Progressive benefits with the anachronistic use of melee weapons

 James Fleck & Polyana Cardoso: Anticancerweb 09(01), 2019

Pancreatic carcinoma is the malignant epithelial tumor with the highest lethality rate. Most of the cases are diagnosed as metastatic or locally advanced disease, which leads to a cure rate of less than 10%. In the palliative scenario, both prospective randomized trials and metanalysis have supported the advantage of chemotherapy over best supportive care. A French trial published at the New England Journal of Medicine in 2011, additionally showed a better median overall survival rate (11.1 months) for patients with metastatic pancreatic carcinoma treated with combined chemotherapy (FOLFIRINOX) when compared to gemcitabine alone (6.8 months).

In an attempt to transfer this knowledge to the curative setting, sequentially three prospective randomized trials were published. They included both completed resected patients with no residual microscopic disease (R0) and patients with pathological (microscopic) residual disease (R1). Although residual microscopic disease has not normally been included in the adjuvant treatment concept, all the three trials accepted R1 patients. Despite the type of resection, all trials have shown consistent increases in disease-free survival (DFS) and overall survival (OS) rates. The table below shows a comparison of the most relevant demographic and outcome data.

The GONKO study, published on JAMA in 2013, included predominantly patients with R0 resection and supported the standard use of gemcitabine as pancreatic carcinoma adjuvant systemic treatment. In 2017, the ESPAC 4 study was published in Lancet, showing an adjuvant benefit with the combination of gemcitabine plus capecitabine. An impressive median OS of 39.5 months was observed in pancreatic cancer R0 resected patients. More recently, the PRODIGE 24 study was published in the New England Journal of Medicine, revealing further improvement on median DFS (21.6 months) and median OS (54.4 months) with the adjuvant use of modified FOLFIRINOX (decreased dose intensity of irinotecan and withdrawal of fluorouracil bolus). The prognostic gain occurred with expressive, but tolerable toxicity in pancreatic cancer patients R0 + R1 with good performance status. The median DFS observed in the control arm (12.8 months) is consistent with the use of gemcitabine in the previous adjuvant studies. However, the PRODIGE 24 showed an unexpected increase in median OS on the gemcitabine arm (35 months), which was later explained by crossover use of FOLFIRINOX. Published in December 2018, the PRODIGE 24 created a new standard of adjuvant treatment ( modified FOLFIRINOX) for patients with pancreatic cancer R0 and R1 with good performance status. It sounds ironical, that in the era of intelligent, customized and less toxic treatments, a prognostic gain was obtained with combined chemotherapy melee weapons.

 

                        

References:

 

Thierry Conroy, Françoise Desseigne, Marc Ychou, et al:  FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer, N Engl J Med 364: 1817 – 1825, 2011

Helmut Oettle, Peter Neuhaus, Andreas Hochhaus, et al: Adjuvant Chemotherapy with Gemcitabine and Long-term Outcomes Among Patients with Resected Pancreatic Cancer the CONKO-001 Randomized Trial, JAMA 310(14): 1473 – 1481, 2013

John P Neoptolemos, Daniel H Palmer, Paula Ghaneh, et al:Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial, Lancet389: 1011-1024, 2017

T. Conroy, P. Hammel, M. Hebbar, M. Ben Abdelghani, et al: FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer, N Engl J Med379: 2395 – 2406, 2018