Adjuvant Therapy of Pancreatic Cancer: Have We Raised the Bar?

Adjuvant Therapy of Pancreatic Cancer: Have We Raised the Bar?

By Pelin Cinar, MD, MS, and Vincent J. Picozzi, MD

Article Highlights

  • Survival rates continue to be disappointing after surgical resection of pancreatic cancer.
  • Because of the concern for micrometastatic disease, multiple trials, such as ESPAC-1, CONKO-001, and JASPAC-01, have investigated the role of systemic therapy in the adjuvant setting.
  • In the United States, chemoradiation is often reserved for patients at high risk of local recurrence (e.g., R1 resection).
  • Recent trials are investigating the role of chemotherapy in combination with immunotherapy or vaccines.
  • The field is eagerly awaiting the results of recently closed and currently ongoing trials in the adjuvant setting to determine if the pancreatic cancer survival rate can be increased from 20% to 40% by 2020.

Surgical resection of pancreatic adenocarcinoma is generally a sine qua non for curative treatment, but survival rates continue to be disappointing. Although the 5-year survival rate for lymph node–negative disease is 25% to 30%, patients with lymph node–positive disease have a 5-year survival of approximately 10%.1-7 Despite these unfavorable results, adjuvant therapy in the form of systemic therapy with or without radiation therapy is recommended for all patients who undergo pancreatic adenocarcinoma resection. Although the role of chemotherapy has been shown effective in improving outcomes, the role of radiation therapy is less clear in the adjuvant setting. Enrollment on a clinical trial, if available, should strongly be considered for all eligible patients. The optimal timing of initiating adjuvant therapy is up to 12 weeks postoperatively, which accounts for potential postoperative complications and healing time.8 Prior to initiation of chemotherapy, postoperative CT scans and CA 19-9 levels (if elevated prior to surgery) should be obtained.

Prior Adjuvant Therapy Trials

Systemic therapy

Because of the concern for micrometastatic disease, multiple trials have investigated the role of systemic therapy in the adjuvant setting. Despite multiple trials over the past 30 years, results have been hauntingly similar, without substantial improvement in survival rates (Table 1). Median overall survival (OS) has increased in the observation arm of trials over time, presumably as a result of more effective salvage therapies after disease recurrence.

Table 1
The role of systemic therapy was investigated in the ESPAC-1 trial, which showed improvement in median OS of 20.1 months with 5-fluorouracil (5-FU) compared with 15.1 months in the observation-only arm.9 Subsequently, the landmark study CONKO-001 showed improvement in median OS (22.1 vs. 20.2 months) and median disease-free survival (DFS; 13.4 vs. 6.9 months) with gemcitabine versus observation alone.10 After this study, 6 months of gemcitabine became the standard of care in the adjuvant setting of resected pancreatic adenocarcinoma. Because of the positive outcome observed with the use of 5-FU or gemcitabine, the ESPAC-3 trial set out to investigate whether one of these agents was superior to the other. There were no differences in the median OS of approximately 23 months, but 5-FU was associated with a higher rate of grades 3 to 4 toxicity, including mucositis, diarrhea, and myelosuppression.11 More recently, the JASPAC-01 study showed that S-1 was superior to gemcitabine in OS (hazard ratio, 0.56; p < 0.0001) and 2-year survival rates (70% vs. 53%).5 S-1 is currently unavailable in the United States, but it is widely used in Asia and some European countries for pancreatic and gastric cancers.5

The role of chemoradiotherapy

One of the earlier trials studying the role of adjuvant chemoradiation was a prospective randomized study conducted by the Gastrointestinal Tumor Study Group. Although median survival was 20 months with 5-FU–based chemoradiation compared with 11 months with observation, this study was terminated early because the accrual goal was not reached.12 Multiple other phase III trials, including European Organisation for Research and Treatment of Cancer study EORTC 40891,13 Radiation Therapy Oncology Group study RTOG 9704,14 and ESPAC-1,9 also investigated the role of chemoradiation. Although the first two trials showed no significant difference in OS, ESPAC-1 showed that patients had worse outcomes if they received chemoradiation. The poorer outcome was possibly related to delayed systemic therapy. However, the use of radiation therapy in this study was criticized in a variety of ways (e.g., field design and radiation dose).

A meta-analysis of 15 prospective, randomized trials showed that adjuvant chemoradiation compared with surgery alone did not improve DFS (odds ratio [OR] 0.99), 2-year survival (OR 0.90), or OS (OR 0.99), whereas adjuvant chemotherapy improved all three outcomes (OR 2.12, 1.38, and 1.98, respectively).15 As a result of these conflicting findings, chemoradiation is not routinely used in Europe for adjuvant therapy. In the United States, chemoradiation is often reserved for patients at high risk of local recurrence (e.g., R1 resection).

Why Have We Not Raised the Bar?

Treatment of pancreatic adenocarcinoma has been challenging because of the lack of effective therapies and the limited knowledge of tumor biology. The pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment is complex and consists of multiple components, including pancreatic stellate cells, endothelial cells, immune cells, and fibroblasts, and an extensive paracrine and autocrine network resides in a stiff extracellular matrix.16-19 The desmoplastic reaction that is characteristic of the PDAC stroma20,21 has been associated with increased cell proliferation and migration that leads to metastasis in PDAC,22-25 and it disturbs the pancreatic tissue architecture by changing the layout of blood and lymphatic vessels.15,20  As a result of these observations, the early metastatic potential for pancreatic cancer raises concern about disease control after surgical resection.

Adjuvant trials in the past have investigated the role of gemcitabine and 5-FU with and without radiation, as outlined in this article. These single agents provide up to 10% activity in pancreatic cancer.26-29 The limited availability in the past of effective therapies likely accounts for the similar results observed in these trials. Furthermore, 30% to 35% of patients do not complete adjuvant therapy because of prolonged postoperative recovery and comorbidities. With the emergence in the advanced and metastatic setting of more effective combinations of therapy, such as FOLFIRINOX and gemcitabine with nab-paclitaxel, the question remains whether these regimens will also be effective in the adjuvant setting.

Current Therapies

Recent trials have begun to address some of the deficiencies of prior trials by investigating the role of chemotherapy in combination with immunotherapy or vaccines. One such vaccine is GVAX, which is composed of GM-CSF–secreting pancreatic cell lines. In a phase II trial, patients were treated with intradermal GVAX at 8 to 10 weeks after surgical resection and were subsequently treated with concurrent chemoradiation with 5-FU. Patients were then treated with up to three sessions of immunotherapy given 1 month apart and a boost given 6 months after completion of immunotherapy. The treatment was well tolerated; the median DFS was 17.3 months, and the median survival was 24.8 months.30 Because of the promising results, a subsequent trial with GVAX in combination with SBRT and FOLFIRINOX is currently underway (NCT01595321).

Table 2
Algenpantucel-L is a vaccine that induces a hyperacute reaction as a result of two human pancreatic cancer cell lines (HAPa-1 and HAPa-2) that are genetically modified to express epitopes of a-galactosyl, a carbohydrate present in the cells of most mammals except humans. A phase II trial of this vaccine along with chemoradiation showed encouraging results of 1-year DFS and OS rates of 62% and 86%, respectively.31 The subsequent phase III trial, which recently closed to accrual, combined algenpantucel-L with chemotherapy (gemcitabine with or without chemoradiation). Results of this trial are not yet available. In addition to these trials, current ongoing trials are listed in Table 2.

In conclusion, although gemcitabine is currently the standard of care, we are far from raising the bar, with disappointing 5-year survival rates of 10% to 30% in patients with resectable disease. In 2010, the Pancreatic Cancer Action Network announced its goal to double pancreatic cancer survival by 2020. With the exciting new direction of combination therapies, including those with novel agents and immunotherapy, the survival rates may improve. The field is eagerly awaiting the results of the recently closed and currently ongoing trials in the adjuvant setting to determine if the survival rate can be increased from 20% to 40%.

Until the results of these studies are available, the use of combination therapies remains unproven. As we have learned from trials in colorectal cancer, chemotherapy combinations or targeted therapies that are effective in advanced disease may not be associated with additional benefit in the adjuvant setting. At this time, in the absence of data from randomized clinical trials, the additional toxicity of combination chemotherapy is unproven in the adjuvant setting.