The extent of resection also carries prognostic significance—a patient who undergoes a complete (R0) resection has a better prognosis than a patient who undergoes a resection with microscopically (R1) or grossly (R2) positive margins.

Margin clearance >1.5 mm is necessary for optimal locoregional control, and the extent of clear margins in R0 resections may be used to estimate the risk of locoregional failure [11].

When PDA is resected with negative margins, the dominant predictor of prognosis is involvement of the locoregional lymph nodes at the time of resection [12].

Tumor size and differentiation appear to be of prognostic significance, with tumors ≥2 cm and poorly differentiated tumors suggesting inferior overall survival [13–15].

Common serum biomarkers include CA 19-9 and CEA [16].

Genetic deficiencies were identified most commonly in 12 core signaling pathways, including cell cycle control, DNA damage control, and apoptosis. Among other breakthroughs, these data also demonstrated that PDA was a cancer of relatively few mutations (averaging 63 mutations per tumor) with key genes such as KRAS, TP53, and SMAD4 frequently affected.

These include efforts to discover novel targeted therapies and those that leverage genetic information to trial combination therapies.

One example is an interplay discovered in preclinical studies between AKT activity and radiosensitivity [23].

The most common lesson that can be gleaned from available data is that both locoregional and distant failures of disease control are common (exceeding 50 % each in many reports) [24–26].

In a retrospective study of 1,130 patients with resected PDA, the patterns of failure were analyzed.

This study and others highlight the importance of adjuvant systemic therapy in preventing both local and distant recurrence and of adjuvant radiation therapy in preventing local recurrence [28–31].

The stratification between high and low rates of locoregional control appeared to be associated with the use of adjuvant CRT with the authors advocating for its routine use.

These data are supported by reports from single-institution series documenting improved local control rates versus historical control data, particularly in postsurgical node- or margin-positive cohorts [33, 34].

The multidisciplinary treatment for these patients is often discussed on a case-by-case basis with options including systemic chemotherapy, palliative surgical or percutaneous interventions, and palliative radiotherapeutic approaches.

As demonstrated by the Johns Hopkins experience, a multidisciplinary clinic can result in a more accurate diagnosis, and treatment recommendations can be made in a more expeditious manner [10, 38, 39].

This is achieved by successful collaboration among the numerous specialties that are dire to delivering care to patients with PDA—medical oncology, radiation oncology, surgery, radiology, pathology, palliative care and pain medicine, and gastroenterology.

For the purposes of this chapter, we will focus on trimodality care with chemotherapy, radiation therapy, and surgery.

Up-front surgery for resectable PDA

Neoadjuvant therapy for resectable PDA

Adjuvant therapy for resected PDA

Neoadjuvant/definitive therapy for borderline resectable and locally advanced, unresectable PDA

Salvage therapy for unresectable locally recurrent PDA

Systemic therapy and/or palliative therapy for metastatic disease

An exception to this may be patients with comorbidities that prohibit chemotherapy or poor performance status (ECOG > 2).

Goals of systemic therapy should be discussed with patients prior to initiation of therapy, and enrollment into clinical trials is strongly encouraged.

Close follow-up of patients undergoing therapy is indicated.

In patients with resectable disease confined to the pancreas, up-front surgery is typically recommended; however, neoadjuvant therapy is standard at some centers [40] and is currently being evaluated in a cooperative group study (NCT01821612).

Combination chemotherapy, particularly FOLFIRINOX and gemcitabine/nab-paclitaxel, with or without radiotherapy is beginning to repeatedly demonstrate a capacity to downstage patients into a surgical paradigm of management.

The use of RT after surgical resection to enhance local disease control is controversial; however, patients resected with positive margins and/or nodes should receive 6 months of adjuvant chemotherapy with or without RT.

There are both institutional and regional biases that are prevalent in the literature, with many European centers using adjuvant therapy routinely after surgery, while centers in the United States tend to be more selective [27, 43].

For resectable PDA, we typically recommend up-front surgery followed by adjuvant chemotherapy with or without CRT.

Multidisciplinary treatment is the cornerstone of therapy for patients with PDA who present with unresectable locally advanced or local recurrent disease after resection.

Depending on performance status, mono- or combination systemic chemotherapy may be considered as initial therapy prior to radiation (CRT or SBRT) for appropriate patients with locally advanced, unresectable disease.

Patients should be evaluated for recovery from hematologic and non-hematologic toxicity prior to initiation of RT (usually 1–2-week break).

Patients who progress with metastatic disease are not candidates for RT unless required for palliative purposes.

If resected patients with a good performance status relapse (locally or distantly) after receiving adjuvant gemcitabine or 5-FU monotherapy, FFX or Gem/NP are options depending on the length of time since completion of adjuvant therapy.

For patients with locally advanced/unresectable and locally recurrent PDA, we treat with induction Gem (poor PFS), Gem/NP, or FFX for 2–12 months followed by definitive CRT or SBRT.

In the setting of LAPC, SBRT has become an option in the neoadjuvant, salvage, and palliative setting with dose adjustment based on goals (Table 7.2).