It is estimated that 10% to 20% of patients with pancreatic cancer present with resectable disease. Although surgery offers curative intent, the median survival after curative resection is less than 2 years. To improve clinical outcomes in this patient population, clinical studies have investigated the role of perioperative therapy, including neoadjuvant and adjuvant treatment in resectable pancreatic cancer. The role of adjuvant therapy has been well established by large randomized phase III studies, whereas benefit of the neoadjuvant approach remains inconclusive. Here, we review various treatment modalities and their clinical benefits in resectable pancreatic cancer.
Key points
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Several landmark phase III studies have demonstrated a survival benefit with adjuvant systemic chemotherapy in patients with resected pancreatic cancer.
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The benefit of adjuvant chemoradiation in this population remains controversial.
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Understanding of the role of neoadjuvant treatment in resectable pancreatic cancer is largely limited by small early-phase studies.
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Predictive biomarkers, such as the human equilibrative nucleoside transporter 1 (hENT1), are emerging in the adjuvant setting.
Introduction
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of less than 5%. It is the fourth leading cause of cancer-related mortality in the United States and is projected to rise to the second leading cause by 2030. Surgical resection offers the only chance for cure in pancreatic cancer; unfortunately, only 10% to 20% of patients present with resectable disease at the time of diagnosis because of the lack of effective means of early detection and the presentation of only vague clinical symptoms. Even in patients who undergo curative surgical resections, the 5-year survival rate remains low at 10% to 20%. Clinical studies have explored the role of perioperative therapy, including adjuvant and neoadjuvant treatment, and the survival benefits of adjuvant therapy have been well established over the past few years. The role of neoadjuvant therapy has been explored but remains largely undefined. Efforts to identify predictive and prognostic biomarkers have been intense with encouraging results. Moreover, promising novel therapies have been incorporated in the adjuvant and neoadjuvant settings that may potentially improve survival.
Introduction
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of less than 5%. It is the fourth leading cause of cancer-related mortality in the United States and is projected to rise to the second leading cause by 2030. Surgical resection offers the only chance for cure in pancreatic cancer; unfortunately, only 10% to 20% of patients present with resectable disease at the time of diagnosis because of the lack of effective means of early detection and the presentation of only vague clinical symptoms. Even in patients who undergo curative surgical resections, the 5-year survival rate remains low at 10% to 20%. Clinical studies have explored the role of perioperative therapy, including adjuvant and neoadjuvant treatment, and the survival benefits of adjuvant therapy have been well established over the past few years. The role of neoadjuvant therapy has been explored but remains largely undefined. Efforts to identify predictive and prognostic biomarkers have been intense with encouraging results. Moreover, promising novel therapies have been incorporated in the adjuvant and neoadjuvant settings that may potentially improve survival.
Definition of resectable pancreatic adenocarcinoma
Traditionally, to better prognosticate patients with solid tumors, pathologic staging with the TNM (tumor, node, and metastases) classification system is commonly used. However, because most patients with pancreatic cancer are not eligible for resection, clinical staging is more practical than TNM staging, in particular for patients with localized disease, a group wherein the tumor’s vascular involvement is the deciding factor for resection. An expert consensus group published its criteria on the resectability of pancreatic adenocarcinoma in 2009. Using multidetector computed tomography with triple-phase study, patients without distant metastases or evidence of tumor extension to the superior mesenteric vein and portal vein, and with clear fat planes around the celiac axis, the hepatic artery, and superior mesenteric artery are categorized as resectable. These criteria have clearly distinguished resectable pancreatic cancer from borderline resectable and locally advanced disease, and they have been well recognized and incorporated into clinical trial design. The same criteria are adopted in the National Comprehensive Cancer Network guidelines.
Adjuvant therapy
Major Phase III Trials of Adjuvant Therapy
Pancreatic cancer has a high rate of early metastases. Even in patients with resectable pancreatic cancer who undergo surgical resection, up to 70% of recurrence occurs at distant sites. The rationale of adjuvant treatment is to administer therapy systemically with the intent of eradicating occult metastases. The benefits of adjuvant therapy have been validated in several large phase III clinical trials ( Table 1 ).
| Trial | Year | Pts | Treatment | ≥T3% | N+ % | R0% | Failure, % | Median Survival, mo | Survival Rate, % | |
|---|---|---|---|---|---|---|---|---|---|---|
| Local | Distant | |||||||||
| CONKO-001 | 2007, 2013 | 368 |
| 86 | 72 | 83 | 38 | 53 | 22.8 vs 20.2 ( P = .01) | 20.7 vs 10.4 (5 y) 12.2 vs 7.7 (10 y) |
| ESPAC3 | 2010 | 1088 |
| NA | 72 | 65 | NA | NA | 23.6 vs 23.0 ( P = .39) | 49.1 vs 48.1 (2 y) |
| RTOG 9704 | 2008 | 451 |
| 75 | 66 | 66 | 28 | 73 | 20.5 vs 17.1 ( P = .08) | 22 vs 18 |
| JASPAC 01 | 2013 | 378 |
| 87 | 63 | 87 | 21 | 47 | 25.9 vs not matured ( P <.0001) | 53 vs 70 (2 y) |
Gemcitabine was approved by the US Food and Drug Administration for its superior clinical benefit compared with 5-fluorouracil (5-FU) in advanced pancreatic cancer. Since then, gemcitabine has become the cornerstone treatment for pancreatic cancer. The benefit of gemcitabine in the adjuvant setting was demonstrated in the CONKO-001 trial (Charité Onkologie 001). This is the first phase III trial evaluating the role of adjuvant chemotherapy in patients with resectable pancreatic cancer, and it is a landmark study of this population. In CONKO-001, 368 patients who underwent resection for pancreatic cancer in Germany and Austria were stratified by tumor stage, nodal status, and resection status. Patients were randomly assigned to receive either 6 cycles of gemcitabine 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks or be observed without any treatment protocol. The primary endpoint was disease-free survival (DFS), and the secondary endpoints included overall survival (OS), toxicity, and quality of life. Results were first published in 2007. Gemcitabine was well tolerated with rare adverse events. Grade 3 or 4 hematologic side effects were experienced in 3.8% of patients, and 3.1% had grade 3 or 4 nonhematologic adverse events. Of 186 patients in the gemcitabine group, 111 (62%) patients completed all 6 cycles of treatment. The gemcitabine group had a superior median DFS over observation alone (13.4 vs 6.9 months, P <.001). An updated result was later published in 2013, which not only confirmed the benefit in DFS, but more importantly, demonstrated a prolonged OS in the gemcitabine group (22.8 vs 20.2 months; P = .01). The 5-year survival rate was 20.7% in the gemcitabine group compared with 10.4% in the observation group. The 10-year survival rate was 12.2% versus 7.7%, respectively. This is the first time an actual 10-year survival outcome was reported in patients with resectable pancreatic cancer. This study also established the pivotal role of adjuvant gemcitabine in treating this patient population.
Although gemcitabine was superior to 5-FU in advanced pancreatic cancer, whether this survival advantage persisted in the adjuvant setting remained to be determined. The ESPAC-3 (European Study Group for Pancreatic Cancer 3) trial was initially designed to evaluate the survival benefit of adjuvant chemotherapy with either 5-FU and gemcitabine versus observation alone following resection for pancreatic cancer. After the CONKO-001 trial demonstrated a survival benefit with gemcitabine in resectable pancreatic cancer, the observation group in the ESPAC-3 study was removed. Therefore, this study directly compared the clinical efficacy of gemcitabine to 5-FU in the adjuvant setting. In the ESPAC-3 study, 1088 patients who underwent resection for pancreatic cancer from 159 centers in Europe, Australia, Canada, and Japan were randomized to receive a 6-month course of adjuvant chemotherapy with 5-FU at 425 mg/m 2 plus leucovorin 20 mg/m 2 on days 1 to 5, or gemcitabine 1000 mg/m 2 on days 1, 8, and 15 every 28 days. The 5-FU was associated with more grade 3 or 4 gastrointestinal side effects (eg, stomatitis, diarrhea), whereas the gemcitabine arm had more grade 3 or 4 hematologic toxicities. Overall, gemcitabine was better tolerated with a severe adverse event rate of 7.5%, compared with 14.0% in the 5-FU group. It was speculated that the 5-FU schedule (bolus on days 1–5) was partially responsible for the higher rate of adverse events. There was no significant difference in DFS between the 2 groups. Median OS was 23.0 months for the 5-FU group and 23.6 months for the gemcitabine group, respectively, and this was not statistically significant. Therefore, this study demonstrated that adjuvant 5-FU is equally effective as gemcitabine in resectable pancreatic cancer. In a practical sense, patients with resectable pancreatic cancer who cannot tolerate gemcitabine may receive 5-FU as adjuvant therapy.
On the other side of the Pacific Ocean, Japanese researchers have been exploring the efficacy of S-1 in the treatment of pancreatic cancer. S-1 is an oral fluoropyrimidine that results in survival outcomes similar to gemcitabine in patients with advanced pancreatic cancer. The JASPAC 01 (Japan Adjuvant Study Group of Pancreatic Cancer 01) trial was designed to assess the efficacy of S-1 compared with gemcitabine in the adjuvant setting. In this study, 385 patients were assigned to receive either adjuvant gemcitabine (1000 mg/m 2 , on days 1, 8, and 15, every 4 weeks for 6 courses) or S-1 (80, 100, or 120 mg/d depending on body surface area, days 1–28, every 6 weeks for 4 courses) after surgical resection for pancreatic cancer. The primary endpoint was OS. S-1 was well tolerated and associated with fewer hematologic adverse events. Median OS was 25.9 months in the gemcitabine group and not mature in the S-1 group when the results were presented at the American Society of Clinical Oncology (ASCO) 2013 annual meeting. The 2-year survival rate was 53% for gemcitabine and 70% for S-1. S-1 demonstrated clear noninferiority when compared with gemcitabine (hazard ratio [HR] 0.56, P <.0001), and was even superior to gemcitabine ( P <.0001). This study showed the promising role of S-1 as the new standard adjuvant treatment for resected pancreatic cancer in Japan, and longer follow-up is needed to confirm the survival benefit of S-1.
The RTOG 9704 (Radiation Therapy Oncology Group 9704) trial has incorporated radiation into adjuvant therapy. The study was designed to compare the effectiveness of gemcitabine and 5-FU as adjuvant chemotherapy in combination with radiation. Both groups had 5-FU–based chemoradiation as the backbone. In this study, 451 patients with resected pancreatic cancer were treated with chemoradiation with 5-FU at 250 mg/m 2 per day concurrent with 50.4 Gy radiation after the surgery. In addition, they were assigned to receive either 5-FU at the same dose or gemcitabine (1000 mg/m 2 once weekly), which was given for 3 weeks before, and for 12 weeks after chemoradiation. The median OS was 20.5 months in the gemcitabine group, and 17.1 months in the 5-FU group; the 5-year survival was 22% and 18% for these 2 groups, respectively. The difference in survival was not statistically significant. Multivariate analysis revealed a trend toward better survival outcomes with gemcitabine over 5-FU ( P = .08). Subgroup analysis showed a survival benefit in patients with tumors in the head of the pancreas (HR 0.80, 95% confidence interval 0.63–1.00; P = .05). Since the publication of this study, many institutions in the United States use this regimen of systemic gemcitabine plus 5-FU–based chemoradiation in the adjuvant treatment of resectable cancer in the head of the pancreas.
In summary, several large phase III studies have established the survival benefit of adjuvant chemotherapy in pancreatic cancer. Gemcitabine has been the most commonly used adjuvant agent, and 5-FU was found to have equal efficacy. S-1 was recently found to be noninferior, and even superior to gemcitabine in patients with resectable pancreatic cancer in Japan. Chemoradiation can be used as part of adjuvant therapy in patients with tumors in the head of the pancreas.
Controversy over Adjuvant Radiation Therapy
Although adjuvant chemotherapy was proven to improve survival in patients with resectable pancreatic cancer, the benefit of radiation therapy in the adjuvant setting remains debatable. In the 1980s, the Gastrointestinal Tumor Study Group first observed a survival benefit in 43 patients who received postoperative combined radiation therapy and 5-FU (n = 21) compared with observation alone (n = 22; OS 20 vs 11 months, P = .03). This was followed by a European Organization for Research and Treatment of Cancer study, in which 218 patients with pancreatic head and periampullary cancers were randomized to receive adjuvant radiation therapy and 5-FU versus observation alone after resection. The treatment group demonstrated a trend toward improved survival, but the data did not reach statistical significance (2-year survival rate of 34% vs 26%; P = .099).
The ESPAC-1 trial was a phase III study assessing the roles of adjuvant chemoradiation and chemotherapy, in which 541 patients were randomized by a 2-by-2 design to receive no treatment (observation arm), chemoradiation, chemotherapy, or combined chemoradiation and chemotherapy. This study demonstrated an improved survival in patients who received chemotherapy compared with those who did not receive chemotherapy (5-year survival rate was 21% vs 8%, P = .009). In addition, adjuvant chemoradiation was found to be detrimental, with a 5-year survival rate of 10% in patients who received chemoradiation versus 20% in patients who did not ( P = .05). However, this study was criticized for its study design and confounding factors. For example, because of allowed modifications in the study, a significant number of patients in the “no chemotherapy” group and “chemotherapy only” group received chemoradiation, which confounds the interpretation of the results. Regardless, the incorporation of radiation therapy in the adjuvant setting after resection of pancreatic cancer has fallen out of favor among European researchers. However, in the United States, adjuvant radiation therapy is largely considered to be part of the ideal adjuvant therapy. The ongoing RTOG 0848 trial, which directly compares patients treated with chemotherapy alone versus chemotherapy plus chemoradiation may offer a definitive answer on the benefit of radiation therapy in resectable pancreatic cancer.
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