Radiographic patterns of first disease recurrence after neoadjuvant therapy and surgery for patients with resectable and borderline resectable pancreatic cancer.

BACKGROUND: More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer. METHODS: Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence. RESULTS: Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06-0.77; P = .02). CONCLUSION: After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.

Value of Pretreatment 18F-fluorodeoxyglucose Positron Emission Tomography in Patients With Localized Pancreatic Cancer Treated With Neoadjuvant Therapy.

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) imaging is not routine in patients with localized pancreatic cancer (PC). We evaluated the prognostic value of PET/CT in patients who received neoadjuvant therapy. Methods: Patients with localized PC underwent pretreatment PET/CT with or without posttreatment (preop) PET/CT. Maximum standardized uptake values (SUV) were classified as high or low based on a cut point of 7.5 at diagnosis (SUVdx) and 3.5 after neoadjuvant therapy (preoperative; SUVpreop). Preop carbohydrate antigen 19-9 (CA19-9) was classified as normal ( ≤ 35 U/mL) or elevated. Results: Pretreatment PET/CT imaging was performed on 201 consecutive patients; SUVdx was high in 98 (49%) and low in 103 (51%). Preop PET/CT was available in 104 (52%) of the 201 patients; SUVpreop was high in 60 (58%) and low in 44 (42%). Following neoadjuvant therapy, preop CA19-9 was normal in 90 (45%) patients and elevated in 111 (55%). Median overall survival (OS) of all patients was 27 months; 33 months for the 103 patients with a low SUVdx and 22 months for the 98 patients with a high SUVdx (p = 0.03). Median OS for patients with low SUVdx/normal preop CA19-9, high SUVdx/normal preop CA19-9, low SUVdx/elevated preop CA19-9, and high SUVdx/elevated preop CA19-9 were 66, 34, 23, and 17 months, respectively (p < 0.0001). OS was 44 months for the 148 (74%) patients who completed all intended neoadjuvant therapy and surgery and 13 months for the 53 (26%) who did not undergo surgery (p < 0.001). Conclusion: Pretreatment PET/CT avidity and preop CA19-9 are clinically significant prognostic markers in patients with PC.

Impact of Neoadjuvant Chemoradiation on Pathologic Response in Patients With Localized Pancreatic Cancer.

Introduction/Background: Multimodal neoadjuvant therapy has resulted in increased rates of histologic response in pancreatic tumors and adjacent lymph nodes. The biologic significance of the collective response in the primary tumor and lymph nodes is not understood. Methods: Patients with localized PC who received neoadjuvant therapy and surgery with histologic assessment of the primary tumor and local-regional lymph nodes were included. Histopathologic response was classified using the modified Ryan score as follows: no viable cancer cells (CR), rare groups of cancer cells (nCR), residual cancer with evident tumor regression (PR), and extensive residual cancer with no evident tumor regression (NR). Nodal status was defined by number of lymph nodes (LN) with tumor metastases: N0 (0 LN), N1 (1-3), N2 (≥4). Results: Of 341 patients with localized PC who received neoadjuvant therapy and surgery, 107 (31%) received chemoradiation alone, 44 (13%) received chemotherapy alone, and 190 (56%) received chemotherapy and chemoradiation. Histopathologic response consisted of 15 (4%) CRs, 59 (17%) nCRs, 188 (55%) PRs, and 79 (23%) NRs. Patients who received chemotherapy alone had the worst responses (n = 21 for NR, 48%) as compared to patients who received chemoradiation alone (n = 25 for NR, 24%) or patients who received both therapies (n = 33 for NR, 17%) (Table 1; p = 0.001). Median overall survival for all 341 patients was 39 months; OS by histopathologic subtype was not reached (CR), 49 months (nCR), 38 months (PR), and 34 months (NR), respectively (p = 0.004). Of the 341 patients, 208 (61%) had N0 disease, 97 (28%) had N1 disease, and 36 (11%) had N2 disease. In an adjusted hazards model, modified Ryan score of PR or NR (HR: 1.71; 95% CI: 1.15-2.54; p = 0.008) and N1 (HR: 1.42; 95% CI: 1.1.02-2.01; p = 0.04), or N2 disease (HR: 2.54, 95% CI: 1.64-3.93; p < 0.001) were associated with increased risk of death. Conclusions: Neoadjuvant chemotherapy alone is associated with lower rates of pathologic response. Patients with CR or nCR have a significantly improved OS as compared to patients with PR or NR. Nodal status is the most important pathologic prognostic factor. Neoadjuvant chemoradiation may be an important driver of pathologic response.

Detection of germline variants using expanded multigene panels in patients with localized pancreatic cancer.

BACKGROUND: Current guidelines recommend genetic testing for all patients with pancreatic cancer (PC). METHODS: Patients with localized PC who received neoadjuvant therapy between 2009 and 2018 were identified. Genetic consultation (including personal and family history of cancer), genetic testing, and variant data were abstracted. RESULTS: Of 510 patients identified, 163 (32%) underwent genetic counseling and genetic testing was performed in 127 (25%). Patients who underwent genetic testing were younger (median age: 63 vs. 67, p = 0.01). Multi-gene testing was performed in 114 (90%) of 127 patients, targeted gene testing was performed in 8 (6%), and not specified in 5 (4%). Of 127 patients who underwent genetic testing, 20 (16%) had pathogenic (P)/likely pathogenic (LP) variants, observed in ATM (n = 7/105,7%), CHEK2 (n = 3/98, 3%), BRCA1 (n = 2/117, 2%), BRCA2 (n = 2/122, 2%), PALB2 (n = 1/115, 1%), MUTYH (n = 1/98, 1%), CDKN2A (n = 1/94, 1%), STK11 (n = 1/97, 1%), NBN (n = 1/98, 1%), and MSH6 (n = 1/97, 1%). Of 20 patients with either a P/LP variant, nine (45%) had a prior cancer, three (15%) had a first-degree relative with PC, and six (30%) had an any-degree relative with PC. CONCLUSION: Pathogenic/likely pathogenic variants were identified in 16% of patients who underwent genetic testing, 60% of which occurred in the homologous recombination pathway.

Role of Molecular Profiling of Pancreatic Cancer After Neoadjuvant Therapy: Does it Change Practice?

INTRODUCTION: Tumor profiling can improve the selection of oncologic therapies in patients with pancreatic cancer (PC). The impact of neoadjuvant therapy on tumor testing is unknown. METHODS: Molecular profiling using commercially available 53-, 315-, or 472-gene next generation sequencing (NGS) panels was performed on surgical specimens following neoadjuvant therapy. All specimens with 472-gene sequencing also had immunohistochemical (IHC) testing. Treatment recommendations were based on somatic variants and IHC staining. RESULTS: NGS was performed on 74 patient specimens: 42 (57%) with a 472-gene panel, 28 (38%) with a 315-gene panel, 3 (4%) had 472- and 315-gene panels, and 1 (1%) patient had 53- and 472-gene panels (78 total tests). Likely pathogenic/pathogenic variants were identified in 73 (94%) of the 78 tests. Of the 73 samples with variants identified, 13 (18%) variants were associated with an actionable treatment: ATM (n = 10), BRCA1 (n = 1), PIK3CA (n = 1), and BRCA2 (n = 1). No patient had more than one actionable variant. Based on NGS results, the most commonly recommended therapy was a platinum agent (n = 12/78, 15%). Of the 46 specimens that underwent IHC analysis, overlapping chemotherapeutic treatment recommendations were identified in 40 (87%) specimens. CONCLUSION: Using current multigene NGS panels, actionable variants were identified in 13 (18%) of 74 surgical specimens and primarily involved genes of the DNA repair pathway. Anecdotal reproducibility of test concordance was low.

Importance of Normalization of CA19-9 Levels Following Neoadjuvant Therapy in Patients With Localized Pancreatic Cancer.

OBJECTIVE: Carbohydrate antigen 19-9 (CA19-9) is a prognostic marker for patients with pancreatic cancer (PC), but its value as a treatment biomarker is unclear. SUMMARY BACKGROUND DATA: Although CA19-9 is an established prognostic marker for patients with PC, it is unclear how CA19-9 monitoring should be used to guide multimodality treatment and what level of change in CA19-9 constitutes a meaningful treatment response. METHODS: CA19-9 measurements at diagnosis (pretx), after completion of all planned neoadjuvant therapy (preop), and after surgery (postop) were analyzed in patients with localized PC who had an elevated CA19-9 (≥35 U/dL) at diagnosis. Patients were classified by: 1) quartiles of pretx CA19-9 (Q1-4); 2) proportional changes in CA19-9 (ΔCA19-9) after the completion of neoadjuvant therapy; 3) normalization (CA19-9 <35 U/dL) of preop CA19-9; and 4) normalization of postop CA19-9. RESULTS: Among 131 patients, the median overall survival (OS) was 30 months; 68 months for the 33 patients in Q1 of pretx CA19-9 (<80 U/dL) compared with 25 months for the 98 patients in Q2-4 (P = 0.03). For the 98 patients in Q2-4, preop CA19-9 declined (from pretx) in 86 (88%), but there was no association between the magnitude of ΔCA19-9 and OS (P = 0.77). Median OS of the 98 patients who did (n = 29) or did not (n = 69) normalize their preop CA19-9 were 46 and 23 months, respectively (P = 0.02). Of the 69 patients with an elevated preop CA19-9, 32 (46%) normalized their postop CA19-9. Failure to normalize preop or postop CA19-9 was associated with a 2.77-fold and 4.03-fold increased risk of death, respectively (P < 0.003) as compared with patients with normal preop CA19-9. CONCLUSIONS: Following neoadjuvant therapy, normalization of CA19-9, rather than the magnitude of change, is the strongest prognostic marker for long-term survival.

Survival of patients with borderline resectable pancreatic cancer who received neoadjuvant therapy and surgery.

BACKGROUND: It is difficult to successfully deliver multimodality therapy to patients with operable pancreatic cancer. Data on the natural history of such efforts are necessary for physicians to guide shared decision-making with patients and families. We report the survival of consecutive patients with borderline resectable pancreatic cancer who received neoadjuvant therapy before surgery. METHODS: Data regarding demographics, neoadjuvant therapy, surgery, pathology, and survival duration were abstracted on consecutive patients with borderline resectable pancreatic cancer diagnosed between 2009 and 2017 and not treated on available clinical trials. Borderline resectable pancreatic cancer was defined based on ≥1 of the following: local tumor anatomy, pretreatment serum carbohydrate antigen 19-9 >2,000 U/mL, and the presence of radiographic lesions indeterminate for metastases. RESULTS: Neoadjuvant therapy was delivered to 185 patients with borderline resectable pancreatic cancer who were not enrolled in competing clinical trials; 13 (7%) patients received chemoradiation, 12 (7%) received chemotherapy, and 160 (86%) received both. Of the 185 patients, 115 (62%) completed all intended neoadjuvant therapy and surgery; 81 (70%) of 115 underwent pancreaticoduodenectomy; and vascular reconstruction was performed in 51 (44%). A margin negative resection was achieved in 111 (97%) of 115 patients, and 83 (72%) were node negative. Median overall survival for all 185 patients was 20 months; 31 months for the 115 patients who completed all neoadjuvant therapy and surgery as compared to 13 months for the 70 patients who were not resected (P < .0001). CONCLUSION: After neoadjuvant therapy, surgical resection was performed in 62% of patients with borderline resectable pancreatic cancer. Those who normalized preoperative serum carbohydrate antigen 19-9 and had node negative pathology achieved the longest survival. To further improve median survival for all patients, we are incorporating adaptive approaches to neoadjuvant therapy sequencing based on objective assessments of response.

A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer.

PURPOSE: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. PATIENTS AND METHODS: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. RESULTS: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. CONCLUSIONS: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. CLINICAL TRIAL REGISTRY NO: NCT01647828.

Distal splenorenal and mesocaval shunting at the time of pancreatectomy.

BACKGROUND: When pancreatic neoplasms occlude or encase the superior mesenteric-portal-splenic vein confluence with abutment of the posterior lateral wall of the superior mesenteric artery, a mesocaval shunt with or without a distal splenorenal shunt allows for safe dissection of the porta hepatis and separation of the pancreatic tumor from the superior mesenteric artery. Herein we report long-term results of the largest known series of portosystemic shunts performed at the time of pancreatectomy. METHODS: All patients who underwent pancreatic resection with a mesocaval shunt or distal splenorenal shunt were identified from our prospective database. Demographics, perioperative treatment, and outcomes were reviewed. RESULTS: A total of 34 patients underwent mesocaval shunt or distal splenorenal shunt, including 25 at the time of pancreatoduodenectomy, 6 during total pancreatectomy, and 3 after prior pancreatectomy. There were 15 mesocaval shunts, 16 distal splenorenal shunts, 2 combined mesocaval/distal splenorenal shunts, and 1 distal splenoadrenal vein shunt. The mesocaval group included 11 temporary and 6 permanent (3 delayed) shunts. Median operative time was 9 hours (range 6.5-13), median estimated blood loss was 950 mL (range 200-5,000), and median duration of hospital stay was 11 days (range 7-35). Four patients experienced complications that required intervention (Clavien-Dindo grade ≥III), but there were no 90-day mortalities. For patients with adenocarcinoma, median overall survival was 31 months at a median follow-up of 19 months. All but 1 shunt (distal splenorenal) were patent at last follow-up. CONCLUSION: Mesenteric venous shunting facilitates a safe and complete tumor resection in patients who require a complex pancreatectomy, many of whom would otherwise be deemed inoperable.

A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: One facet of precision medicine is the use of tumor molecular profiling to guide chemotherapeutic selection. We conducted the first prospective clinical trial of molecular profiling to guide neoadjuvant therapy in patients with operable pancreatic ductal adenocarcinoma (PDAC). We hypothesized that more effective systemic therapy would prevent disease progression during neoadjuvant therapy and, therefore, allow more patients to undergo surgery. METHODS: In patients with resectable and borderline resectable (BLR) PDAC, molecular profiling consisted of immunocytochemical staining of pretreatment endoscopic ultrasound-guided fine needle aspiration tumor biopsies using 6 biomarkers. Neoadjuvant systemic therapy was selected based on the molecular profiling results. The primary endpoint was the completion of all intended neoadjuvant therapy and surgery. RESULTS: The trial enrolled 130 patients; 61 (47%) resectable and 69 (53%) BLR. Molecular profiling was reported within a median of 5 business days (IQR: 3). Of the 130 patient samples, 95 (73%) had adequate cellularity for molecular profiling and 92 (71%) patients received molecular profile-directed therapy. Of the 92 patients who had predictive profiling, 74 (80%) received fluoropyrimidine-based therapy and 18 (20%) received gemcitabine-based therapies. Of the 130 patients, 107 (82%) completed all intended neoadjuvant therapy and surgery; 56 (92%) of the 61 with resectable PDAC and 51 (74%) of 69 with BLR PDAC. CONCLUSIONS: We report the first prospective clinical trial that utilized molecular profiling to select neoadjuvant therapy in patients with operable PDAC. Such high resectability rates have not been observed in prior neoadjuvant trials, suggesting that molecular profiling may improve the efficacy of chemotherapy in these patients.

Locally advanced pancreas cancer: Staging and goals of therapy.

BACKGROUND: Patients with locally advanced pancreatic cancer have historically been considered inoperable. The purpose of this report was to determine resectability rates for patients with locally advanced pancreatic cancer based on our recently described definitions of type A and type B locally advanced pancreatic cancer. METHODS: An institutional prospective pancreas cancer database was queried for consecutive patients with locally advanced pancreatic cancer treated between January 2009 and June 2017. All pretreatment imaging was re-reviewed and patients were categorized as locally advanced pancreatic cancer type A or type B. Demographics, induction therapy, resection type, and outcomes were reviewed. RESULTS: We identified 108 consecutive patients; 12 were excluded from analysis due to the absence of available pretreatment imaging or they had not yet completed all intended neoadjuvant therapy. Of the remaining 96 patients (45 type A, 51 type B), disease progression occurred in 19 (20%) during induction therapy and 30 (31%) were deemed inoperable at final preoperative restaging. Therefore, 47 (49%) of 96 patients were taken to surgery and 40 (42%) underwent successful resection (28 [62%] of 45 type A and 12 [24%] of 51 type B); an RO resection was achieved in 32 (80%). Metastatic disease was found intraoperatively (6 at laparoscopy, 1 at laparotomy) in 7 (15%) of 47 patients. There were no mortalities; 6 (15%) patients experienced major postoperative complications. Resected patients had a median overall survival of 38.9 months. CONCLUSION: Locally advanced pancreatic cancer can be dichotomized into type A and B with distinctly different probabilities of completing all therapy to include surgery; thereby allowing goals of therapy to be established at the time of diagnosis. Multimodality therapy that includes surgery can be accomplished in selected patients with locally advanced pancreatic cancer and is associated with a median overall survival that approximates earlier stages of disease. (Surgery 2017;160:XXX-XXX.).

HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma.

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Should functional renal scans be obtained prior to upper abdominal IMRT for pancreatic cancer?

BACKGROUND: Upper abdominal irradiation for pancreatic cancer is administered in close proximity to the radiation-sensitive kidneys. There is difficulty in defining dose-volume parameters to predict late renal toxicity after partial kidney irradiation. Less than 10% of the general population is estimated to have asymmetrical kidney function; however, there are no studies that examine this in patients with pancreatic cancer. The primary purpose of this study was to determine the prevalence of asymmetrical kidney function in patients with pancreatic cancer. A secondary aim was to determine if asymmetrical kidney function was associated with abnormal laboratory values or kidney size on computed tomography scans. Finally, we aimed to develop recommendations for when a functional renal scan in patients with pancreatic cancer should be ordered. METHODS AND MATERIALS: We performed a retrospective review of patients with resectable, borderline resectable, and locally advanced pancreatic cancer who received abdominal radiation therapy and had preradiation functional renal scans between 2009 and 2015. Asymmetrical kidney function was defined as a difference between the 2 kidneys that was ≥60%/40% on a functional renal scan. Serum studies (blood urea nitrogen [BUN], creatinine [Cr], and glomerular filtration rate [GFR]) and abdominal computed tomography scans were routinely obtained before simulation. RESULTS: Of the 204 patients examined, 23 (11.2%) had asymmetrical kidney function that was identified on preradiation functional renal scans. Elevated Cr or BUN, a GFR <60, or a medical history that suggested abnormal renal function were not significantly associated with asymmetrical kidney function. Only 6 of 23 patients (26%) with asymmetrical kidney function had a notable difference in kidney size. CONCLUSIONS: In our series, approximately 11% of patients with pancreatic cancer have asymmetrical kidney function that was not identified by kidney size, serum BUN, Cr, GFR, or a significant medical history. These data suggest that in cases in which renal radiation doses exceed a V18 of 20% to 30% or there is concern about baseline renal function, a functional renal scan should be considered.

Is Adjuvant Therapy Necessary for All Patients with Localized Pancreatic Cancer Who Have Received Neoadjuvant Therapy?

BACKGROUND: Among patients with localized pancreatic cancer (PC), the benefit of adjuvant therapy after neoadjuvant therapy and surgery is unknown. METHODS: Patients with localized PC who completed all intended neoadjuvant therapy and surgery were categorized based on the receipt of adjuvant therapy and by pathologic lymph node status (LN-/LN+). RESULTS: Data was available from 234 consecutive patients, 121 (52%) with resectable and 113 (48%) with borderline resectable PC. Of the 234 patients, 92 (39%) were LN+ and 142 (61%) were LN-. The median overall survival (OS) for the 234 patients was 39 months, 42.3 months for patients who received any adjuvant therapy and 34.1 months for those who did not (p = 0.29). Of the 92 LN+ patients, the median OS with and without adjuvant therapy was 29.5 and 23.2 months, respectively (p = 0.02). Of the142 LN- patients, the median OS was 45 months with or without adjuvant therapy (p = 0.86). In an adjusted hazard model, additional adjuvant therapy had a significant protective effect among LN+ patients (HR 0.39; 95% CI 0.21-0.70; p = 0.002) but not in LN- patients (HR 0.89; 95% CI 0.53-1.52; p = 0.68). CONCLUSION: Among patients with localized PC who received neoadjuvant therapy and surgery, the benefit of adjuvant therapy was limited to those with node-positive disease.

Multimodality Therapy in Patients With Borderline Resectable or Locally Advanced Pancreatic Cancer: Importance of Locoregional Therapies for a Systemic Disease.

Historically, the clinical staging of pancreatic cancer has centered on the surgical management of the primary tumor, because few effective chemotherapeutic agents were available and long-term survival was only achieved in the context of surgical resection. Such a strategy of complete oncologic surgical care is reasonable when surgery is both the principal therapy and highly effective. However, complex surgery for pancreatic cancer-often performed in older patients after a lengthy period of induction therapy-can be associated with significant morbidity and mortality. The majority of patients with pancreatic cancer present either locally advanced or metastatic disease at the time of diagnosis. In this article, we will discuss the role of multimodality management of patients with borderline resectable and locally advanced pancreatic cancer. Considering that surgery has a modest impact on the natural history of pancreatic cancer in most patients, a neoadjuvant approach to treatment sequencing is favored for patients with borderline resectable pancreatic cancer, and this same rationale has been extended to select patients with locally advanced disease who demonstrate an exceptional response to induction therapy.

Venous thromboembolism prophylaxis during neoadjuvant therapy for resectable and borderline resectable pancreatic cancer-Is it indicated?

PURPOSE: To describe venous thromboembolism (VTE) rates in patients with pancreatic cancer (PC) during neoadjuvant therapy. METHODS: Factors associated with VTE were evaluated using multivariable logistic regression modeling in patients with resectable and BLR PC treated with neoadjuvant therapy between 2009 and 2014. RESULTS: Prevalent VTEs were detected in 13 (5%) of the 260 patients. Incident VTEs were detected in 26 patients (10%); 9 (8%) of the 109 resectable and 17 (11%) of the 151 BLR patients (P = 0.53). Of the 26 incident events, 9 (35%) were PEs, 9 (35%) were extremity DVTs, and 8 (31%) involved the SMV/PV. VTEs were catheter-related in 7 (27%) of the 26 patients. Rh(D) antigen positivity was associated with a decreased risk of incident VTE (OR:0.32, 95%CI:0.11-0.85, P = 0.02). Completion of neoadjuvant therapy to include surgery occurred in 176 (75%) of the 234 patients without incident VTE as compared to 14 (54%) of the 26 patients with incident VTE (P = 0.02). The median survival for all 260 patients was 24.3 months: 17.0 months versus 24.6 months for patients who did and did not develop incident VTE during neoadjuvant therapy (P = 0.11). CONCLUSIONS: Patients with localized PC who receive neoadjuvant therapy are at significant risk of VTE and thromboprophylaxis may be warranted. J. Surg. Oncol. 2016;114:581-586. © 2016 Wiley Periodicals, Inc.

Evolution of the Management of Resectable Pancreatic Cancer.

In pancreatic cancer, as with many other solid tumors, a commonly held surgical adage-a chance to cut is a chance to cure-has been promulgated throughout the years. Following such reasoning, surgical extirpation of a localized tumor would prevent tumor dissemination and metastatic tumor progression. However, decades of surgical experience have demonstrated that surgical resection alone provides a limited median survival benefit. Despite the optimization of surgical technique and perioperative management over the past three decades, little progress has been made to improve the limited survival of patients with localized pancreatic cancer who receive surgery. In this article, we discuss the rationale for a novel management strategy for patients with resectable pancreatic cancer, which may improve patient selection and the delivery of multimodality therapy.

Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy.

BACKGROUND: Enthusiasm for neoadjuvant therapy is growing from the emerging consensus that pancreatic cancer is a systemic disease at the time of diagnosis. Those who remain in favor of upfront surgery often cite the lack of reported data to support alternative treatment sequencing. We therefore report the results of all patients treated outside of a clinical trial under the direction of a multidisciplinary pancreatic cancer working group. METHODS: We reviewed all patients with resectable pancreatic cancer treated with neoadjuvant therapy (NeoTx) from 2009 to 2013; we excluded those patients treated on prospective clinical trials as they will be the subject of subsequent reports. Data regarding demographics, NeoTx, operative outcomes, pathology, and survival data were abstracted from a prospective database. RESULTS: NeoTx was initiated in 69 patients; median age was 65 years (interquartile range [IQR]: 11) and median carbohydrate antigen 19-9 at diagnosis was 96.5 (IQR 210). NeoTx consisted of chemotherapy alone (n = 10, 14%), chemotherapy and radiation (chemoradiation, n = 53, 77%), or both (n = 6, 9%). Median carbohydrate antigen 19-9 after NeoTx was 39 (IQR 104) corresponding to a median decrease of 60%. Operative resection was completed in 60 (87%) of the 69 patients. At restaging after NeoTx, 5 (7%) of 69 patients were not considered candidates for surgery because of the development of metastatic disease (n = 4) or an inadequate performance status (n = 1). At the time of surgery, 4 (6%) of 64 patients had metastatic disease found at laparoscopy. Of the 60 patients who underwent surgical resection, a complete pathologic response was observed in 2 (3%) patients; 20 (33%) had positive lymph nodes, and the median number of positive lymph nodes was 2 (IQR 3). R0 resections were achieved in 58 (97%) of the 60 patients. Additional postoperative adjuvant therapy was administered to 37 (62%) of the 60 patients. Median survival of all 69 patients was 31.5 months; 44.9 months for the 60 patients who completed all NeoTx and resection compared with 8.1 months for the 9 patients who were not resected (log rank P < .001). CONCLUSION: NeoTx for resectable pancreatic cancer was associated with a median overall survival of 32 months; something not reported for patients treated with surgery first if based on intent-to-treat analysis. Treatment sequencing may provide an oncologic benefit beyond that of the selection bias afforded surgery after a period of induction therapy.

Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium.

PURPOSE: Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. PATIENTS AND METHODS: Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. RESULTS: From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). CONCLUSION: mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma.

Neoadjuvant therapy for localized pancreatic cancer: guiding principles.

The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.