**7. Neoadjuvant treatment**

Regardless of the relative poor prognosis of the disease and considering that an adequate treatment is the only option for surviving a pancreatic cancer, resectable and borderline resectable pancreatic cancer patients should be considered for curative intention treatments [32].

Theoretically, treating patients with neoadjuvant chemotherapy might favor the eradication of microscopic metastatic disease to obtain better results in terms of survival. It may also help in making a "selection" of patients to undergo surgery: if the patient presents disease progression during treatment, an unnecessary surgery could be avoided in patients that otherwise would have had a rapid disease progression after surgery, considering also that oncological surgery for pancreatic cancer is not free of morbidity and mortality [33].

A decision analysis model to assess what was the best treatment strategy for resectable pancreatic cancer supported the use of neoadjuvant chemotherapy showing that it provided longer survival in comparison to surgery followed by adjuvant chemotherapy [34].

Geus et al. [35] reviewed 12,857 non-metastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated adjuvant chemotherapy. Across propensity scorematched analysis, comparing the clinical outcomes of neoadjuvant therapy versus upfront surgery for pancreatic cancer by stage, neoadjuvant therapy was associated with a significant survival benefit after matching (median survival 22.9 vs. 17.3 months; log-rank P < 0.0001) compared with conventional upfront surgery followed by adjuvant therapy, in stage III patients.

Mokdad et al. [36] reviewed the data from a cohort of 15,237 patients (National Cancer Database 2006–2012) with stage I–II adenocarcinoma of the head of the pancreas that were treated with curative intention, comparing neoadjuvant treatment (chemotherapy or chemoradiotherapy combination) with patients who underwent upfront resection with or without adjuvant treatments (chemotherapy or chemoradiotherapy combination) to evaluate the overall survival impact of those modalities. The authors of this manuscript showed that patients who had received neoadjuvant treatment had better results in terms of survival when compared with patients who underwent surgery as an upfront treatment. The median survival was 26 months for the neoadjuvant group and 21 months for the group who underwent surgery as an upfront treatment, but also a higher pathological tumor stage, a higher incidence of lymph node compromise, and a lesser R0 resection in the group that did not receive neoadjuvant treatment were seen. A two-arms Markov model showed that the median overall survival was longer for the neoadjuvant cohort (22 months) in comparison with the adjuvant group (20 months) [37]. Despite this information that shows better outcomes in terms of survival when neoadjuvant treatments have been done, to date, there are no phase 3 randomized clinical trials that support the use of neoadjuvant treatments in pancreatic cancer patients. Most of the available data are limited to retrospective evidence or to one-arm design-prospective clinical trials [38].

better survival, with a reported median overall survival of 11.1 months versus 6.8 months, respectively (HR for death 0.57 (95% CI, 0.45–0.73), p < 0.001) [30]. This trial was basically conducted among French population and did not include patients of 76 years or older. In patients with ECOG 2 and those with ECOG 0–2 older than 75 years, a lower intensity chemotherapy regimen like gemcitabine with or without nab-paclitaxel should be considered. Von Hoff et al. published in 2013 that the combination of gemcitabine and nab-paclitaxel improves overall survival compared with gemcitabine alone (median OS 8.5 vs. 6.7 months, HR 0.72, CI 0.62–0.83, P < 0.001) [31]. Patients older than 75 years were also included in this study. Chemotherapy should not be recommended in patients with a poor performance status (ECOG 3–4) due to

lack of benefit and because a higher risk of toxicity with worsening of quality of life.

Regardless of the relative poor prognosis of the disease and considering that an adequate treatment is the only option for surviving a pancreatic cancer, resectable and borderline resectable

Theoretically, treating patients with neoadjuvant chemotherapy might favor the eradication of microscopic metastatic disease to obtain better results in terms of survival. It may also help in making a "selection" of patients to undergo surgery: if the patient presents disease progression during treatment, an unnecessary surgery could be avoided in patients that otherwise would have had a rapid disease progression after surgery, considering also that oncological

A decision analysis model to assess what was the best treatment strategy for resectable pancreatic cancer supported the use of neoadjuvant chemotherapy showing that it provided lon-

Geus et al. [35] reviewed 12,857 non-metastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated adjuvant chemotherapy. Across propensity scorematched analysis, comparing the clinical outcomes of neoadjuvant therapy versus upfront surgery for pancreatic cancer by stage, neoadjuvant therapy was associated with a significant survival benefit after matching (median survival 22.9 vs. 17.3 months; log-rank P < 0.0001) compared with conventional upfront surgery followed by adjuvant therapy, in stage III

Mokdad et al. [36] reviewed the data from a cohort of 15,237 patients (National Cancer Database 2006–2012) with stage I–II adenocarcinoma of the head of the pancreas that were treated with curative intention, comparing neoadjuvant treatment (chemotherapy or chemoradiotherapy combination) with patients who underwent upfront resection with or without adjuvant treatments (chemotherapy or chemoradiotherapy combination) to evaluate the overall survival impact of those modalities. The authors of this manuscript showed that patients who had received neoadjuvant treatment had better results in terms of survival when compared with patients who underwent surgery as an upfront treatment. The median survival

pancreatic cancer patients should be considered for curative intention treatments [32].

surgery for pancreatic cancer is not free of morbidity and mortality [33].

ger survival in comparison to surgery followed by adjuvant chemotherapy [34].

**7. Neoadjuvant treatment**

184 Advances in Pancreatic Cancer

patients.

In recent years, the use of systemic preoperative chemotherapy alone or in combination with radiation therapy has been offered to an increasing number of patients with the main intention of reducing the size of the tumor, increasing the likelihood of negative resection margins, and testing the effects of cytotoxic medications in vivo [39].

Phase 2 clinical trials have evaluated the use of neoadjuvant therapy for resectable and borderline resectable pancreatic cancer patients, either with chemotherapy or with chemoradiotherapy combination (**Table 1**).

One quarter of the patients who underwent neoadjuvant chemoradiotherapy had disease progression, and surgery was not performed. Disparities on reported results among patients who underwent surgery showed an R0 resection rate between 12.5 and 96% of the total resected patients. Patients who had progression after treatment did it mainly with distance metastasis (59–73%), most of them located at the liver. Local recurrence rate was seen between 0 and 25% according to different reports. Reported overall survivals show also differences; patients who only received neoadjuvant treatment with chemoradiation had reported survival between 8 and 34 months; patients who underwent only neoadjuvant chemotherapy achieved survivals up to 19 months.

Chemotherapy without radiation has been explored as an option for neoadjuvant treatment in pancreatic cancer. A phase 2 clinical trial in the neoadjuvant setting using gemcitabine with or without cisplatin showed a resection rate of 54% and a median overall survival of 28 months in resected patients [40]. Unfortunately, similar trials using gemcitabine plus cisplatin doublet showed inferior results [41]. Due to the heterogeneity of these studies that included different types of patients such as resectable, borderline resectable, and unresectable patients at diagnosis, but also that have used different modalities of radiotherapy and different schedules and schemes of chemotherapy, no conclusion can be drawn regarding the overall impact on survival and what are the most effective chemotherapy agents or the best combination of chemotherapy agents for resectable pancreatic cancer.

Since 2011, after the results of PRODIGE trial, many case series with neoadjuvant FOLFIRINOX for locally advanced pancreatic cancer have been published, but sample sizes of most studies have been too small to draw definitive conclusions about the efficacy and safety of this treatment approach; however, its use followed by chemoradiation as a multimodality treatment has shown promising results (**Table 2**).


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

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

> 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

**Clinical stage Radiation Resection R0** 

22/ 22 LA: 22 (100%) IMRT 50.4 Gy 12 (54.5%) 5 (42) 24.7 (19.0–30.3)

CHRT: 50.4 Gy and 5-FU\*

CHRT: 50.4 Gy and GEM\*\*

22/22^ BR 22 (100%) CHRT 50.4 Gy^ 15 (68%) 15 (100) 21.7

Noady: neoadjuvant, BR: borderline resectable, LA: locally advanced, SBRT: stereotactic body radiosurgery, IMRT: intensity-modulated radiation therapy, HIGRT: hipofractionated radiation therapy, NC: not correspond, CHRT:

\*\*For unresectable patients post FOLFIRINOX, radiation sensitization patients received concurrent gemcitabine plus

¨¨Patients who appeared to convert to resectable disease underwent surgical exploration, and patients with stable disease

of oxaliplatin, 180 mg/m<sup>2</sup>

Marthey/2015/Cohort 77/77 LA: 77 (100%) 54 Gy\*\*\* 28 (36.3%) 25 (89) 22 (12.3-29.9)

**resection (%)**

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

Neoadjuvant Treatment for Nonmetastatic Pancreatic Cancer

40 (31.4%) 35(92) 34

10 (55.5%) 8 (80%) 32.7 (23.1-42.3)

of irinotecan hydrochloride, 400 mg/m<sup>2</sup>

orally twice daily) prior to pancreatectomy. 10

of

SBRT 36 Gy 11 (44%) 7 (63%) NA

SBRT 30-40 Gy# 21 (13.2%) 5 (24) 15

After FOLFIRINOX and before surgical exploration.

of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation

CHRT¨¨ 31 (30.6%) 16 (52) 26 (18-33)

**Median overall survival range (mo)**

187

**Author/year/type No. patients** 

Boone/2013/ Retrospective

Faris/2013/ Retrospective

Ferrone/2015/ Retrospective

Hosein/2012/ Retrospective

Mellon/2015/ Retrospective

Sadot/2015/ Retrospective

Katz/2016/ Prospective single-arm

IMRT.

#

^

**with Noady FOLFIRINOX/ total**

25/ 25 BR: 12 (48%),

40/127 BR:15 (12%),

18/18 BR 4 (22%), LA 14 (78%)

21/159 BR 110 {69%),

101/101 BR: 31 (30.6%),

chemoradiation, 5-FU: fluorouracil, GEM: gemcitabine.\*

were typically initiated with chemoradiotherapy with 5-FU or GEM.

(50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m<sup>2</sup>

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

\*\*\*External radiotherapy for consolidation.

leucovorin calcium, and then 2400 mg/m<sup>2</sup>

Modified FOLFIRINOX treatment: (85 mg/m<sup>2</sup>

patient initiated adjuvant therapy with GEM.

After neoadjuvant chemotherapy.

LA: 13 (52%)

LA 25(20%)

A: 49 (31%)

LA: 70 (69.3%)

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


Noady: neoadjuvant, BR: borderline resectable, LA: locally advanced, SBRT: stereotactic body radiosurgery, IMRT: intensity-modulated radiation therapy, HIGRT: hipofractionated radiation therapy, NC: not correspond, CHRT: chemoradiation, 5-FU: fluorouracil, GEM: gemcitabine.\* After FOLFIRINOX and before surgical exploration.

\*\*For unresectable patients post FOLFIRINOX, radiation sensitization patients received concurrent gemcitabine plus IMRT.

\*\*\*External radiotherapy for consolidation.
