**8. Therapeutics**

The standard chemotherapy regimen for advanced pancreatic cancer has historically been monotherapy with gemcitabine [49]. In patients with metastatic PDAC, gemcitabine with nab‐ paclitaxel improved median overall survival (8.5 vs 6.7 months, HR = 0.72, *p* < 0.001), one‐year survival (35 vs 22%), two‐year survival (9 vs 4%), and improved objective response rate (23 vs 7%) when compared with gemcitabine alone [50]. The most common Grade 3 or higher toxicity events were neutropenia, fatigue, and neuropathy.

Given that the majority of patients who undergo resection with curative intent relapse within 2 years [51], the CONKO‐001 trial set to evaluate the efficacy of gemcitabine as adjuvant therapy administered as a dose of 1 g/m2 on day 1, 8, and 15 every 4 weeks for 6 months. After a median follow‐up of 136 months, patients treated with gemcitabine had an increased median disease‐ free survival (13.4 vs 6.7 months, HR, 0.55 [95% CI, 0.44–0.69]; *p* < 0.001) and prolonged overall survival (HR, 0.76 [95% CI, 0.61–0.95]; *p* = 0.01) versus those patients who were only observed after resection. In 2010, a randomized controlled trial compared the use of fluorouracil plus folinic acid versus gemcitabine as adjuvant chemotherapy. There was no difference in survival between the two treatments [52]. Although alternative chemotherapy regimens have since emerged, utilizing other agents as either monotherapy or in combination with gemcitabine, few studies have demonstrated significantly improved results [24].

There has been increased interest in the use of neoadjuvant therapy for the treatment of pancreatic adenocarcinoma given the potential for better treatment tolerance, improved delivery to an undisturbed tumor bed, avoidance of delay in therapy, treatment of occult micrometastatic disease, and the potential of down staging borderline/unresectable tumors. In a meta‐analysis evaluating 14 Phase II trials involving gemcitabine and 5‐FU chemotherapy regimens (either as monotherapy or combination therapy), there was no difference in local recurrence between patients who were initially considered resectable prior to systemic therapy and those who were not. Only 1.8% of patients had a complete tumor response, while 18.8% of all patients had partial tumor response based on RECIST criteria or criteria defined by the authors of each respective study. Pathologic response was not reported. While there was no difference in survival between the groups of patients deemed resectable pretreatment and those determined to be unresectable, approximately one‐third of tumors initially classified as borderline/unresectable were suitable for resection after neoadjuvant therapy [53].

Despite the lack of Phase III trials addressing neoadjuvant therapy, it is important to emphasize its role in selecting patients who will be good surgical candidates once restaged after comple‐ tion of treatment. It not only allows for better patient selection based on tumor biology, but also increases the possibility of R0 resection and patient completion of multimodal therapy. In contrast to the findings described previously, a neoadjuvant approach using gemcitabine‐ based chemo radiation resulted in a median survival of 34 months for the patients who were candidates for PD versus 7 months for those who did no undergo surgical resection. Addi‐ tionally, this study revealed that a gemcitabine‐based approach to neoadjuvant therapy is superior to 5‐FU and paclitaxel‐based preoperative regimens in terms of better survival of patients after PD [54].

The FOLFIRINOX regimen, combining 5‐flurouracil, leucovorin, irinotecan, and oxaliplatin, was first implemented in the ACCORD‐11 trial conducted by the PRODIGE group. Among 342 patients with previously untreated metastatic PDA, this regimen resulted in an increase in median overall survival from 6.8 months in the gemcitabine group to 11.1 months in the FOLFIRINOX group (HR = 0.57, *p* < 0.001). However, the regimen resulted in increased Grade 3 or 4 adverse effects secondary to treatment, such as neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, and sensory neuropathy. The toxicity of the regimen thus raises concern for its use in patients with more advanced age, poor ECOG status, or greater comorbidities. For this group of patients, gemcitabine with nab‐paclitaxel may be a better option due to its safer toxicity profile, although response to treatment is not as impressive as that observed with FOLFIRINOX. The efficacy of FOLFIRINOX as first‐line therapy in the metastatic setting has prompted the evaluation of its potential in the neoadjuvant setting for patients with borderline or locally advanced disease. FOLFIRINOX followed by chemora‐ diation as neoadjuvant therapy has been shown to be safe in selected patients and has been shown to result in R0 resections [55]. As FOLFIRINOX continues to become increasingly incorporated into clinical practice, further study of patients who tolerate the regimen will help determine predictive factors associated with improved response to this therapy [56–68].
