**5. Second-line systemic therapy for metastatic or local advanced unresectable adenocarcinoma of the pancreas**

After progression to a first-line therapy, subsequent treatment will depend greatly on the patient performance status and which drugs were or not given before. Other factors to take in account are molecular abnormalities like dMMR/MSI-H or mutations that can be targeted (druggable mutations).

Patient that received gemcitabine-based chemotherapy as the first-line therapy can be treated with a combination of 5-FU and nanoliposomal irinotecan (nal-IRI). The phase III Napoli-1 trial showed an overall survival difference of 1.9 months (6.1 versus 4.2) when compared with 5-fluorouracil monotherapy (HR 0.67) [39]. 45% of the patients had received 5-FU treatment as a previous line, but only 10% of the patients had received irinotecan previously. A subgroup analysis showed that the benefit was maintained in patients that had received 5-FU but not in those previously treated with irinotecan. A recent update of this trial showed an estimated 1-year survival of 26% for nanoliposomal irinotecan plus 5-FU combination versus 16% for 5 FU alone [40].

Nanoliposomal irinotecan is not yet widely available. Phase two trials have shown than irinotecan plus 5-fluorouracil and leucovorin (FOLFIRI) has modest activity, but comparable to nal-Iri, in patients previously treated with gemcitabine, with an overall response rate of 15% and 35% of stable disease, time to progression 3.7 months and median OS of 6 months [41, 42]. The 2018 American Society of Clinical Oncology (ASCO) guidelines for treatment of metastatic PC endorses the use of FOLFIRI in countries were nal-Iri is not available [43].

Oxaliplatin-containing regimens such as FOLFOX or oxaliplatin plus 5-FU have yielded mixed results as a second line in this setting, with poor accrual and modest benefit. The multicenter German phase III Conko-003 trial compared OFF regimen (oxaliplatin, folinic acid and fluorouracil) against fluorouracil and folinic acid (FF) in patients that had disease progression after gemcitabine treatment. This trial resulted positive in terms of overall survival (median overall survival 5.9 months for OFF regimen and 3.3 months for FF regimen, HR 0.66 p = 0.01) and in terms of time to progression (2.9 months for OFF and 2.0 months for FF respectively, HR 0.68, p = 0.19). Reported neurotoxicity grade 1–2 was higher among OFF- treated patients (38% versus 7% in FF group) [44]. Conversely, the phase III PANCREOX trial failed to show benefit for FOLFOX as second line therapy as compared to 5FU single therapy [45]. With those results, oxaliplatin based regimens are less preferred than nal-Iri or irinotecan-based regimens, but still an option in patients who cannot receive the latter for any circumstances and are still fit and willing to pursue further therapy.

When the combination of irinotecan, oxaliplatin, leucovorin and 5FU (FOLFIRINOX) regimen is given as a first line therapy, patient in good shape could be treated with a gemcitabine-based regimen. Reports have shown feasibility of this regimen [46, 47], but there are no phase III trials supporting this recommendation. As a result, from first line chemotherapy toxicity and declined performance status, it is advisable to use an attenuated regimen in this situation, reducing doses or changing schedules to biweekly administration [48].

Patients with poor performance status, but still fit enough and willing to receive further therapy, should not receive multiagent regimens. Gemcitabine or 5-FU single drug could represent an option for those patients, given the toxicities associated with more intense regimens and modest benefit.

An analysis that included 1503 patients from 34 trials for the second line of treatment for pancreatic cancer showed a median overall survival of 6 months among treated patients and 2.8 months for patients that underwent best supportive care but no chemotherapy (p = 0.013). Patients treated with either gemcitabine or platinum-based chemotherapy showed better outcomes when compared with other regimens, reported progression free survival was 4 months versus 1.6 months (p 0.059) and reported median overall survival was 6 months versus 5.3 months (p = 0.1), respectively [49].

*Current Systemic Treatment Options for Metastatic and Unresectable Pancreatic Cancer DOI: http://dx.doi.org/10.5772/intechopen.93225*

Immunotherapy may represent an option in a very selected group of patients. A phase II trial showed promising activity of pembrolizumab, a PD-1 blocking antibody, in gastrointestinal cancers with deficiency of mismatch repair (dMMR) or high microsatellite instability (MSI-H) [50]. These finding lead to the site agnostic FDA approval for checkpoint inhibitors for dMMR/MSI-H tumors. ASCO 2018 guidelines for metastatic pancreatic cancer recommends dMMR/MSI-H testing to all patients with metastatic PC seeking for second line therapy, although this has modest real impact in PC, given that those abnormalities are present in only percent less than one percent of the patients [7].

Multiple gene testing with next generation sequencing test can lead to the identification of potentially target therapy that can be helpful for patients with metastatic PC, but there is no trial showing clear benefit of using this strategy. There are ongoing randomize trials exploring these options, making it a better option when available.

Stromal-depleting agents such as PEGPH20 have shown promising results in a phase 2 trial in untreated patients when combining with gemcitabine-Nab-paclitaxel in high hyaluronic acid population. These results have not been reproduced when PEGPH20 has been combined with FOLFIRINOX [51].
