Contemporary Management of Borderline Resectable and Locally Advanced Unresectable Pancreatic Cancer

This article reviews the literature and highlights the areas of controversy regarding management of borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). The lack of consensus on the definitions of BRPC and LAPC leads to major limitations in designing clinical trials and evaluating their results. The role of combination chemotherapy regimens, which have improved overall survival in metastatic disease, is an area of active investigation.

Abstract

Adenocarcinoma of the pancreas remains a highly lethal disease, with less than 5% survival at 5 years. Borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC) account for approximately 30% of newly diagnosed cases of PC. The objective of BRPC therapy is to downstage the tumor to allow resection; the objective of LAPC therapy is to control disease and improve survival. There is no consensus on the definitions of BRPC and LAPC, which leads to major limitations in designing clinical trials and evaluating their results. A multimodality approach is always needed to ensure proper utilization and timing of chemotherapy, radiation, and surgery in the management of this disease. Combination chemotherapy regimens (5-fluorouracil, leucovorin, irinotecan, oxaliplatin, and gemcitabine [FOLFIRINOX] and gemcitabine/nab-paclitaxel) have improved overall survival in metastatic disease. The role of combination chemotherapy regimens in BRPC and LAPC is an area of active investigation. There is no consensus on the dose, modality, and role of radiation therapy in the treatment of BRPC and LAPC. This article reviews the literature and highlights the areas of controversy regarding management of BRPC and LAPC.

Implications for Practice:

Pancreatic cancer is one of the worst cancers with regard to survival, even at early stages of the disease. This review evaluates all the evidence for the stages in which the cancer is not primarily resectable with surgery, known as borderline resectable or locally advanced unresectable. Recently, advancements in radiation techniques and use of better combination chemotherapies have improved survival and tolerance. There is no consensus on description of stages or treatment sequences (chemotherapy, chemoradiation, radiation), nor on the best chemotherapy regimen. The evidence behind the treatment paradigm for these stages of pancreatic cancer is summarized.

Introduction

Pancreatic cancer (PC) is the fourth leading cause of cancer death in the U.S., with approximately 40,000 deaths of an estimated 42,000 annual cases of PC in 2014 [1]. Resectable disease comprises only 15% to 20% of patients at presentation. The vast majority of patients with PC present at advanced stages of disease, with approximately 50% of patients having metastatic disease [2] and an additional 25% to 35% of patients presenting with either borderline resectable pancreatic cancer (BRPC) or locally advanced unresectable pancreatic cancer (LAPC) [3].

In BRPC and LAPC, the tumor is localized to the pancreatic area but adheres to or involves adjacent vascular structures, including celiac axis vessels, superior mesenteric artery (SMA), superior mesenteric vein (SMV), and portal vein. BRPC is defined as tumor with limited involvement of the adjacent vascular structures where vascular reconstruction options are feasible [3]. There is no consensus in the surgical oncology community on the definition of what degree of vascular reconstruction should be considered resectable in the management of pancreatic cancer.

Median overall survival (mOS) ranges from 5.5 to 22 months for BRPC and LAPC patients; LAPC survival reaches an mOS of approximately 16 months, whereas that of BRPC rarely reaches 2 years [2, 4–8]. The objective of treatment in BRPC is to achieve downstaging of the tumor to facilitate margin-negative (R0) resection. Optimal treatment for BRPC is still controversial with regard to the type, dose, and regimen of chemotherapy, use of radiation therapy (RT), RT field and dose, and sequence of the multimodality treatment approach. The objective of LAPC management is disease control. The chance of resection in patients with LAPC is less than 5%. LAPC is treated with combination chemotherapy or combined chemoradiation therapy (CRT). These approaches have not shown any improvement in survival [6, 7]. In this review, we highlight the evidence that defines the treatment approach for BRPC and LAPC. We include both the BRPC and LAPC in all the sections of our review, bearing in mind that the staging of the disease is different across different trials.

Methods

We reviewed the literature from 1981 through 2015 via an online search on PubMed with MESH terms LAPC, BRPC, treatment, surgery, systemic, and radiation. We included all randomized trials, with limitations of low accrual and toxicities of the regimen used, specifically at higher radiation doses. We reviewed safety data of radiation and chemoradiation in phase I and II trials. We also reviewed academic center experiences in the management of LAPC and BRPC. We then chose recent or ongoing trials through the ClinicalTrials.gov website. We subdivided trials into stereotactic body radiation therapy (SBRT), RT, CRT, and ongoing studies. In each section, we elaborated on the evidence behind each modality of BRPC and LAPC treatment.

Staging

BRPC stage is defined as tumor limited to the pancreatic bed, with limited involvement of the vessels that potentially can be reconstructed. More specifically, according to the American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus definition, which has been incorporated into the National Comprehensive Cancer Network guidelines, borderline resectable tumors have (a) no distant metastases; (b) venous involvement of the SMV/portal vein with or without impingement and narrowing of the lumen; (c) short segment venous occlusion but with suitable vessel proximal and distal to occlusion, allowing for safe resection and reconstruction; (d) gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of hepatic artery, without extension to celiac axis; and (e) tumor abutment of the SMA not to exceed 180° of the circumference [9]. LAPC is defined as the involvement of the celiac axis or encasement of more than 180° of the SMA (T4) and/or involvement of SMV/portal vein with no reconstruction options, irrespective of nodal involvement, provided that no distant metastasis exists outside the pancreatic bed [8]. Historically, BRPC has been included in trials that involve LAPC patients.

Recent literature has shown that PC patients with involvement of the adjacent mesenteric vessels who were undergoing R0 resections had the same survival outcomes as those who underwent resection for primarily resectable PC [10–12]. The main challenge in the surgical management of BRPC is the high rate of positive margins at the reconstructed vessel segments, leading to high risk of local and systemic recurrence [13]. Selection of patients who will benefit from neoadjuvant therapy or direct surgical resection is often challenging and highly dependent on the experience of multidisciplinary tumor board personnel.

Treatment

The poor survival in BRPC patients treated with the traditional approach of up-front surgical resection followed by adjuvant therapy has prompted investigators to explore alternative treatment algorithms. Advantages of performing neoadjuvant therapy include downstaging of the tumor, increasing rates of R0 resections, treating occult micrometastatic disease, and improving the selection of patients with early progression to metastatic disease. A disadvantage in patients undergoing pancreaticoduodenectomy before any neoadjuvant treatment is the potential for a prolonged recovery, which may prevent the timely delivery of adjuvant therapy to control possible micrometastatic disease. This delay could be circumvented with the neoadjuvant treatment approach. In addition, and probably most importantly, newer and better chemotherapy combinations with considerably better response rates (31% with 5-fluorouracil [5FU], leucovorin, irinotecan, oxaliplatin, and gemcitabine [FOLFIRINOX] and 28% with gemcitabine/nab-paclitaxel [14]) have been established in the metastatic disease setting. No randomized trials have evaluated the role of the up-front neoadjuvant approach. The majority of evidence for neoadjuvant therapy comes from single-institution retrospective case series [13, 15, 16]. Table 1 summarizes the major clinical trials involved in BRPC/LAPC treatment.

Table 1.

Summary of all trials involving RT and CRT in the treatment of BRPC and LAPC

The poor survival in BRPC patients treated with the traditional approach of up-front surgical resection followed by adjuvant therapy has prompted investigators to explore alternative treatment algorithms. Advantages of performing neoadjuvant therapy include downstaging of the tumor, increasing rates of R0 resections, treating occult micrometastatic disease, and improving the selection of patients with early progression to metastatic disease.

Radiation-Based Treatment

Chemoradiation Versus No Treatment

In a prospective randomized trial of 31 LAPC patients, CRT (n = 16) compared with observation (n = 15) was studied. The regimen for CRT was 5FU (200 mg/m²) concurrent with 50.4-Gy RT divided into 28 fractions. The trial revealed an OS benefit for the CRT arm (13.2 vs. 6.4 months; p = .0009) [10]. Using the Surveillance, Epidemiology, and End Results registry, 1,700 LAPC patients were identified, 56% of whom received no treatment; 44% received a form of treatment. Of those that were treated, 13% received RT, 7% received chemotherapy alone, and 24% received CRT; mOS for the treatment groups was 29 (RT), 15 (chemotherapy), and 47 (CRT) months, respectively, suggesting that CRT may have a significant survival benefit [12].

Chemoradiation Versus Radiation Alone

The use of RT as a single-modality therapy in LAPC patients has been evaluated. In a randomized trial from the Mayo Clinic, patients with unresectable gastrointestinal (GI) tumors (17% PC) were randomized to either 5FU-based CRT or RT alone. The trial demonstrated significant improvement in OS, favoring the CRT arm. The mOS for CRT was 10.4 compared with 6.3 months in the RT-alone arm [18]. The Gastrointestinal Tumor Study Group (GITSG) 9273 reported the same outcome when RT (40/20 split-course) was compared with CRT (60/30 split-course) in LAPC patients. This trial randomized 194 patients to RT alone, RT with 40 Gy plus 5FU, or 60 Gy plus 5FU. The RT-alone arm was closed after an interim analysis showed significant benefit in delaying disease progression in the combined-modality arms [19]. The Eastern Cooperative Oncology Group (ECOG) 8282 trial enrolled 114 LAPC patients randomized to RT alone versus CRT (5FU and mitomycin C [MMC]); no survival advantage was identified (7.1 vs. 8.4 months, p = .16). More toxicities were reported in patients on the CRT arm [11]. A pooled analysis of the 794 patients in the GITSG 9273 and ECOG 8282 trials showed a significant OS advantage for CRT over RT alone [13]. Although the trials were conducted using older RT techniques, the results suggest an advantage of CRT over RT in the management of LAPC patients.

RT Intensification

Intensification of RT has been evaluated in nonrandomized trials. These reports have shown a spectrum of results, necessitating randomized trials. A single institution reported 22 LAPC patients who were treated with SBRT (45 Gy/3 fractions over 5–10 days) [47]. Acute toxicity was significant. Deterioration of performance status, nausea, and increased pain within the first 14 days of treatment, gastric ulcer in 4 patients, and gastric perforation in 1 patient were reported. Six patients developed local progression, and OS was 6 months. A follow-up of the trial reported higher rates of gastric ulceration [48]. More favorable outcomes were reported using smaller treatment fields, more conformal techniques, and hypofractionated protocols.

A retrospective series included 73 patients with BRPC (57) and LAPC (16) treated with induction chemotherapy (the majority received gemcitabine) followed by SBRT (35–40 Gy/5 fractions) with surgical exploration for potentially resectable patients 4 weeks post-SBRT; 32 of 57 BRPC patients underwent surgery, and 31 had R0 resection. mOS was 16.4 months for patients who underwent resection. No acute grade 3 or worse toxicities were observed, and long-term grade 3 or worse toxicities were reported as 5%. The 1-year local control rate in nonsurgical patients was 81% [49].

Another prospective trial of gemcitabine chemotherapy with SBRT (30 Gy/3 fractions) enrolled 23 LAPC patients and reported 14 partial responses, with two patients converted to resectable disease. The dose was well tolerated, and mOS was 10.6 months [50]. In a phase II trial specific for LAPC, 5FU was concurrently delivered with 45 Gy intense-modulated RT followed by 25 Gy SBRT; 16 of 19 patients were reported to have no local progression and mOS of 8.1 months. Two of the patients experienced grade 3 toxicity [21]. In contrast, 45-Gy RT was administered over 5–10 days in 22 LAPC patients, whose mOS was 5.7 months; only 1 patient was alive at 1 year of follow-up [47].

Table 2 summarizes the results of recently conducted trials in LAPC. The rate of local control with SBRT has ranged from 78% to 84%, which compares favorably to historic controls using external beam radiotherapy (EBRT) [30, 44, 53]. The toxicity observed in these studies varied depending on the dose and schedule of administration. Because of the low tolerance of the GI tract to RT, the observed toxicity profile varied based on the amount of RT delivered to the GI tract. Further randomized trials are needed to define its true efficacy and safety. In tertiary care centers, SBRT could be considered an alternative to conventional fractionation CRT as long as patients are informed of potential risks.

Table 2.

Summary of the trials evaluating SBRT in locally advanced pancreatic cancer

Chemoradiation Versus Chemotherapy Alone

A linked Medicare/Surveillance, Epidemiology, and End Results database showed that 44% of patients with LAPC or BRPC received some form of therapy, and the adjusted mean survival durations for patients undergoing CRT, RT alone, chemotherapy alone, and no therapy were 47, 29, 27, and 15 weeks, respectively [54]. Although the study did not randomize patients, the trial provides evidence that the benefit of RT was limited by the age of the patients (>65 years).

The Fédération Francophone de Cancérologie Digestive et Société Française de Radiothérapie (FFCD-SFRO) trial randomized EBRT (60 Gy/30 fractions) with concomitant 5FU (300 mg/m² over 24 hours, 5 days/week) and cisplatin (20 mg/m² on days 1–5 during weeks 1 and 5) followed by gemcitabine (1,000 mg/m² per week, 3 weeks on and 1 off) until progression, compared with gemcitabine alone. The trial was halted because of low accrual, with the results showing a median 31 months of follow-up. The group receiving gemcitabine alone had significantly better 1-year survival (53% vs. 32%), and mOS was reported as 13 versus 8.6 months, with lower rates of toxicities [38]. The authors concluded that the intensive high RT doses compromised systemic therapy and resulted in inferior outcomes in the CRT arm. In a phase II single-arm trial, the addition of MMC to 5FU and RT followed by surgical resection resulted in mOS of 16 months in patients with BRPC who underwent resection. This regimen was proven safe, with no grade 4 toxicities [55].

In a study by Klaassen et al., 148 patients with LA cancer of the stomach (n = 57) and PC (n = 91) were randomized to 5FU alone (600 mg/m² once weekly) or CRT (40 Gy and 5FU). The OS was similar in both treatment arms, such that in the PC subgroup, OS was 8.2 versus 8.3 months. Of note, more toxicities were experienced by patients treated with CRT: grade 3 toxicities were reported in 27% of the 5FU-alone arm compared with 51% in the CRT arm [36]. Methyl semustine (MeCCNU) was compared with 5FU with concurrent RT (60 Gy) and showed no OS difference, with a higher toxicity profile in the MeCCNU arm (87% myelosuppression and 23% GI toxicity) [8].

In the GITSG 9283 trial, CRT with 5FU was compared with a multidrug regimen of streptozotocin, MMC, and 5FU chemotherapy in LAPC patients. CRT was superior to the multidrug chemotherapy regimen with respect to OS (9.7 vs. 7.4 months) [37]. Doxorubicin was also compared with 5FU as a radiosensitizer in the GITSG 9277 trial. The median OS for the 5FU arm was 8.5 months, versus 7.6 months for the doxorubicin arm (p > .8). The risk ratio for 5FU was 58% compared with 51% for doxorubicin, and toxicity was significantly different, with 53% of patients in the doxorubicin arm experiencing a toxicity compared with 36% in the 5FU arm [56]. The results of these trials established 5FU-based CRT as the treatment of choice for BRPC and LAPC. Limitations of these trials include outdated RT techniques, noncompliance with protocol treatment, unconventional dose and schedule of chemotherapy, and limited diagnostic imaging techniques.

In the gemcitabine era, several trials have compared CRT to the chemotherapy-only approach. These trials revealed conflicting results. FFCD-SFRO compared induction chemotherapy with gemcitabine followed by maintenance therapy with gemcitabine to induction CRT (5FU/cisplatin, 60 Gy) followed by gemcitabine maintenance therapy in 109 patients. The reported mOS for the gemcitabine-alone arm was 14.3 compared with 9 months in the CRT arm (p = .03). Grade 3/4 toxicities were higher in the CRT arm, during both induction (36% vs. 22%) and maintenance (32% vs. 18%) therapy [38]. The inferior outcome observed with CRT was attributed to the poor accrual of patients to the study, toxicity in the CRT arm limiting administration of subsequent maintenance therapy, or the lack of effectiveness of RT. On the other hand, ECOG 4201, which compared gemcitabine with or without RT (50.4 Gy/28 fractions) in LAPC patients, was also prematurely terminated because of poor accrual, but it showed a significantly better mOS with CRT (11.1 vs. 9.2 months) at the expense of a significantly higher rate of grade 4 and 5 (fatal) toxicities (41% vs. 9%) [39].

Gemcitabine was prospectively studied with concurrent RT. Ninety-six patients with BRPC received 7 weekly doses of gemcitabine (400 mg/m²) concurrent with RT (30 Gy/10 fractions). Approximately 50% of patients were hospitalized during preoperative therapy because of toxicities from therapy; 73 patients underwent surgical resection. There were no complete histologic responders. The mOS for the entire cohort was 22.7 months. The survival for patients who had resection was 34 months in comparison with 7.1 months for those who did not undergo resection. Major postoperative surgical complications, including perioperative death, bleeding, and sepsis, were reported in 9% [59]. The same investigators explored administering 8 weeks of gemcitabine-cisplatin before a similar regimen of CRT (30 Gy RT over 2 weeks concurrent with 4 weekly courses of gemcitabine at 400 mg/m²) in 90 resectable adenocarcinoma patients with pancreatic head or uncinate process tumors; only 62 patients underwent surgical resection. The survival for the entire group was 17.4 months, with a survival of 31 vs. 10.5 months for patients who did versus did not undergo pancreaticoduodenectomy, respectively [59].

In an attempt to minimize treatment-related toxicity by modifying the RT field, a study of 20 patients with potentially resectable pancreatic cancer received two 21-day cycles of gemcitabine (1,000 mg/m² on days 1 and 8), one administered before and one after a 28-day course of CRT (RT 36 Gy in 15 fractions plus gemcitabine 1,000 mg/m² on days 1, 8, and 15). RT was administered to the gross tumor target volume with 1 cm margins and did not include RT to the regional nodal basins; 19 of 20 patients completed therapy without interruption, and one patient had grade 3 GI toxicity. Seventeen patients underwent resection, 16 with R0 resection; 1 patient had a complete pathologic response on final pathology. With a median follow-up of 18 months, the median and 2-year survival rates were 26 months and 61%, respectively [23].

These trials have shown conflicting evidence of the overall benefit of CRT in neoadjuvant treatment for BRPC and LAPC.

Induction Chemotherapy Followed by Chemoradiation

The hypothesis for induction chemotherapy followed by CRT strategy is to treat occult micrometastatic disease up front with systemic chemotherapy before consolidation with regional therapy. In the Groupe d’Etude et de Recherche en Cancreologie Onco-Radiotherapie (GERCOR) trial, gemcitabine-based induction chemotherapy was given over 3 months, followed by randomization to either continuing gemcitabine or CRT (5FU and 55 Gy). Of the 181 patients enrolled in the study, 51 (29%) developed metastasis after induction chemotherapy. The remaining 128 patients were randomized. The median progression-free survival (PFS) for the CRT and chemotherapy arms was 10.8 and 7.4 months (p = .005), respectively. The median survival was 15 months for the CRT arm and 11.7 months (p = .0009) for the chemotherapy-only arm [43].

In the phase III LAP-07 trial, the role of erlotinib as an induction therapy agent and the role of RT after induction therapy were evaluated in patients with LAPC. In the first randomization, 724 patients were treated with erlotinib (100 mg/day) plus gemcitabine or gemcitabine alone for 4 months. Patients who did not have progression were further randomized to RT. Four hundred twenty patients without evidence of progression were then randomized to CRT (RT 50.4 Gy, capecitabine 1,600 mg/m²/day) or continuation of gemcitabine chemotherapy. There was no difference in PFS (10.7 vs. 9.3 months; p = .15) or OS (13.6 and 11.9 months, hazard ratio 1.19, p = .09) in patients assigned to gemcitabine or gemcitabine plus erlotinib. The median survival for the CRT arm was 15.3 compared with 16.3 months in the chemotherapy-only arm (hazard ratio 1.03, p = .83) [5].

The role of combination chemotherapy regimens in LAPC and BRPC has been evaluated in single-institution retrospective series. At Massachusetts General Hospital, 22 patients with LAPC received FOLFIRINOX as induction therapy. Of the 22, 12 were explored (most with RT after chemotherapy). Five patients underwent R0 resections, and seven had surgically unresectable disease, of whom six had intraoperative radiation therapy administered. Of those six, only one experienced progressive disease. The R0 resection rate of 23% (5 of 22 patients) may reflect a new era of converting LAPC to a resectable PC [7].

FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 BRPC patients evaluated at Wisconsin University. Progression of disease precluded surgery in 6 of the 18 patients (33%). The other 12 resected patients had R0 margins. No responses were reported [59].

Miami University also reported 18 patients with LAPC. At maximum response or tolerability, seven (39%) were converted to resectability by radiologic criteria; five had R0 resections, one had R1 resection, and one had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined CRT, giving an overall R0 resection rate of 44%. After a median follow-up of 13.4 months, the 1-year PFS was 83% and the 1-year OS was 100% (95% confidence interval 85%–100%) [60].

At the University of Pittsburgh, 25 PC patients were enrolled, 13 (52%) LAPC and 12 (48%) BRPC. Four patients (16%) refused treatment or were lost to follow-up. Twenty-one patients (84%) were treated with a median of 4.7 cycles of FOLFIRINOX; seven patients (33%) underwent surgical resection after treatment with FOLFIRINOX alone, two (10%) of whom were initially unresectable. Two patients underwent resection after FOLFIRINOX and SBRT. The R0 resection rate for patients treated with FOLFIRINOX with or without SBRT was 33% (55% BRPC, 10% LAPC). Five patients (24%) demonstrated a significant pathologic response [61].

At the Ohio State University, 43 patients with BRPC (18) and LAPC (25) were treated with modified FOLFIRINOX. Resection was attempted in 72% of cases, including 11 of 25 LAPC cases (44%). R0 resection was obtained in 86.4%, or 19 of 22, with an 18-month median PFS for patients undergoing resection compared with 8 months for patients who did not undergo resection [6]. At Memorial Sloan-Kettering Cancer Center, LAPC patients (101) received FOLFIRINOX followed by CRT. Partial response was observed in 31% of patients converted to resectable disease (55% R0). Patients that progressed on induction FOLFIRINOX had an mOS of 11 months compared with 26 months for resected stage III disease. This is the first study to have all stage 3 (T4) PC patients treated homogeneously regardless of the tumor’s resectability status [62]. At Emory University, 14 patients received FOLFIRINOX followed by CRT. Four of the patients had BRPC and received two to six cycles of FOLFIRINOX followed by CRT (three with capecitabine and one with gemcitabine). Two patients underwent R0 resections; 10 patients had LAPC and received a median of 3 cycles of FOLFIRINOX followed by CRT (8 capecitabine and 2 gemcitabine). Six of the 14 patients were downgraded to resectable disease, with 5 achieving R0 resection (2 of 4 BRPC patients and 3 of 10 LAPC patients), with a rate of 36% R0 resection [4].

These treatment approaches were well tolerated, specifically with the use of modified FOLFIRINOX, where the dose of irinotecan is decreased to 165 mg/m² and bolus 5FU is discontinued from the treatment regimen. Furthermore, all patients on the FOLFIRINOX treatment receive granulocyte colony-stimulating factor support, as the risk of febrile neutropenia on this regimen exceeds 25% [4, 12].

An ongoing single-arm trial (ALLIANCE) evaluating neoadjuvant FOLFIRINOX followed by CRT, with postoperative gemcitabine for two cycles, recently presented preliminary results at the 2015 American Society of Clinical Oncology meeting. Twenty-one patients completed induction chemotherapy followed by CRT, 15 of whom underwent resection; 14 of the 15 patients had R0 resection (93%). Eighteen patients were still alive at 10 months after follow-up [63].

These recent academic center experiences with combination chemotherapy and CRT, followed by resection, show promise in the treatment of LAPC and BRPC.

Practical Approach to Treatment

The optimal treatment approach and sequence between chemotherapy, CRT, choice of chemotherapy, modality and dose of radiation, and timing of surgery for BRPC and LAPC is yet to be defined. The trials reviewed here have considerable limitations including the lack of standard definitions of BRPC and LAPC stages [2, 24, 64]. Therefore, future treatment paradigms and clinical trials must distinguish these two stages on a clear ground. The introduction of oxaliplatin and irinotecan to 5FU (FOLFIRINOX) and nab-paclitaxel to gemcitabine in advanced-stage PC has resulted in a significant improvement in response rates, PFS, and OS [14, 65]. Initial reports from retrospective studies suggest that induction chemotherapy using these agents may improve outcome in BRPC and LAPC. The use of high-dose RT using intense-modulated RT or SBRT has shown promise in early nonrandomized trials. The incorporation of these multiagent chemotherapeutic regimens and novel RT techniques in the management of BRPC and LAPC will require further randomized trials. The latest evidence is summarized in this review to help guide decisions on treatment the of BRPC and LAPC patients.

The role of RT in unselected patients is controversial, suggesting that the benefit from RT in this setting may be modest at best. Molecularly selecting patients with BRPC and LAPC with low risk of systemic disease may provide an approach to improve the therapeutic benefit for RT. Iacobuzio-Donahue et al. analyzed DPC4, a tumor suppressor gene (SMAD4), immune-labeling on PC tissue from autopsy samples in patients with LAPC and metastatic disease [66]. DPC4 (MADH4, SMAD4) encodes a nuclear transcription factor shown to be genetically inactivated in >50% of PCs. Of the 65 patients studied, 41 had loss of DPC4 immunolabeling, indicating rates of gene inactivation of 63% in PC. Loss of the DPC4 gene was highly correlated with the presence of widespread metastasis but not with local progression (p = .007) [66]. DPC4 may be a predictive marker in determining which patients have the propensity to develop systemic metastasis. Loss of DPC4/SMAD4 can be assessed on biopsy specimens, and therefore, this assessment may be used in selecting patients who potentially have a more favorable outcome and benefit from RT local treatment. DPC4 testing is being incorporated in BRPC and LAPC clinical trials such as RTOG 1201 (which is still recruiting participants: https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1201).

The role of RT in unselected patients is controversial, suggesting that the benefit from RT in this setting may be modest at best. Molecularly selecting patients with BRPC and LAPC with low risk of systemic disease may provide an approach to improve the therapeutic benefit for RT.

A promising avenue in PC clinical research is immune checkpoint inhibition. This regulates immune responses by enhancing preexisting anticancer immunity. Several different checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) are being evaluated in clinical trials. Other approaches are the development of therapeutic cancer vaccines that enhance the immune response against tumor-specific or tumor-associated antigens. Adoptive T cell transfer is also being studied in PC, in which T cells are extracted from patients’ plasma, genetically modified or treated with chemicals to enhance their activity, and then autotransfused to activate cancer immunity response. Monoclonal antibodies are also in clinical development. Table 3 further summarizes all ongoing clinical trials.

Table 3.

Summary of ongoing trials for BRPC and LAPC (data available at ClinicalTrials.gov)

Conclusion

LAPC and BRPC management has relied on multimodality treatment methods involving chemotherapy, radiation, and surgery. We would continue to implement discussions between the different subspecialties. In patients with preserved performance status, induction chemotherapy with FOLFIRINOX is advised given the better response rate that has been reported. In patients with borderline performance status who are >65 years of age, gemcitabine/nab-paclitaxel could be a better regimen. Frail patients should either receive single-agent gemcitabine followed by CRT or be referred to supportive care. Treatment response is to be assessed by cross-sectional imaging every 2 months and evaluation for possible surgery. If no response or local progression is found, CRT should be instituted, with the hope of downstaging and converting to resectable disease. If after induction chemotherapy and CRT there is no response and resection is not possible, we advise watchful waiting with imaging every 2 or 3 months, and chemotherapy treatment when progression is evident. When possible, we strongly suggest that oncologists refer BRPC and LAPC patients for enrollment in clinical trials.

Author Contributions

Conception/Design: Walid L. Shaib, Andrew Ip

Collection and/or assembly of data: Walid L. Shaib, Andrew Ip

Manuscript writing: Walid L. Shaib, Andrew Ip, Kenneth Cardona, Olatunji B. Alese, Shishir K. Maithel, David Kooby, Jerome Landry, Bassel F. El-Rayes

Final approval of manuscript: Walid L. Shaib, Andrew Ip, Kenneth Cardona, Olatunji B. Alese, Shishir K. Maithel, David Kooby, Jerome Landry, Bassel F. El-Rayes

Disclosures

The authors indicated no financial relationships.