**14. Neoadjuvant therapy**

There are no randomized controlled trials that compare neoadjuvant to adjuvant therapy for patients with resectable disease. Potential benefits of neoadjuvant therapy include identifying those patients with occult metastatic disease thereby selecting patients who would probably not benefit from surgery. Another potential benefit is avoiding delay in chemotherapy for those patients who have postoperative complications or prolonged recovery. Conversely, the response rates to neoadjuvant therapy are low (9-12%) which may allow for disease progres‐ sion with the delay of surgery [119;120]. Since there is stronger data supporting adjuvant therapy, most centers prefer this approach over neoadjuvant therapy for patients with resectable disease.

Patients with borderline resectable cancer or locally advanced disease can be treated with neoadjuvant therapy with the goal of down-staging allowing for possible resection. Currently, there is no defined optimal neoadjuvant therapy for this population of patients supported by randomized controlled trials. The National Comprehensive Cancer Network recommends that patients with borderline resectable disease undergo a laparotomy followed by resection if possible or upfront neoadjuvant therapy. Available options for neoadjuvant therapy include FOLFIRINOX, gemcitabine, gemcitabine-based combination therapy, capecitabine or contin‐ uous infusion 5-FU [40]. It is suggested that chemoradiation should be reserved for patients who do not develop metastatic disease while receiving chemotherapy [40]. A meta-analysis showed that 31.6% of patients with initially borderline/unresectable tumors treated with neoadjuvant therapy were able to undergo resections. These patients had a median survival of 22 months which appears comparable to those patients with initially resectable disease [120].

#### **15. Adjuvant therapy**

Only about 15-20% of cases of pancreatic cancer are considered resectable. Even after resection the prognosis is poor with 5-year survival rates approximating 20% [121]. Systemic chemo‐ therapy and radiation have been used adjuvantly to improve the survival rates. However the optimal choice of adjuvant therapy remains quite controversial. There have been several phase III studies evaluating therapy in the adjuvant setting; these are summarized in Table 2. The GITSG Trial compared concurrent 5-FU based chemoradiation with observation alone after resection. This study was closed early due to slow accrual and only had 49 patients enrolled at the time of analysis. The GITSG Trial showed an improved survival benefit (median survival 20 months *vs.* 11 months, *p*=0.03) favoring the concurrent chemoradiation group [122]. The GITSG study was followed up by the EORTC study which was similar in design, comparing 5-FU based concurrent chemoradiation to observation. The EORTC study demonstrated no survival advantage with adjuvant therapy. The 2-year survival was 26% *vs.* 34% for the observation and treatment arms respectively; this difference was not statistically significant [123]. The ESPAC-1 Trial had a 2 x 2 factorial design in which they compared concurrent chemoradiation, chemotherapy, chemoradiation followed by chemotherapy or observation. This study was only powered to compare the chemotherapy *vs.* no chemotherapy group and the chemoradiotherapy *vs.* no chemoradiotherapy group. The results showed a statistically significant improved median survival for those patients who received chemotherapy (20.1 months) compared to those patients who did not receive chemotherapy (15.5 months). Interestingly this study demonstrated a worse median survival for patients receiving chemo‐ radiotherapy (15.9 months) compared to those patients that did not receive chemoradiother‐ apy (17.9 months) [124]. Three trials were done evaluating the efficacy of gemcitabine. The CONKO-001 trial compared adjuvant gemcitabine to observation. The trial showed a statisti‐ cally significant improvement in median disease free survival of 13.4 months (gemcitabine arm) compared to 6.9 months (observation arm). There was no difference in overall survival, but this was attributed to the fact that most patients in the observation arm received gemcita‐ bine on relapse [104]. Two trials compared 5-FU with gemcitabine. In the RTOG 9704 study all patients received concurrent 5-FU based chemoradiation with either 5-FU or gemcitabine given before and after. The ESPAC-3 trial compared adjuvant 5-FU to gemcitabine without the use of radiation. Both of these studies showed no survival advantage for one arm over the other. However in the RTOG 9704 study those patients stratified to the gemcitabine arm did have a greater proportion of T3 or T4 disease which may account for no improvement in survival. The ESPAC-3 trial did demonstrate that gemcitabine was associated with fewer adverse events [104;124]. The treatment practice for these patients can be quite variable. Some advocate for adjuvant chemotherapy alone without radiotherapy based on the EORTC and ESPAC-1 trials. Others continue to advocate for radiotherapy given the high risk of local failure and the benefit seen in the GITSG study. The dose of radiation given in these studies would be considered suboptimal by today's standards which the supporters of radiotherapy argue explains why the benefit was not seen in the EORTC and ESPAC-1 studies.


**Table 2.** Phase III Adjuvant Therapy Trials

response rates to neoadjuvant therapy are low (9-12%) which may allow for disease progres‐ sion with the delay of surgery [119;120]. Since there is stronger data supporting adjuvant therapy, most centers prefer this approach over neoadjuvant therapy for patients with

Patients with borderline resectable cancer or locally advanced disease can be treated with neoadjuvant therapy with the goal of down-staging allowing for possible resection. Currently, there is no defined optimal neoadjuvant therapy for this population of patients supported by randomized controlled trials. The National Comprehensive Cancer Network recommends that patients with borderline resectable disease undergo a laparotomy followed by resection if possible or upfront neoadjuvant therapy. Available options for neoadjuvant therapy include FOLFIRINOX, gemcitabine, gemcitabine-based combination therapy, capecitabine or contin‐ uous infusion 5-FU [40]. It is suggested that chemoradiation should be reserved for patients who do not develop metastatic disease while receiving chemotherapy [40]. A meta-analysis showed that 31.6% of patients with initially borderline/unresectable tumors treated with neoadjuvant therapy were able to undergo resections. These patients had a median survival of 22 months which appears comparable to those patients with initially resectable disease [120].

Only about 15-20% of cases of pancreatic cancer are considered resectable. Even after resection the prognosis is poor with 5-year survival rates approximating 20% [121]. Systemic chemo‐ therapy and radiation have been used adjuvantly to improve the survival rates. However the optimal choice of adjuvant therapy remains quite controversial. There have been several phase III studies evaluating therapy in the adjuvant setting; these are summarized in Table 2. The GITSG Trial compared concurrent 5-FU based chemoradiation with observation alone after resection. This study was closed early due to slow accrual and only had 49 patients enrolled at the time of analysis. The GITSG Trial showed an improved survival benefit (median survival 20 months *vs.* 11 months, *p*=0.03) favoring the concurrent chemoradiation group [122]. The GITSG study was followed up by the EORTC study which was similar in design, comparing 5-FU based concurrent chemoradiation to observation. The EORTC study demonstrated no survival advantage with adjuvant therapy. The 2-year survival was 26% *vs.* 34% for the observation and treatment arms respectively; this difference was not statistically significant [123]. The ESPAC-1 Trial had a 2 x 2 factorial design in which they compared concurrent chemoradiation, chemotherapy, chemoradiation followed by chemotherapy or observation. This study was only powered to compare the chemotherapy *vs.* no chemotherapy group and the chemoradiotherapy *vs.* no chemoradiotherapy group. The results showed a statistically significant improved median survival for those patients who received chemotherapy (20.1 months) compared to those patients who did not receive chemotherapy (15.5 months). Interestingly this study demonstrated a worse median survival for patients receiving chemo‐ radiotherapy (15.9 months) compared to those patients that did not receive chemoradiother‐ apy (17.9 months) [124]. Three trials were done evaluating the efficacy of gemcitabine. The CONKO-001 trial compared adjuvant gemcitabine to observation. The trial showed a statisti‐ cally significant improvement in median disease free survival of 13.4 months (gemcitabine

resectable disease.

242 Updates on Cancer Treatment

**15. Adjuvant therapy**

#### **16. Metastatic disease**

Systemic therapy for metastatic pancreatic cancer is aimed at minimizing disease-related symptoms and prolonging survival. For several years the standard of care was 5-fluorouracil (5-FU)-based combinations with an observed survival benefit over best supportive care. The median survival with 5-FU-based combinations on average approximates 6 months versus 3 to 4 months with best supportive care [125]. In 1996, gemcitabine was approved for treatment of metastatic pancreatic cancer after a phase III trial demonstrated a clinical benefit response of 23.8% for those in the gemcitabine group compared to only 4.8% in the 5-FU group (P=0.0022). Secondary endpoints evaluated in the trial included survival rate, which at 12 months was 18% for the gemcitabine arm and 2% for the 5-FU arm [126]. Several gemcitabinebased combinations have been investigated with the goal of further improving its therapeutic efficacy. Sun *et al.* performed a meta-analysis investigating gemcitabine-based combinations compared with gemcitabine monotherapy. The meta-analysis found that combination therapy provided a modest 1-year overall survival with a RR of 0.90 (P=0.04). However, this benefit with combination therapy was associated with more grade 3-4 toxicities including vomiting, diarrhea, neutropenia, anemia and thrombocytopenia. Based on subgroup analyses patients with a good performance status appeared to derive the most survival benefit from combination therapy [127]. The combination of gemcitabine and erlotinib was compared to gemcitabine alone in a phase III trial where a very modest improvement in median survival was observed (6.24 months *vs.* 5.91 months). In this study, 53% of samples were classified as EGFR positive. Interestingly EGFR status did not have any association with response or disease stability [128]. In 2011, Conroy *et al.* reported results of a randomized controlled trial of FOLFIRINOX compared to gemcitabine. The combination chemotherapy regimen improved the objective response rate from 9.4% in the gemcitabine group to 31.6% in the FOLIRINOX group (P<0.001). Median survival was also improved to 11.1 months in the FOLFIRNOX arm compared to 6.8 months in the gemcitabine arm (P<0.001). The combination chemotherapy, as seen with prior combination regimens, was associated with more adverse events [129]. Recently, the combi‐ nation of nab-paclitaxel and gemcitabine was approved for first-line therapy in metastatic adenocarcinoma of the pancreas. Objective response rates were 23% and 7% in the nabpaclitaxel plus gemcitabine arm and single agent gemcitabine arms, respectively (P<0.0001). Progression free survival was also improved with a median PFS of 5.5 months in the combi‐ nation arms compared with 3.7 months in the single agent arm (P<0.0001). There was also an observed median survival benefit of 8.5 months for the nab-paclitaxel plus gemcitabine arm while the single agent gemcitabine arm only had a median survival of 6.7 months (P<0.0001) [130] (Table 3).

#### **17. Palliation**

Palliation of pancreatic cancer patients may be the goal of operative exploration or may result from operative findings indicating unresectablility. Palliation can be performed


**Table 3.** Selected studies for palliative chemotherapy in the metastatic setting

**16. Metastatic disease**

244 Updates on Cancer Treatment

[130] (Table 3).

**17. Palliation**

Systemic therapy for metastatic pancreatic cancer is aimed at minimizing disease-related symptoms and prolonging survival. For several years the standard of care was 5-fluorouracil (5-FU)-based combinations with an observed survival benefit over best supportive care. The median survival with 5-FU-based combinations on average approximates 6 months versus 3 to 4 months with best supportive care [125]. In 1996, gemcitabine was approved for treatment of metastatic pancreatic cancer after a phase III trial demonstrated a clinical benefit response of 23.8% for those in the gemcitabine group compared to only 4.8% in the 5-FU group (P=0.0022). Secondary endpoints evaluated in the trial included survival rate, which at 12 months was 18% for the gemcitabine arm and 2% for the 5-FU arm [126]. Several gemcitabinebased combinations have been investigated with the goal of further improving its therapeutic efficacy. Sun *et al.* performed a meta-analysis investigating gemcitabine-based combinations compared with gemcitabine monotherapy. The meta-analysis found that combination therapy provided a modest 1-year overall survival with a RR of 0.90 (P=0.04). However, this benefit with combination therapy was associated with more grade 3-4 toxicities including vomiting, diarrhea, neutropenia, anemia and thrombocytopenia. Based on subgroup analyses patients with a good performance status appeared to derive the most survival benefit from combination therapy [127]. The combination of gemcitabine and erlotinib was compared to gemcitabine alone in a phase III trial where a very modest improvement in median survival was observed (6.24 months *vs.* 5.91 months). In this study, 53% of samples were classified as EGFR positive. Interestingly EGFR status did not have any association with response or disease stability [128]. In 2011, Conroy *et al.* reported results of a randomized controlled trial of FOLFIRINOX compared to gemcitabine. The combination chemotherapy regimen improved the objective response rate from 9.4% in the gemcitabine group to 31.6% in the FOLIRINOX group (P<0.001). Median survival was also improved to 11.1 months in the FOLFIRNOX arm compared to 6.8 months in the gemcitabine arm (P<0.001). The combination chemotherapy, as seen with prior combination regimens, was associated with more adverse events [129]. Recently, the combi‐ nation of nab-paclitaxel and gemcitabine was approved for first-line therapy in metastatic adenocarcinoma of the pancreas. Objective response rates were 23% and 7% in the nabpaclitaxel plus gemcitabine arm and single agent gemcitabine arms, respectively (P<0.0001). Progression free survival was also improved with a median PFS of 5.5 months in the combi‐ nation arms compared with 3.7 months in the single agent arm (P<0.0001). There was also an observed median survival benefit of 8.5 months for the nab-paclitaxel plus gemcitabine arm while the single agent gemcitabine arm only had a median survival of 6.7 months (P<0.0001)

Palliation of pancreatic cancer patients may be the goal of operative exploration or may result from operative findings indicating unresectablility. Palliation can be performed operatively and nonoperatively and this decision should be individualized depending on the overall status of the patient. Whether palliation is accomplished operatively or nonoperatively, relief of obstructive jaundice, duodenal obstruction, and back pain are the primary goals. About 65% to 75% of patients with pancreatic cancer will develop symp‐ toms of obstructive jaundice [131]. In patients with obstructive jaundice endoscopic biliary stenting and surgical biliary bypass are palliative options. Endoscopic biliary stenting is associated with lower complication rates and shorter hospital stays while maintaining similar efficacy and overall survival compared with surgical bypass [132]. In the event that endoscopic management is not successful, external biliary drainage can be attempted. Duodenal obstruction develops in about 15% to 20% of patients with pancreatic cancer [133]. Traditionally duodenal obstruction had been palliated with gastrojejunostomy, but with data showing similar efficacy with enteral stents, improved cost-effectiveness and shorter hospitalizations this option has become a viable alternative [134].

Most patients with pancreatic cancer, at some point in their disease course, will experience severe cancer-related pain. This pain can be a severely debilitating symptom leading to poor quality of life and decreasing performance status. In addition to systemic analgesics, regional celiac plexus nerve block is effective at alleviating pain [135]. In general, endoscopic palliative measures are preferred for those patients with known unresectable disease or those with a poor performance status. For patients who are discovered to have unresectable or metastatic disease on open exploration and expected to have a life expectancy of at least 3 to 6 months operative palliative measures (choledochojejunostomy, gastrojejunostomy and intraoperative chemical splanchnicectomy) can be considered for symptoms of obstruction and pain [136].

#### **18. Conclusions**

Multiple diagnostic and therapeutic modalities in the evaluation and treatment of pancreatic cancer have not resulted in a meaningful survival advantage in patients with pancreatic cancer. This dismal performance is primarily related to the inherent aggressive tumor biology of pancreatic adenocarcinoma. Early diagnosis and curative resection, when possible, holds promise for better survival but surgery in itself carries a definite morbidity and mortality, even in specialized centers. Hence, pancreatic adenocarcinoma should be managed at high volume centers in a multi-disciplinary setting and in light of proposed guidelines, until better treatment options are available in the future.

#### **Author details**

Zeeshan Ramzan, Phat Le, Payal Kapur and Sergio Huerta\*

\*Address all correspondence to: Sergio.Huerta@UTSouthwestern.edu

University of Texas Southwestern Medical Center / VA North Texas Health Care System, USA

#### **References**

[1] Mayo SC, Gilson MM, Herman JM, Cameron JL, Nathan H, Edil BH et al. Manage‐ ment of patients with pancreatic adenocarcinoma: national trends in patient selec‐ tion, operative management, and use of adjuvant therapy. J Am Coll Surg 2012; 214(1):33-45.

[2] Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62(1):10-29.

with data showing similar efficacy with enteral stents, improved cost-effectiveness and

Most patients with pancreatic cancer, at some point in their disease course, will experience severe cancer-related pain. This pain can be a severely debilitating symptom leading to poor quality of life and decreasing performance status. In addition to systemic analgesics, regional celiac plexus nerve block is effective at alleviating pain [135]. In general, endoscopic palliative measures are preferred for those patients with known unresectable disease or those with a poor performance status. For patients who are discovered to have unresectable or metastatic disease on open exploration and expected to have a life expectancy of at least 3 to 6 months operative palliative measures (choledochojejunostomy, gastrojejunostomy and intraoperative chemical splanchnicectomy) can be considered for symptoms of obstruction and pain [136].

Multiple diagnostic and therapeutic modalities in the evaluation and treatment of pancreatic cancer have not resulted in a meaningful survival advantage in patients with pancreatic cancer. This dismal performance is primarily related to the inherent aggressive tumor biology of pancreatic adenocarcinoma. Early diagnosis and curative resection, when possible, holds promise for better survival but surgery in itself carries a definite morbidity and mortality, even in specialized centers. Hence, pancreatic adenocarcinoma should be managed at high volume centers in a multi-disciplinary setting and in light of proposed guidelines, until better treatment

University of Texas Southwestern Medical Center / VA North Texas Health Care System,

[1] Mayo SC, Gilson MM, Herman JM, Cameron JL, Nathan H, Edil BH et al. Manage‐ ment of patients with pancreatic adenocarcinoma: national trends in patient selec‐ tion, operative management, and use of adjuvant therapy. J Am Coll Surg 2012;

shorter hospitalizations this option has become a viable alternative [134].

**18. Conclusions**

246 Updates on Cancer Treatment

**Author details**

USA

**References**

214(1):33-45.

options are available in the future.

Zeeshan Ramzan, Phat Le, Payal Kapur and Sergio Huerta\*

\*Address all correspondence to: Sergio.Huerta@UTSouthwestern.edu


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**Chapter 11**
