After neoadjuvant chemotherapy.

In general, according to data mainly obtained from retrospective studies with a small number of patients with disease in borderline and locally advanced stages, between 13 and 68% of patients could undergo surgery after neoadjuvant treatment, achieving R0 resection in a

Published results of a meta-analysis that included 13 different publications, with different methodologies including 325 patients with locally advanced pancreatic cancer treated with FOLFORINOX regimen, with some of the patients that after this treatment underwent radiotherapy or chemoradiation, showed that 28% of the patients (91 of 325 included in this analysis) underwent surgery with a pooled proportion of patients who achieved R0 surgery of 78% [42]. In this same meta-analysis, which included a total of 689 patients with different stages, as mentioned before, all received FOLFIRINOX; some of them underwent other therapies such as radiation or radio-chemotherapy, and not all the patients treated with FOLFIRINOX as neoadjuvant treatment could undergo surgery, the reported median overall survival across all the studies was 10–32.7 months and the reported progression-free survival ranged from 3 to 20.4 months. In a small multicenter prospective single-arm trial that included 22 borderline resectable pancreatic cancer patients, Katz et al. assessed the use of four cycles of neoadjuvant-modified

range of 24–100%, with a median survival that usually exceeds 20 months.

**Table 1.** Phase II trials of patients treated with neoadjuvant therapies.

186 Advances in Pancreatic Cancer

¨¨Patients who appeared to convert to resectable disease underwent surgical exploration, and patients with stable disease were typically initiated with chemoradiotherapy with 5-FU or GEM.

^ Modified FOLFIRINOX treatment: (85 mg/m<sup>2</sup> of oxaliplatin, 180 mg/m<sup>2</sup> of irinotecan hydrochloride, 400 mg/m<sup>2</sup> of leucovorin calcium, and then 2400 mg/m<sup>2</sup> of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m<sup>2</sup> orally twice daily) prior to pancreatectomy. 10 patient initiated adjuvant therapy with GEM.

**Table 2.** FOLFIRINOX studies only with BR and LA pancreatic cancer.

FOLFIRINOX followed by 5.5 weeks of radiation therapy with a total dose of 50.4 Gy in 28 fractions with concurrent capecitabine twice daily during radiation [43]. Grade 3 or higher toxicity was reported in 64% of patients. Fifteen patients underwent pancreatectomy, 80% of them required vascular resection, and R0 resection was achieved in 93% of the resected patients. The reached median overall survival was 21.7 months. Using another regimen of neoadjuvant chemotherapy, a single patient case report showed efficacy achieving R0 resection in this patient who had unresectable locally advanced diseased and was treated with gemcitabine plus nab paclitaxel combination followed by FOLFIRINOX before surgery [44].

To address the question if neoadjuvant treatments or adjuvant treatments will result with better outcomes, different prospective trials are currently ongoing, and their aim is to find out the real impact of the neoadjuvant treatments in resectable and borderline resectable pancreatic cancer patients. Those trials include neoadjuvant chemotherapy, neoadjuvant versus adjuvant chemotherapy, neoadjuvant chemoradiation, neoadjuvant chemoradiation versus upfront surgery, and other modalities as well [45–49].

borderline resectable pancreatic cancer patients, SLAGO's main recommendation is to consider FOLFIRINOX schedule as the best choice for neoadjuvant treatment; then after selected patients that do not have disease progression after chemotherapy could be considered for radiotherapy with capecitabine as radio-sensibilizer before surgery. For patients who have contraindication to receive FOLFIRINOX and in older than 76 years, neoadjuvant treatment

Neoadjuvant Treatment for Nonmetastatic Pancreatic Cancer

http://dx.doi.org/10.5772/intechopen.75739

189

Pancreatic cancer is one of the most lethal malignancies among all types of solid tumors. Most of the patients are diagnosed at unresectable or at advanced stages with no chances of cure. Early diagnosis is critical to give the patient the chance of cure; however, most of the patients are diagnosed where the tumor is not amenable to be resected. Even more, many of the patients who will undergo an R0 resection will relapse before 2 years after surgery.

We would like to remark that there is no strong evidence to make final conclusions in order to define the best upfront treatment in non-metastatic resectable and borderline resectable pancreatic cancer patients. For resectable patients at diagnosis, upfront surgery is still the standard of care followed by adjuvant chemotherapy. In this subgroup of patients, radiotherapy and chemoradiotherapy do not seem to be the best choice. On the other hand, neoadjuvant chemotherapy has not been explored yet in well-designed clinical trials, and its use has been just limited to small experiences. Borderline resectable pancreatic cancer patients are a subgroup where upfront surgery has a low chance of achieving an R0 resection; therefore, these patients must be considered to receive neoadjuvant treatments in order to improve complete tumor resection and as a consequence to improve survival. As in the resectable subset of patients, radiotherapy or chemoradiotherapy has not shown a real impact in this group. FOLFIRINOX followed or not by chemoradiotherapy seems to be the best option to improve resectability, for achieving complete resection and pathological downstaging and for improving overall survival in resected patients. Final reports from clinical trials will set the key whether or not neoadjuvant treatment, in resectable and borderline resectable pancreatic cancer patients, should be mandatory or recommended.

\*, Sergio Panay Serra2

\*Address all correspondence to: oncodemia@yahoo.com; caglevicc@falp.org

2 Medical Oncology Department, Fundacion Arturo Lopez Perez, Santiago, Chile

3 Unit of Investigational Cancer Drugs, Medical Oncology Department, Fundacion Arturo

, Elizabeth Milla Ramirez2

1 Oncólogo Médico, Clínica Alemana Santiago, Santiago, Chile

, Carlos Gallardo Araneda A3

and Mauricio Mahave Caceres3

,

with gemcitabine plus nab paclitaxel combination can be an option [55].

**9. Conclusions**

**Author details**

Christian Caglevic Medina1

Lopez Perez, Santiago, Chile

Jaime Anabalon Toha2

Concerning toxicity among patients treated with neoadjuvant treatments that have been reported, mostly as local experiences or as small institutional trials, there are no clear data concerning side effects of neoadjuvant therapies, nor there are data on perioperative morbidity and mortality, comparing patients who underwent upfront surgery and patients who received neoadjuvant treatment and then underwent surgery. The biggest data on quality of life come from reports in the metastatic setting. The quality of life report of the PRODIGE-4 trial (mentioned earlier), FOLFIRINOX chemotherapy reduced the quality of life impairment compared with gemcitabine, but also it has benefit in the quality of life that can be a surrogate for survival, as physical functioning and some symptoms severity were prognostic factors for survival [50]. In a meta-analysis of FOLFIRINOX in locally advanced pancreatic cancer, 60% of the patients presented G3 or higher side effects, neutropenia and diarrhea being the most frequent events among treated patients. There were no related deaths attributable to FOLFIRINOX [42]. In a retrospective analysis of patients undergoing FOLFIRINOX as neoadjuvant treatment followed by surgery, Marchegiani et al. concluded that among patients who underwent neoadjuvant chemotherapy, there were less postoperative pancreatic fistula and less postoperative pancreatic hemorrhage but delayed in gastric emptying [51].
