Neoadjuvant and perioperative chemotherapy for localized pancreatic cancer: Leveraging small and large databases in the absence of Level 1 evidence

Level 1 evidence often is lacking secondary to ongoing trials, new treatment paradigms, or lack of feasibility. For example, small, retrospective, single institutional series suggested no benefit to completion lymph node dissection with sentinel node metastases for melanoma.¹ A large surveillance, epidemiology, and end results (SEER) tumor registry study also demonstrated no survival advantage.¹ These data guided clinical practice before publication of the Multicenter Selective Lymphadenectomy Trial (MSLT)-II prospective randomized trial that confirmed the nonrandomized studies. For Merkel cell cancer, a rare neuroendocrine tumor of the skin, a randomized trial regarding sentinel node biopsy is infeasible. However, SEER registry data comparing sentinel lymph node biopsy and nodal observation demonstrated a prognostic and therapeutic advantage to sentinel node biopsy.²

Evolving treatment paradigms for localized pancreatic cancer

Effective multiagent chemotherapy has revolutionized the treatment of metastatic and localized pancreatic cancer. FOLFIRINOX and nab-paclitaxel/gemcitabine improve survival for patients with metastatic pancreatic cancer.³ As a result, the use of neoadjuvant and adjuvant multiagent chemotherapy for localized pancreatic cancer has increased. Prospective randomized data and retrospective studies demonstrate profound improvement in survival for resected localized pancreatic cancer with the addition of multiagent chemotherapy, 45–60-month median survival.^4-6

Multiple clinical trials are investigating the timing and content of adjuvant therapy for localized pancreatic cancer. However, there is a dearth of Level 1 data to guide therapeutic paradigms. Small and large database studies can bridge these knowledge gaps. In this column, localized pancreatic cancer is divided into four subgroups: locally advanced, borderline resectable, high-risk, and imminently resectable.

Locally advanced pancreatic cancer

Effective chemotherapy has improved survival and resectability for locally advanced pancreatic cancer. With traditional neoadjuvant chemoradiation, such patients are rarely converted to resectable. Multiple centers have reported outcomes with neoadjuvant therapy for locally advanced pancreatic cancer and note increased conversion rates with multiagent chemotherapy. Investigators at the Medical College of Wisconsin, Milwaukee, reported outcomes in 108 consecutive patients with locally advanced pancreas cancer treated in 2009−2017.⁷

The most common definition for locally advanced pancreatic cancer is greater than 180° encasement of the superior mesenteric artery (SMA), celiac, hepatic artery, or unreconstructable occlusion of the portal vein. The group from Wisconsin further subdivides these patients into Type A and Type B.7 Evans Type A has more than 180° involvement of the SMA/hepatic artery but less than 270, greater than 180° involvement of the celiac not involving the aorta. Evans Type B patients have more extensive vascular involvement. Most patients received FOLFIRINOX or nab-paclitaxel/gemcitabine, with radiation. A total of 50 percent of patients went to the operating room, and successful outcomes were reported in 42 percent, 62 percent for Type A, and 24 percent for Type B. Median overall survival after resection was approximately 40 months.

The Mayo Clinic, Rochester, MN, reported outcomes for 123 patients receiving total neoadjuvant therapy from 2010 to 2017.⁴ The neoadjuvant regimen was most often FOLFIRINOX or nab-paclitaxel/gemcitabine, followed by radiation therapy. Chemotherapy regimens were changed for nonresponders. Only 37 percent had locally advanced disease; the remainder were borderline resectable. The investigators reported significant downstaging, even with little radiographic response. Three factors were associated with survival: more than six cycles of chemotherapy, decreased carbohydrate antigen (CA)-19-9, and pathologic response. Survival was not associated with anatomic classification or change in chemotherapy. Overall survival was almost 60 months.

Borderline resectable

In the absence of Level 1 data, neoadjuvant multiagent chemotherapy has become the standard of care for borderline resectable pancreatic cancer.³ The Alliance for Clinical Trials in Oncology defines borderline resectable as more than 180-degree involvement of the superior mesenteric vein (SMV)/portal vein that is reconstructable, the involvement of the SMA/celiac axis of more than 180 degrees, or short segment hepatic artery involvement. The Japanese Society of Pancreatic Surgery reported outcomes in 884 patients with borderline resectable pancreatic cancer treated in 2011−2013, the largest series to date. In this manuscript, upfront surgery is compared with neoadjuvant chemotherapy +/- radiation. In the upfront surgery group, 93 percent of the patients were resected versus 75 percent in the neoadjuvant group. Despite the lower resection rates, neoadjuvant therapy was associated with improved survival, 25.7 versus 19.0 months, and increased R0 resection rates.⁸

The role of radiotherapy for borderline resectable pancreatic cancer is unclear. Results from a prospective randomized trial by the Alliance comparing neoadjuvant FOLFIRINOX with/without radiation are pending. Unfortunately, much of the retrospective data regarding neoadjuvant radiation therapy combines locally advanced and borderline resectable.

Our group, using National Cancer Database (NCDB) data, investigated the role of radiation therapy in addition to multiagent chemotherapy for locally advanced and borderline resectable disease. The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons (ACS) and the American Cancer Society. The reader should be mindful that the data used in the study are derived from a deidentified NCDB file. The ACS and the CoC have not verified and are not responsible for the analytic or statistical methodology employed or the conclusions drawn from these data.

A total of 2,703 patients diagnosed in 2006−2014 were included in the study. Radiation therapy was associated with increased complete pathological response rates, R0 resection rates, and downstaging with no improvement in survival. The Japanese Society of Pancreatic Surgery also failed to demonstrate improved survival with neoadjuvant radiation in borderline resectable patients.⁸ Conversely, a multi-institutional French study noted improved survival with radiation therapy after neoadjuvant chemotherapy.⁶

High-risk pancreatic cancer

Many patients are high risk, even when not locally advanced or borderline resectable. NCDB data can classify patients into high and low risk for mortality.⁹ This study included 25,897 patients diagnosed in 2004−2013 with stage I, II, or III pancreatic cancer. Factors associated with mortality include size (</> 2 cm), grade, lymph node metastasis, adjuvant therapy, and surgical margins.

For example, a patient younger than 65 years of age with a small, low-grade tumor, who undergoes an R0 pancreatic resection and is treated with adjuvant therapy, has an expected five-year survival of 51 percent. In contrast, a 70-year-old patient with a larger, high-grade tumor resected with positive margins treated with adjuvant therapy has an expected five-year survival rate of 5 percent. Unfortunately, many of these factors are unknown preoperatively. The National Comprehensive Cancer Network (NCCN) defines preoperative high-risk features as high CA-19-9, lymph node disease, pain, and weight loss.¹⁰ The American Society of Clinical Oncology (ASCO) guideline also includes reversible medical conditions and large size.⁵ In the absence of clear-cut data, expert opinion from both ASCO and NCCN recommends consideration of neoadjuvant therapy for high-risk patients.

Imminently resectable

Surgeons should be mindful that at least 20 to 30 percent of patients treated with neoadjuvant therapy will never undergo surgical resection. The recently published PRODIGE 24/CCTG PA.6 trial is a prospective randomized trial comparing postoperative FOLFIRINOX to gemcitabine in 493 patients enrolled in 2012−2016.¹¹ The survival in the FOLFIRINOX group was 54.4 months versus 35.0 with gemcitabine. Given the excellent outcomes with upfront resection with postoperative multiagent chemotherapy and high dropout rates, the question remains, which patients should undergo upfront surgery?

Although the cancer care community has achieved broad consensus regarding neoadjuvant therapy for advanced tumors, questions remain about how to manage patients who fit into none of these categories. To answer this question, our group examined 13,412 NCDB patients with T1 and T2 tumors diagnosed in 2006−2014.¹³ Four groups were defined: chemotherapy-only, surgery-only, neoadjuvant, and postoperative adjuvant. Chemotherapy-only patients have the worst survival rate, followed by surgery-only. Outcomes are improved with the addition of adjuvant therapy.

Neoadjuvant and postoperative adjuvant chemotherapy had similar survival rates. Only one-quarter of patients who start with curative intent chemotherapy underwent resection. A series from the University of Pittsburgh, PA, reported similar findings.¹² In this series, 552 patients with resected pancreatic adenocarcinoma treated in 2008−2015 were included, and the authors noted improved survival with at least six cycles of perioperative chemotherapy. Similar to our findings, the authors noted no effect on survival if therapy was delivered preoperatively, perioperatively, or postoperatively. One could define a group of patients as imminently resectable if they do not have high-risk features and can be resected with an anticipated negative margin. In this group, upfront resection should be considered.

Conclusion

Although prospective randomized trials remain the gold standard, large and small data sets can inform clinical practice. Large national registries such as the NCDB can be leveraged to answer important clinical questions. When using such databases, it is important that investigators understand the limitations of the data, study clinically meaningful hypothesis-driven questions, apply appropriate controls, and account for imbalance in study arms with appropriate techniques such as propensity matching.

In the rapidly evolving clinical paradigms for localized pancreatic cancer, a combination of Level 1 data and database studies inform management. Clearly, multiagent chemotherapy has improved survival for localized pancreatic cancer. For locally advanced pancreatic cancers, neoadjuvant treatment should be given. By dividing patients into Evans Type A and B, we can better educate patients about the likelihood of a successful operation. In this setting, with a high risk of R1 resection, it is reasonable to consider the addition of radiation therapy to preoperative multiagent chemotherapy. For patients with borderline resectable tumors four months of neoadjuvant therapy, ideally FOLFIRINOX, and selective use of radiation therapy should be considered. High-risk disease can be defined as the abutment/involvement of major vasculature structures, high cancer antigen 19-9, pain, weight loss, reversible medical comorbidities, and tumor size greater than 2 cm. In such patients, neoadjuvant or perioperative multiagent chemotherapy should be considered. In a select group of patients with imminently resectable tumors, upfront surgery with postoperative adjuvant FOLFIRINOX could be considered.

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