Outcomes of a Clinical Pathway for Borderline Resectable Pancreatic ...

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Dec 10, 2015 - ORIGINAL ARTICLE – PANCREATIC TUMORS. Outcomes of a Clinical Pathway for Borderline. Resectable Pancreatic Cancer. Omar M.
Ann Surg Oncol DOI 10.1245/s10434-015-5006-1

ORIGINAL ARTICLE – PANCREATIC TUMORS

Outcomes of a Clinical Pathway for Borderline Resectable Pancreatic Cancer Omar M. Rashid, MD, JD1, Jose M. Pimiento, MD1, Andrew W. Gamenthaler, MD1, Phuong Nguyen, BS1, Tin T. Ha, BSc1, Tai Hutchinson, RN1, Gregory Springett, MD1, Sarah Hoffe, MD1, Ravi Shridhar, MD1, Pamela J. Hodul, MD1, Brad L. Johnson, MD2, Karl Illig, MD2, Paul A. Armstrong, MD2, Barbara A. Centeno, MD1, William J. Fulp, MS3, Dung-Tsa Chen, PhD3, and Mokenge P. Malafa, MD1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; 2University of South Florida, Tampa, FL; 3Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 1

ABSTRACT Background. Without prospective data establishing a consensus multimodality approach to borderline resectable pancreatic adenocarcinoma, institutional treatment regimens vary. This study investigated the outcomes of the clinical pathway at the author’s institution, which consists of neoadjuvant gemcitabine, docetaxel, capecitabine, and stereotactic radiotherapy followed by surgery. Methods. The study reviewed all cases that met the National Comprehensive Cancer Network (NCCN) diagnostic criteria for borderline resectable pancreatic adenocarcinoma from 1 January 2006, to 31 December 2013. Pancreatectomy rates, margin status, pathologic response, disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) were retrospectively examined. Standard statistical methods and Kaplan–Meier survival analysis were used for statistical comparisons. Results. Of 121 patients who met criteria, 101 entered the clinical pathway, and 94 (93.1 %) completed neoadjuvant chemotherapy and radiation therapy. Of the 101 patients, 55 (54.5 %) underwent pancreatectomy, with 53 patients (96.4 %) having microscopically negative margins (R0) and 2 patients (3.6 %) having microscopically positive margins (R1). Vascular resection was required for 22 patients (40 %), with rates of 95.5 % for R0 (n = 21) and

O. M. Rashid and J. M. Pimiento contributed equally to this work Ó Society of Surgical Oncology 2015 First Received: 16 June 2015 M. P. Malafa, MD e-mail: [email protected]

4.5 % for R1 (n = 1). A pathologic response to treatment was demonstrated by 45 patients (81.8 %) and a complete response by 10 patients (14.5 %). Pancreatectomy resulted in a median DFS of 23 months (95 % conflidence interval [CI] 14.5–31.5), a median DSS of 43 months (95 % CI, 25.7–60.3), and a median OS of 33 months (95 % CI, 25.0–41.0) versus a median DSS and OS of 14 months (95 % CI, 10.9–17.1) for patients without pancreatectomy (DSS: P = 3.5 9 10-13; OS: P = 4.7 9 10-10). Conclusions. The study demonstrated high rates for neoajduvant therapy completion (93.1 %) and pancreatectomy (54.5 %). After pancreatectomy, DSS was significantly improved (43 months), with a pathologic response demonstrated by 81.8 % and a complete response by 14.5 % of the patients. The results support further study of this borderline resectable pancreatic adenocarcinoma clinical pathway.

Pancreatic cancer has increased in incidence during the past several decades and currently is the fourth leading cause of cancer death in the United States.1 During 2015, it is estimated that 46,420 new pancreatic cancers will be diagnosed and 39,590 patients will die of this disease.2 Pancreatic cancer has a poor prognosis, with a 5-year overall survival of 6 % for all patients with this malignancy.3 Pancreatic cancer isolated to the pancreas has the best chance for cure, with a 5-year-survival of 18–24 % after complete surgical resection for patients who have tumors smaller than 2 cm without lymph node metastasis or extension beyond the pancreas.4 Although surgery remains the mainstay of treatment, at presentation, 80– 85 % of patients have advanced disease, precluding them from extirpative procedures.5–7 Even for the 15–20 % who

O. M. Rashid et al.

are candidates for surgery, surgical treatment has been associated with margin-positive rates of 15–85 %, which are associated with worse overall survival.8–11 Due to the importance of negative margins, the first challenge is appropriate staging of pancreatic cancer patients before initiation of treatment, especially in the setting with possible involvement of adjacent vascular structures and no evidence of distant disease.12–15 Between pancreatic cancer that is clearly resectable and locally advanced disease that is unresectable due to extensive involvement of adjacent vascular structures, there exists an entity known as ‘‘borderline resectable,’’ for which the degree of vessel involvement by preoperative staging may not preclude resection entirely. Although these patients are at risk for positive margins,14–18 negative surgical margins have been achieved in highly selected borderline resectable patients after neoadjuvant treatment.12,16,19,20 In fact, meta-analyses have shown negative margin rates of 25–33 % after neoadjuvant treatment for borderline pancreatic cancer patients, with a median overall survival of 18–21 months, matching historical survival rates for resectable pancreatic cancer patients after negative margin resection.21–24 Although most of these studies used a combination of systemic chemotherapy and chemoradiotherapy, different clinical pathways and treatment protocols were used with variable results.19,25–29 Although a randomized phase 2 multi-institutional trial was designed to address these questions, it was closed due to poor accrual.30 Therefore, no consensus neoadjuvant multimodality regimen exists for borderline resectable pancreatic adenocarcinoma. At our institution, a National Cancer Institute-designated National Comprehensive Cancer Network (NCCN) cancer center, patients who present with pancreatic cancer undergo a multidisciplinary evaluation that follows an institutionwide clinical pathway. The diagnostic and staging studies are first obtained and reviewed to determine a consensus stage of pancreatic cancer (resectable, borderline resectable, locally advanced, or metastatic).31 The treatment of patients with borderline resectable pancreatic adenocarcinoma then follows the corresponding clinical pathway. In the absence of randomized trials, neoadjuvant treatment is based on the promising results of gemcitabine, docetaxel, and capecitabine (GTX) induction chemotherapy followed by stereotactic body radiation therapy (SBRT).28 For the current study, we hypothesized that prospective implementation of a borderline resectable pancreatic adenocarcinoma clinical pathway that uses a multidisciplinary approach to staging, patient selection, and management would improve negative margin resection rates and patient outcomes. Because large randomized clinical trials have demonstrated equivalent survival and less toxicity with gemcitabine compared with fluoropyrimadines, we also hypothesized that a larger proportion of patients treated by

our clinical pathway would complete neoadjuvant treatment and be offered curative-intent surgical treatment than what has been reported in the literature.32,33 METHODS Patients For this institutional review board–approved retrospective study, all borderline resectable pancreatic adenocarcinoma patients from 1 January 2006 to 31 December 2013 were identified from the prospectively maintained cancer database (Moffitt Total Cancer Care [TCC]) in Moffitt’s Gastrointestinal Oncology Department. To be included in the TCC protocol, patients provide prospective informed consent, which allows follow-up evaluation of patients throughout their lifetimes with access to medical data for research, donation of tissue samples that can be molecularly analyzed, and recontact with consented patients in the case of a new finding or trial that could benefit them. This database includes patient demographics, preneoadjuvant treatment clinical assessment, postneoadjuvant treatment clinical assessment, surgical procedure details, pathologic tumor stage and histopathologic features, perioperative events and complications, date and location of recurrence, and disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Clinical Pathway First, we retrospectively reviewed our patient group to determine how the diagnosis and staging for borderline resectable pancreatic adenocarcinoma were determined. Second, we reviewed the type, duration, and completion of the neoadjuvant treatment used. Third, we reviewed whether patients were restaged for surgical resection and the outcome of attempted surgical resection. Fourth, we reviewed data on preoperative complications and final pathologic analyses. Finally, surveillance, time to recurrence, DSS, and OS data were reviewed. Since 2005, our group and our clinical pathway have used the definition of borderline resectable pancreatic cancer outlined in the NCCN Pancreatic Cancer Clinical Guidelines. This definition has evolved with the annual updates of the NCCN Guidelines. This definition of borderline resectable pancreatic cancer is the one most commonly used worldwide. Surgical Resection The surgical procedures in this study included standard pancreaticoduodenectomy for tumors of the head and uncinate process, subtotal or distal pancreatectomy, and splenectomy for tumors of the neck, body, or tail. For

Outcomes of a Clinical Pathway for Borderline Resectable Pancreatic Cancer

vascular reconstruction, the saphenous vein, harvested from the groin of the patients, was used. Operative reports, anesthesia records, hospital course, and postoperative visits were reviewed. Postoperative complications were monitored and recorded according to the Dindo–Clavien classification.34 Pathology All of the patients included in our study had pathology specimens from their initial biopsies read and confirmed by our pathologists before initiation of neoadjuvant treatment. The final pathology studies included gross tumor evaluation, histologic grading, lymph node involvement, and margin status (including vascular and retroperitoneal margins). Specimens were evaluated and indicated as having a negative margin (R0) if tumor cells were absent at the inked margin of resection. Tumors within 1 mm of the inked margin but absent from the inked margin still were considered as R0. However, a comment was made in a pathology report regarding the distance of tumor cells from the margin. In addition, tumor regression was graded per the College of American Pathologist grading system35 as follows: grade 4 (complete response with no viable tumor cells remaining), grade 3 (partial response with 1–9 % of viable tumor cells remaining), grade 2b (partial response with 10–49 % of viable tumor cells remaining), grade 2a (partial response with 50–89 % of viable tumor cells remaining), and grade 1 (no response with 90 % or more of viable tumor cells remaining).35 Statistical Analysis Overall survival was calculated from the date of diagnosis to the date of death or last contact. Progression-free survival (PFS) was calculated from the surgical date to the last date at which the patient was known to be free of disease. The Kaplan–Meier method was used to create OS and PFS curves. The median follow-up period was calculated from the date of diagnosis to the last follow-up visit. Statistical analyses were performed with SPSS (Stata Statistical Software, Release 10.0; Strata Corp., College Station, TX, USA). RESULTS Moffitt Clinical Pathway The diagnosis of borderline resectable pancreatic adenocarcinoma was based on a consensus tumor board recommendation according to the NCCN. Patients then entered the clinical pathway, as illustrated in Fig. 1a. At our institution, after three cycles of GTX, the patient is evaluated by a radiation oncologist in preparation for

SBRT. After neoadjuvant treatment, the patient undergoes restaging studies followed by a tumor board restaging conference to evaluate the role of surgery, as shown in Fig. 1a. Patients with metastatic disease are treated with chemotherapy based on the stage 4 pancreatic cancer clinical pathway. If disease progresses to locally advanced status, patients then are treated according to the corresponding clinical pathway. If patients are potentially resectable, they are prepared for surgery with possible vascular resection and reconstruction with assistance from our vascular surgery team. After surgery, the pathology is reviewed, and recommendations are provided regarding possible adjuvant therapy in consultation with medical oncology. After completion of any such therapy, patients undergo close surveillance with physical examination, tumor markers, and imaging every 3 months for 2 years, followed by every 6 months for 5 years, and then annually thereafter. Patients We identified 121 patients with borderline resectable pancreatic adenocarcinoma treated at Moffitt between 1 January 2006 and 31 December 2013 (Fig. 1b). Their baseline characteristics are shown in Table 1. Of the 121 patients, 101 were treated on the clinical pathway, with 94 (93.1 %) completing neoadjuvant treatment. Of the 101 patients who entered the pathway, 55 (54.5 %) subsequently underwent resection. The characteristics and outcomes of the 55 patients who underwent pancreatectomy are shown in Table 2. Outcomes Of the 55 patients who underwent pancreatectomy, 98.4 % (n = 53) had microscopically negative margins (R0), 3.6 % (n = 2) had microscopically positive margins (R1), and 0 % had macroscopically positive margins (R2). Of these patients, 22 (40 %) required vascular resection, with 95.5 % (n = 21) having R0, 4.5 % (n = 1) having R1, and 0 % having R2. A pathologic response to treatment was seen in 45 patients (81.8 %) and a complete pathologic response to treatment in 10 patients (14.5 %). After pancreatectomy, the median periods of survival were 23 months for DFS, 43 months for DSS, and 33 months for OS versus 14 months for DSS (P = 3.5 9 10-13) and OS (P = 4.7 9 10-10) experienced by nonresected patients (Fig. 2). For all 101 patients who entered the clinical pathway, the median survival times were 18 months (95 % CI 14.4–21.7) for OS and 24 months (95 % CI 15.7–32.4) for DSS. The findings showed no difference between DFS, DSS, and OS after vascular resection.

O. M. Rashid et al. FIG. 1 a The borderline resectable pancreatic adenocarcinoma clinical pathway starts with the diagnostic and staging evaluation and then proceeds with neoadjuvant therapy, restaging, and surgical management, according to the multidisciplinary tumor board conference consensus. b Of 121 patients with a diagnosis of borderline resectable pancreatic adenocarcinoma, 101 were treated on the authors’ clinical pathway. CBC, complete blood count; CMP, comprehensive metabolic panel; EUS & FNA, endoscopic ultrasound and fine-needle aspiration of the pancreas

a

1) 2) 3) 4) 5) 6)

Pancreas protocol CT Thorax/Pelvis CT CA 19-9 PET CT CBC CMP EUS & FNA

Tumor board consensus diagnosis

Tumor board consensus re-staging

Potentially resectable? No Locally Advanced CP

Yes Surgery

Gemcitabine+Docetaxel+Capecitabine 3 Cycles EUS Fiducial Placement Stereotatic Body Radiotherapy 30-40 Gy (6-8 Gy x 5 Fractions over 5 days) 1) 2) 3) 4)

b

Pancreas protocol CT Thorax/Pelvis CT CA 19-9 PET CT 121 borderline patients 3 lost to follow up 5 refused treatment 2 resection 10 non-clinical pathway treatment 101 entered clinical pathway 7 did not complete neoadjuvant treatment

94 completed neoadjuvant treatment 39 did not undergo resection

55 underwent resection

DISCUSSION The definition of ‘‘borderline resectable’’ for pancreatic adenocarcinoma has allowed patients who historically have not been offered pancreatectomy the potential for curativeintent surgery. However, the appropriate management of this disease requires a multidisciplinary team with experience in the appropriate staging and in the complex multimodality treatment of these patients. For this reason, we highlight in this report our clinical pathway, from confirmation of the diagnosis to surveillance after surgery. Our series reports outcomes comparable with those of other published series in

the literature (Table 3). It is important to highlight that our institutional clinical pathway represents the only reported model that uses a combination of computed tomography (CT) scan, endoscopic ultrasonography (EUS), fine-needle aspiration (FNA), and positron emission tomography (PET) scan as a means of routinely selecting patients for the borderline resectable treatment pathway (Fig. 1). These selection criteria are important to consider when the reported outcomes of other series are reviewed (Table 3). Although our investigation included consecutive patients, our experience encompassed a transitional period at our institution in which patients who had been given

Outcomes of a Clinical Pathway for Borderline Resectable Pancreatic Cancer TABLE 1 Characteristics of the 121 patients with a diagnosis of borderline resectable pancreatic adenocarcinoma Characteristic

Result (n = 121 patients)

TABLE 2 Pre-, peri-, and postoperative characteristics of the 55 borderline resectable pancreatic adenocarcinoma patients who underwent pancreatectomy Results (n = 55 pancreatectomy patients)

Age (years) Median (mean)

67 (66.1)

Range

45–87

Gender: n (%) Male

73 (60.1)

Female

48 (39.9)

Tumor location: n (%) Head

94 (77.6)

Neck

6 (5)

Body

18 (14.9)

Tail

3 (2.5)

Pretreatment CA19-9 Median (mean)

232 (1148)

Range

1.5–16,600

Tumor size (cm) Median (mean)

3.3 (3.4)

Range

1.7–6.7

ECOG performance status: n (%) 2

2 (1.7)

1

30 (24.8)

0

89 (73.5)

Vessel involvement: n (%) SMV/PV abutment

79 (65.3)

SMV/PV encasement

22 (18.2)

SMV/PV occlusion

2 (1.7)

GDA encasement up to hepatic artery

13 (10.7)

SMA abutment not [ 180

5 (4.1)

ECOG Eastern Cooperative Oncology Group, SMV superior mesenteric vein, PV portal vein, GDA gastroduodenal artery, SMA superior mesenteric artery

GTX and intensity-modulated radiation therapy (with infusional 5-fluorouracil) were enrolled in a more recent protocol using GTX and SBRT. Nonetheless, the basic components of our treatment pathway for borderline resectable pancreatic adenocarcinoma patients did not change during the study period.28 We report a large experience with borderline resectable pancreatic adenocarcinoma as defined by the NCCN5,6,19,36 and a large experience treating patients whose diagnosis was determined after 2005, when the borderline resectable definition was proposed.5,13,15,37 Our patients were evaluated for resectability using CT scan of the abdomen and pelvis with a pancreatic protocol, and most of our patients underwent EUS, corresponding to the imaging methods purposed by other authors.38–40 However, we found that one-third of our patients showed vascular involvement when their diagnosis was determined

ECOG performance status: n (%) 1

9 (16.4)

0

46 (83.6)

Time to surgery (days) Median (mean)

154 (168.3)

Range

113–279

Procedure: n (%) Whipple

49 (89.1)

Distal pancreatectomy

5 (9.1)

Subtotal pancreatectomy

1 (1.8)

SMV resection

16 (29.1)

PV resection

6 (10.9)

EBL (mL) Median (mean) Range

400 (526.9) 150–1550

Surgery duration (min) Median (mean)

475 (480)

Range

190–917

Dindo–Clavien postoperative complication classification: n (%) 1

15 (27.3)

2

4 (7.3)

3

1 (1.8)

4

2 (3.6)

Hospital stay (days) Median (mean)

9 (10.9)

Range

4–77

Pathologic response to treatment: n (%) 1

10 (18.2)

2a 2b

4 (7.3) 13 (23.6)

3

20 (36.4)

4

8 (14.5)

Pathologic stage: n (%) Tx

7 (12.7)

T1

8 (14.5)

T2

7 (12.7)

T3

33 (60)

N0

20 (36.4)

N1

35 (63.6)

ECOG Eastern Cooperative Oncology Group, SMV superior mesenteric vein, PV portal vein, EBL estimated blood loss

by EUS imaging. Thus, CT scanning alone for the patients may have misclassified them as resectable and contributed to the high margin-positive resection rate reported in the literature.41,42 There is broad agreement that pretreatment

O. M. Rashid et al. Overall Survival

Overall Survival

a

1.0 All

Non-Pancreatectomy Pancreatectomy

0.8

Survival

0.8

Survival

c

1.0

0.6 0.4 0.2

0.6

0.4

0.2

0.0

0.0 .00 10.00 20.00 30.00 40.00 50.00 60.00

.00

10.00 20.00 30.00 40.00 50.00 60.00

Time (months)

Time (months)

Disease Specific Survival 1.0

Non-Pancreatectomy Pancreatectomy

Survival

0.8

0.6 0.4 0.2

Disease Free Survival

d

All

0.8

Survival

Disease Specific Survival

b

1.0

e Pancreatectomy

0.8

0.6

0.6

0.4

0.4

0.2

0.2 0.0

0.0

0.0

1.0

.00 10.00 20.00 30.00 40.00 50.00 60.00

.00 10.00 20.00 30.00 40.00 50.00 60.00

Time (months)

Time (months)

.00

10.00

20.00

30.00

40.00

Time (months)

FIG. 2 Kaplan–Meier curves for a overall survival (OS) (median, 17 months; 95 % confidence interval [CI] 14.0–20.0 months) and b disease-specific survival (DSS) (median, 19 months; 95 % CI, 14.7– 23.3) for all borderline resectable pancreatic adenocarcinoma patients (blue line; n = 121). Kaplan–Meier curves for c OS (median, 33 months; 95 % CI 25.0–41.0 vs 14 months; 95 % CI 10.9–17.1;

P = 4.7 9 10-10) and d DSS (median, 43 months; 95 % CI 25.7– 60.3 vs 14 months; 95 % CI 10.9–17.1; P = 3.5 9 10-13) for pancreatectomy (gold line; n = 55) versus nonpancreatectomy patients (blue line; n = 46). e Kaplan–Meier curve for disease-free survival (DFS) (median, 23 months; 95 % CI 14.5–31.5) for pancreatectomy patients (blue line; n = 55)

tissue diagnosis of locoregional pancreatic tumors is indicated and that EUS-guided FNA/core biopsy is the best approach for obtaining a tissue diagnosis.12,14,43,44 Because EUS can also be used for staging of pancreatic tumors with a high degree of sensitivity, specificity, and accuracy, we reasoned that combining EUS with CT staging would improve locoregional staging. Magnetic resonance angiography of the pancreas is rarely used at our institution, although other groups use this routinely.6 This retrospective review evaluated the outcomes of our institutional borderline resectable pancreatic adenocarcinoma clinical pathway. All patients were presented at our multidisciplinary tumor board, with determination of resectability reached by a consensus among clinicians. Additionally, all patients had their pathology reviewed before neoadjuvant treatment was administered. A large portion of our patients either had been treated at our institution or had our recommendation followed at an outside facility, making our cohort more homogeneous. In addition, although the study size was a limitation, our study does represent a large borderline resectable pancreatic

adenocarcinoma series compared with other series reported in the literature.6,15, 38,45 In addition, we are aware that some of the tumors we classified as borderline resectable would be considered technically resectable using other staging schemes.46 Some series have claimed that such tumors can be resected with both short- and long-term outcomes no worse than those achieved after administration of preoperative therapy.46 This approach is not generally recommended due to the high risk of margin-positive resection.47 We have followed the definitions and guidelines of management as outlined by the major consensus authorities in the field such as NCCN, AHPBA, and SSO.18 All patients with borderline resectable pancreatic adenocarcinoma received neoadjuvant treatment, with 93 % completing the regimen and 54.5 % undergoing pancreatectomy, with 96.4 % having R0 margins. Furthermore, the patients had a high pathologic treatment response rate with good perioperative outcomes. The DFS, DSS, and OS rates were comparable with the rates reported in the literature (Table 3). However, because our patients tolerated the GTX regimen so well with a high rate of neoadjuvant treatment

Outcomes of a Clinical Pathway for Borderline Resectable Pancreatic Cancer TABLE 3 Review of the reported borderline resectable pancreatic adenocarcinoma clinical pathway outcomes in the literature, with a summary of the diagnostic criteria used Series

n

Regimen

Completed neoadjuvant therapy n (%)

Resected n (%)

R0 n (%)

Path response n (%)

Survival

MDACC (2008) Type-A19

84

XRT, 5-FU, paclitaxel, or gemcitabine

66 (79)

32 (38)

31 (97)

19 (59)

OS (40 months)

UVHS (2011) Type-A6

30

XRT, capecitabine

25 (83)

12 (40)

10 (83)

10 (83)

VA Mason (2014) NCCN/ AHPBA29

64

Gemcitabine, docetaxel

53 (82.8)

31 (48.4)

27 (87)

3 CR (10)

DFS (24 months) OS (23 months) 1 year (100 %) 2 years (66 %) DFS (23 months)

Current study, NCCN/AHPBA

101

Gemcitabine, docetaxel, capecitabine, SBRT

94 (93)

55 (54.5)

53 (96)

45 (82)

OS (33 months)

8 CR (15)

1 year (100 %) 2 years (80 %) DFS (23 months) DSS (43 months)

Type-A, MD Anderson Cancer Center (MDACC) type-A diagnostic criteria for borderline resectable pancreatic adenocarcinoma XRT radiation therapy, 5-FU 5-fluorouracil, OS overall survival, DFS disease-free survival, UVHS University of Virginia Health System, VA Mason, Virginia Mason Hospital and Medical Center, NCCN/AHPBA National Comprehensive Cancer Network and Americas Hepato-Pancreato-Biliary Association consensus diagnostic criteria for borderline resectable pancreatic adenocarcinoma, CR complete pathologic response, SBRT stereotactic body radiation therapy, DSS disease-specific survival

completion and because they achieved comparable oncologic outcomes, the role of this regimen in the treatment of pancreatic cancer should be revisited, especially in light of the increased toxicity of FOLFIRINOX. Although the authors at Virginia Mason highlight good outcomes without the standard use of radiotherapy, the SBRT chemoradiation regimen we report was well tolerated and produced good oncologic outcomes (Table 2; Fig. 2). We found that 81.8 % of the resected patients demonstrated objective pathologic evidence of response to neoadjuvant treatment, with 14.5 % having a complete pathologic response, showing that this combination of chemotherapy and radiation is effective for pancreatic cancer. However, it is worth noting that despite the high objective pathologic response in the primary tumors, our rate of N1 disease was also high (63.6 %), suggesting that the pathologic response may not correlate with disease control. Therefore, because of this finding and because our study was limited by its small number of patients and its retrospective design, prospective randomized trials are needed to define better the potential benefits of this regimen in the treatment of borderline resectable pancreatic adenocarcinoma. Although the survival rate for resected patients with borderline resectable pancreatic adenocarcinoma is similar to that for patients who had resectable tumors from the onset, the optimal approach to the treatment of borderline resectable pancreatic adenocarcinoma remains in question.6,38,48,49 In conclusion, our results support our hypothesis that implementing a borderline resectable pancreatic adenocarcinoma clinical pathway that uses a multidisciplinary

approach to staging, patient selection, and management produces high rates of negative-margin resection and good oncologic patient outcomes. The results also support our hypothesis that neoadjuvant treatment with gemcitabine-based therapy regimens results in a high neodajuvant therapy completion rate. Future studies of molecular and genetic targets have the potential to guide patient selection further and improve outcomes in the emerging era of precision medicine. Despite these positive results, multi-institutional prospective randomized trials are required to determine which treatment regimen is the optimal approach for the management of borderline resectable pancreatic adenocarcinoma. ACKNOWLEDGMENT We thank Rasa Hamilton (Moffitt Cancer Center) for editorial assistance. This work was supported in part by the Moffitt’s Total Cancer Care Initiative and Collaborative Data Services Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center, under grant number P30-CA076292. This study was supported in part by the National Institutes of Health Grants 1R01 CA-129227-01A1, 5RO1 CA-098473-05, and DAVOS 69-15099-99-01 (to MP Malafa). CONFLICT OF INTEREST

There are no conflicts of interest.

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