The designation of a patient as having borderline resectable pancreatic ductal adenocarcinoma (PDAC) presents a significant clinical challenge because of the existence of multiple definitions and the lack of a standard treatment approach. Pancreatic cancer presents as a continuum, from resectable local disease, to locally advanced unresectable disease because of the involvement of surrounding critical vascular structures. Since the 1990s, a subset of patients between resectable and locally advanced has been recognized. Initially referred to as marginally resectable pancreatic cancer, NCCN coined the term borderline resectable pancreatic cancer to define these patients in its annual guidelines, first published in 1997.¹

Borderline resectable PDAC is best conceptualized as tumors that involve the adjacent vasculature to a limited extent and those for which resection, although possible, will likely be compromised by positive surgical margins in the absence of vascular resection and reconstruction. Of the 338,000 new cases of PDAC diagnosed worldwide, only an estimated 15% to 20% of patients have potentially resectable disease at diagnosis. Approximately 40% have distant metastases, and another 30% to 40% have locally advanced unresectable tumors.

Because surgical resection offers the only chance of cure for nonmetastatic pancreatic cancer, declaring a patient’s disease unresectable is an assignment to therapy without a significant chance for survival beyond 5 years. Consequently, in addition to identifying resectable PDAC, it is important to differentiate borderline resectable PDAC from locally advanced unresectable cancer, because some patients with borderline resectable PDAC can undergo curative resection with similar outcomes to those with resectable disease. Moreover, following current systemic therapy regimens, some patients with locally advanced unresectable PDAC are downstaged to borderline resectable disease and can undergo successful resection of their disease. Therefore, it is a welcome development that there is increasing consensus about the definition of borderline resectable PDAC.

Since the 1997 NCCN definition of resectable, borderline resectable, and unresectable PDAC in the NCCN Guidelines for Pancreatic Adenocarcinoma,¹ their definition has evolved in a deliberate attempt to align with other recent consensus definitions (Table 1).² In 2009, a consensus conference sponsored by the Americas Hepato-Pancreato-Biliary Association (AHPBA) and co-sponsored by the Society for Surgery of the Alimentary Tract (SSAT), the Society of Surgical Oncology (SSO), the gastrointestinal symposium steering committee, and The University of Texas MD Anderson Cancer Center published an expert consensus statement defining resectable and borderline resectable PDAC.³ NCCN endorsed this definition, which differs from the NCCN definition only in the degree of tumor involvement of the superior mesenteric vein-portal vein (SMV-PV).

In the AHPBA/SSAT/SSO definition, all tumors with any degree of abutment or encasement of the SMV-PV are considered borderline resectable. In contrast, the NCCN definition requires distortion of the SMV-PV for the tumor to be considered borderline resectable. By this definition, the absence of evidence of peritoneal or hepatic metastases following a thorough radiologic assessment is a criterion for both resectable and borderline resectable disease. The NCCN Pancreatic Adenocarcinoma Guidelines Panel defines patients with resectable disease as those who have clear fat

Table 1

Definitions of Borderline Resectable Pancreatic Cancer

View Table

In 2013, a more restrictive definition of borderline resectable PDAC was put forth by the experts who designed the inclusion criteria for the Alliance A021101 trial,⁵ the first NCI-supported multi-institutional treatment trial for patients with borderline resectable PDAC. This definition uses the degree of contact described as the interface between tumor and blood vessels rather than subjective terms such as abutment and impingement. The NCCN panel has endorsed this definition for use in clinical trials.

In contrast to the use of only the relationship of the tumor to surrounding vasculature to define borderline resectable PDAC, the group from MD Anderson has used 2 additional distinct criteria to define borderline resectable PDAC.⁶ In this definition, patients with borderline resectable type B disease have potentially resectable anatomy with clinical findings suspicious but not diagnostic for extrapancreatic disease, including indeterminate liver lesions, serum carbohydrate antigen (CA) 19-9 level of 1000 U/mL or greater (with a normal total bilirubin level), or biopsy-proven involvement of regional lymph nodes. Patients with borderline resectable type C disease have potentially resectable anatomy with advanced age (≥80 years), severe comorbidities requiring extensive evaluation or optimization, or depressed performance status (ECOG ≥2).

Although the NCCN panel agreed that patients with metastases to nodes beyond the field of resection derive no benefit from resection, institutions differ in their approaches to peripancreatic lymph nodes. The NCCN panel recommends that patient factors be considered when deciding whether the patient is a surgical candidate. Patient age, comorbidities, performance status, and frailty are all things to be discussed during the multidisciplinary review. Treatment of older patients should follow the NCCN Guidelines for Older Adult Oncology (available at NCCN.org).

Patients commonly present to the oncologist with a non–pancreatic protocol CT already performed. The NCCN panel feels that, if the CT scan is not of high quality, a pancreatic protocol CT is recommended. The pancreatic protocol CT is the most widely available and best validated imaging modality for diagnosis and staging of patients with pancreatic cancer.⁷ Recently, a multidisciplinary expert consensus group defined standardized language for the reporting of imaging results.⁸ Uniform quality imaging and reporting can help improve the accuracy and consistency of identifying patients with borderline resectable PDAC. NCCN Member Institutions vary in the use of additional staging technologies, such as endoscopic ultrasound (EUS). The role of EUS staging is felt to be complementary to CT or MRI, providing additional information for patients whose initial scans show no lesion or whose lesions have questionable involvement of the vasculature or lymph nodes. However, the panel agreed that although the EUS has a high level of accuracy in assessing the involvement of certain vessels such as the PV, this technique is less accurate in imaging tumor invasion of the SMA.⁹

Distinguishing resectable from borderline resectable pancreatic cancer is also important because of the sequencing of multimodality therapy. In the setting of borderline resectable disease, neoadjuvant therapy has been highly debated. However, although no randomized phase III trials support its use, most NCCN Member Institutions prefer an initial approach involving neoadjuvant therapy as opposed to immediate surgery for patients with borderline resectable disease. Although neoadjuvant therapy is also incorporated into the management of resectable disease at some institutions, most NCCN Member Institutions prefer upfront surgery in these patients. Some surgeons have questioned the inclusion of vein involvement in the definition of borderline resectable PDAC. In a multi-institutional retrospective study, they reported no difference in R0 resection in 70 patients who had vein resection and 422 patients who did not (66 vs 75%; P = not significant) without neoadjuvant therapy.¹⁰ In contrast, most institutional series report R0 resection rates of more than 90% in patients with borderline resectable PDAC receiving neoadjuvant therapy.^11,12

The theoretical and practical advantages of a neoadjuvant approach in patients with borderline resectable PDAC include increasing the likelihood of a negative margin resection, potentially decreasing the number of pathologically involved lymph nodes in responsive patients, decreasing the likelihood of performing a vein resection, and identifying patients with poor tumor biology who experience disease progression during systemic therapy and therefore are unlikely to benefit from surgery. It is heartening that the many definitions of borderline resectable PDAC are converging. A uniform definition can help in assessing the varied approaches to these patients and help identify the most promising strategies for prospective studies designed to improve outcomes.