Palliative chemotherapy in pancreatic cancer—treatment sequences

Abstract

First line options for palliative chemotherapy in pancreatic cancer For years, gemcitabine has been the standard of care and the only therapeutic option in patients with metastatic pancreatic cancer (mPC). The benefit of gemcitabine treated patients in stage IV pancreatic cancer was very limited with 5.65 months (1). Subsequent phase II and phase III studies that aimed to improve the outcome of gemcitabine in combination with different compounds over gemcitabine monotherapy failed. The first positive trial was published in 2007. In this study gemcitabine with erlotinib, a potent and selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, revealed a statistically, albeit clinically not really meaningful benefit of 0.33 months (2). However, patients that developed a skin rash showed a hitherto unknown extension of overall survival with up to 11 months (3). This association has been confirmed in subsequent studies. In 2011 and 2013 data of two phase III studies were released showing a statistically relevant and clinically meaningful improvement in the overall survival of mPC patients thus providing two first line chemotherapeutic options. The PRODIGE-4/ACCORD-11 trial investigated the benefits of therapy with FOLFIRINOX compared with gemcitabine. In this study the treatment with FOLFIRINOX showed an objective response rate of approximately 31.6% and a median overall survival of 11.1 versus 6.8 months in the gemcitabine mono cohort (4) (Table 1). These data were very encouraging demonstrating for the first time not only a nearly doubling of the overall survival, but also high objective response rates. And yet, it has to be noted that in this PRODIGE trial a highly selective patient cohort was chosen with patients included who were under an age of 76 years with an ECOG of 0 or

Precision Therapy of Pancreatic Cancer: From Bench to Bedside

“…Until 2011, gemcitabine was the only validated standard of care [10,11]. Since then however, FOLFIRINOX (a combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin) successfully competes with gemcitabine by increasing OS by 4.3 months (OS 11.1 vs. 6.8 months; p < 0.001) [12,13]. Unlike the combination therapy of gemcitabine plus nab-paclitaxel (gem/nab-Pac) established in 2013, which has a similar OS outcome to FOLFIRINOX (OS of 8.5 months compared to 6.7 months with gemcitabine only, p < 0.001) [13,14], mainly patients with good Eastern Cooperative Oncology Group (ECOG) performance status (99.4% ECOG < 2) have been administered with FOLFIRINOX in the ACCORD trial, DOI: 10.1159/000509232 impeding a direct comparison between the two studies [3,11].…”

“…The gem/nab-Pac regimen is recommended for patients who received FOL-FIRINOX in the front line, provided they have a good performance status [11,20]. For the others, monotherapy with gemcitabine or combination of gemcitabine plus erlotinib may be an option [13,21]. To date, no standard-of-care recommendation exists for those patients who have progressed beyond two lines of systemic therapies, and enrollment in clinical trials is advisable if the ECOG score allows [11,20].…”

“…Targeting Breast Cancer-Induced Genomic Instability A successful example, where basic "bench" research let to the definition of a distinct patient population likely to benefit from targeted treatment, is the recently conducted clinical phase 3 POLO trial. This study examined patients with a familial inherited susceptibility to pancreatic cancer by germline mutations in the tumor suppressor genes BRCA1/2 [22], which occurs with an incidence of around 4-7% of all pancreatic cancer cases [13,23,24]. As has been reported for ovarian and breast cancer [23,25], BRCA loss-of function mutations cause genomic instability via disruption of the homologous recombination (HR) DNA-damage repair mechanism (HR) and thus increase the risk of PDAC formation [24].…”

“…Since then however, FOLFIRINOX (a combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin) successfully competes with gemcitabine by increasing OS by 4.3 months (OS 11.1 vs. 6.8 months; p < 0.001) [12, 13]. Unlike the combination therapy of gemcitabine plus nab-paclitaxel (gem/nab-Pac) established in 2013, which has a similar OS outcome to FOLFIRINOX (OS of 8.5 months compared to 6.7 months with gemcitabine only, p < 0.001) [13, 14], mainly patients with good Eastern Cooperative Oncology Group (ECOG) performance status (99.4% ECOG <2) have been administered with FOLFIRINOX in the ACCORD trial, impeding a direct comparison between the two studies [3, 11]. However, substantial side effects like febrile neutropenia, thrombocytopenia, diarrhea, sensory neuropathy, and alopecia are more commonly seen with the FOLFIRINOX regimen, suggesting FOLFIRINOX as a first-line therapy rather for younger patients with a good performance status [11, 12].…”

“…For those patients, almost 50% [11], who progress under first-line therapy, options for second-line treatments are available. The choice of second-line therapy depends on preceding first-line therapy, the patient’s ECOG score, and prior adverse events, like polyneuropathy [13]. The standard front-line therapy gem/nab-Pac is commonly followed by a 5-FU-based regimen, like OFF (oxaliplatin, 5-FU, folinic acid), resulting in an OS of 5.9 months compared to 3.3 months in the 5-FU control [11, 16, 17].…”