setting. Chemoradiotherapy with improved methods of delivering conformal radiotherapy can be used in selected patients with locally advanced disease. At present, the role of radiation therapy in the adjuvant setting remains controversial. Much work remains to be done, and recruiting pancreatic cancer patients and their biological samples into carefully designed clinical trials to test new strategies and drugs is essential to achieve better results in this devastating disease.

References

[1.] Burris H, Moore MJ, Andersen J et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol, 1997, 15, 2403-2413.

[2.] Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 2007, 25, 1960-1966.

[3.] Heinemann V, Hinke A, Bock S et al. Gemcitabine combinations (gem + x) vs gemcitabine (gem) alone in the treatment of advanced pancreatic cancer: a meta-analysis of sixteen randomized trials. Proc ASCO, 2007, 25, Abstr. 4515.

[4.] Banu E, Banu A, Fodor A et al. Meta-analysis of randomised trials comparing gemcitabine-based doublets versus gemcitabine alone in patients with advanced and metastatic pancreatic cancer. Drugs Aging, 2007, 24, 865-879.

[5.] Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med, 2004, 350, 1200-1210.

[6.] Kalser MH and Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg, 1985, 120, 899-903.

[7.] Regine WF, Winter KW, Abrams R et al. RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. Proc ASCO, 2006, 24, Abstr. 4007.

Commentary by Alfredo Carrato and Carmen Guillen-Ponce (1)

(1) Medical Oncology Department, Elche University Hospital, Spain