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Abstract
Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients’ setting are very heterogeneous, and only few randomized studies are available.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Locally advanced or metastatic cancer of pancreatic or biliary tract origin is bitterly characterized by poor prognosis and chemotherapy represents the main chance of cure.
Few treatment options are still available after the failure of first-line chemotherapy. Although the majority of published studies are mainly Phase II single-arm trials, new insight into the topic has been added in recent years.
CONKO-003 Phase III trial showed the efficacy of salvage chemotherapy in patients with pancreatic cancer progressing after gemcitabine treatment. So the oxaliplatin, folinic acid, 5-fluorouracil regimen (oxaliplatin, folinic acid and fluorouracil) can be regarded as a standard of care in such patients.
Results of NAPOLI-1 trial, presented at last ASCO meeting, pointed out the efficacy of MM-398 in treating progressive pancreatic cancer after gemcitabine failure.
Lacking results of ad hoc, controlled studies, a gemcitabine-based treatment could sensibly be considered in patients receiving first-line regimens devoid of gemcitabine such as FOLFIRINOX.
The emerging interest in genomic analysis has leaded in identifying new actionable targets in pancreatic tumors such as EGFR, mTOR, neoangiogenesis, IGF-1R, MDR, NF-κB and hedgehog signaling. Many target molecules have been investigated in Phase II trials while controlled studies are presently ongoing.
Following the rapid development of immunotherapy in solid tumors, encouraging results of a Phase II randomized study with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) have recently been published, inciting more powerful studies in this field.
No Phase III trial has established a standard second-line treatment for biliary tract cancers up to now. However, either gemcitabine or fluoropyrimidine combinations can be selected if not previously used.
Target therapy is also emerging in management of biliary tract cancers. However, despite promising data in preclinical models, former, clinical experiences showed disappointing results. Therefore, more attempts to identify new therapeutic targets and draw innovative clinical studies are desirable.
Due to its good toxicity profile, metronomic chemotherapy can represent a chance to hinder tumor progression in patients with refractory pancreatic and biliary tract cancers. However, the lack of robust data should boost clinical studies to prove the efficacy of metronomics and test its role as partner of more innovative combinations.