Pancreatic ductal adenocarcinoma (PDAC) is

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1 GASTROENTEROLOGY 2013;144: Therapeutic Advances in Pancreatic Cancer Andrew Scott Paulson 1, Hop S. Tran Cao 2, Margaret A. Tempero 1, Andrew M. Lowy 3, 1 University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California; 2 Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas; and 3 Department of Surgery, Division of Surgical Oncology, University of California, San Diego, Moores Cancer Center, La Jolla, California Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better shortterm outcomes, major progress toward increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5 10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of borderline resectable pancreatic cancer a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future. Keywords: Pancreatic Cancer; Chemotherapy; Adjuvant Therapy. Resectable Cancer Pancreatic ductal adenocarcinoma (PDAC) is usually detected at a late stage, when 20% of patients are eligible for potentially curative resection; most of these patients have disease recurrence. Although mortality from PDAC has decreased significantly, particularly among patients treated at highvolume centers, pancreatectomy continues to cause significant morbidities that can affect physicians ability to deliver adjuvant therapy. It is therefore important to optimize surgical techniques in terms of oncologic and safety parameters. Although surgery offers the only chance to cure patients with pancreatic cancer, the disappointing survival rates after even margin-negative pancreatectomy indicate the aggressive nature of this disease and the need for effective (neo) adjuvant therapy. Chemotherapy, alone or in combination with radiation, has some benefit for patients with advanced pancreatic cancer. Only recently, however, have results from large studies been published that consistently support its effectiveness as an adjuvant. Several research centers provide patients with neoadjuvant therapy to increase the marginal survival benefits of adjuvant therapy. A subset of patients has recently been defined as having borderline resectable pancreatic cancer, based on a specific set of anatomic features identified by pancreatic imaging. These tumors might be resected at specialized * Authors share co-first authorship. Authors share co-senior authorship. Abbreviations used in this paper: ESPAC, European Study Group for Pancreatic Cancer; 5-FU, 5-fluorouracil; hent-1, human equilibrative nucleoside transporter 1; LDP, laparoscopic distal pancreatectomy; MDACC, MD Anderson Cancer Center; PDAC, pancreatic ductal adenocarcinoma; RAPD, robotic-assisted distal pancreatectomy and pancreaticoduodenectomy; SMV, superior mesenteric vein by the AGA Institute /$

2 May 2013 THERAPEUTIC ADVANCES IN PANCREATIC CANCER 1317 Table 1. Studies of Minimally Invasive Pancreatectomies That Focused on PDAC Study, first author Approach PDAC patients (total) Conversion rate, % R0 rate, % Mean/median lymph node yield Adjuvant therapy a Median overall survival (mo) Distal pancreatectomy Fernández-Cruz 5 Laparoscopic 13 (82) Kooby 6 Laparoscopic 23 (23) Daouadi 7 Laparoscopic 14 (94) NR NR Daouadi 7 Robotic-assisted 13 (30) NR NR Pancreaticoduodenectomy Dulucq 8 Laparoscopic 11 (25) b b NR NR Kendrick 9 Laparoscopic 31 (65) b 15 b NR NR Palanivelu 10 Laparoscopic 9 (42) NR 50 Giulianotti 11 Robotic-assisted 27 (50) c NR d Zeh 12 Robotic-assisted 14 (50) NR NR, not reported. a Percentage of patients eligible for adjuvant therapy that went on to receive it. b Rate or number applies to total cases or all malignancies and are not specific to PDAC cases. c The authors reported their data from Italy and the United States separately. d Please see text for details. centers, but are likely to have positive margins if a surgeryfirst approach is taken. This new category of pancreatic tumors must be considered separately in the design of clinical trials. Minimally Invasive Surgery for Pancreatic Cancer Refinements in laparoscopic instruments and advances in robotic platforms that improve ergonomics and increase movement precision and dexterity are continually expanding the roles for minimally invasive surgery. This technology was first introduced to pancreatic surgery in the mid-1990s. 1,2 Yet, because of the inherent challenges presented by the retroperitoneal location and notoriously unforgiving nature of the pancreas, along with its close proximity to major vascular structures, the popularity of minimally invasive pancreatic surgery has been slow to increase, with most reports published in the past 5 years. Most studies to evaluate minimally invasive pancreatectomy have focused primarily on the treatment of patients with low-grade tumors rather than PDAC, and on perioperative surgical outcomes. A recent meta-analysis by Venkat et al 3 examined perioperative outcomes of laparoscopic distal pancreatectomy (LDP) for any pancreatic lesion, and reported reduced loss of blood, length of hospital stay, and risk of overall complications and infections, but similar rates of postoperative fistula and mortality, compared with open surgery. Although the authors also found that LDP and open surgery produced equal rates of margin positivity, the findings were reported from 4 series that included only a small subset of PDACs. Importantly, there was insufficient data to draw conclusions about the effects of LDP on lymph node retrieval, time to receipt of adjuvant therapy, and disease-free and overall survival. Published studies on robotic surgery and treatment of right-sided lesions have also lacked important outcomes data. A comprehensive review of robotic pancreatic surgery by Winer et al 4 reported the feasibility of roboticassisted distal pancreatectomy and pancreaticoduodenectomy (RAPD), describing its benefits compared with laparoscopy, which might include lower rates of conversion and less blood loss. Oncologic outcomes, when reported, have for the most part been limited to margin status and lymph node yield. Table 1 presents studies that focused on oncologic outcomes from PDAC. Minimally Invasive Distal Pancreatectomy Taken together, studies of LDP for PDAC have shown acceptable rates of R0 resection (64% 100%) and adequate lymph node yield (n 9 19). In a series study published by Fernández-Cruz et al, 5 all patients progressed to chemotherapy after surgery, with a median survival time of 14 months. Kooby et al 6 performed a retrospective review to compare results from 23 LDPs with those from 189 open distal pancreatectomies in patients with PDAC. They reported that patients receiving LDP lost less blood and had shorter hospital stays, but that there was no difference in oncologic outcomes between groups. On multivariate analysis, LDP was not independently associated with reduced survival time. Daouadi et al 7 reported several advantages of robotic surgery over conventional laparoscopy, including a higher rate of R0 resection, a greater lymph node yield, and a lower rate of conversion. However, no survival data were reported. Minimally Invasive Pancreaticoduodenectomy Studies of LPD have reported rates of R0 resection from 88% to 100%, and a yield from 14 to 21 lymph nodes; these data are encouraging. 8,9 Palanivelu et al 10 reported excellent long-term outcomes for a series of patients who underwent LDP, with median survival times of 50 months. However, the small number of patients in the study, and the low number with nodal involvement (2 of 9), reveal the study s bias toward patients with early-stage disease.

3 1318 PAULSON ET AL GASTROENTEROLOGY Vol. 144, No. 6 Table 2. Trials of Adjuvant Therapy for Resected PDAC Trial (year published) Treatment group No. of patients Median disease-free survival (mo) P value Median overall survival (mo) CONKO-001 (2007) 17 Gemcitabine (6 cycles) Observation ROTG (2008) 18a 5-FU and 5-FU chemoradiation 201 NR NS b Gemcitabine and 5-FU chemoradiation 187 NR 20.5 ESPAC-3 (2010) 19c 5-FU and folate (6 cycles) Gemcitabine (6 cycles) P value CONKO, Charité Onkologie Clinical Studies in GI Cancers; NR, not reported; NS, not statistically significant; ROTG, Radiation Oncology Therapy Group. a Results shown reflect only patients with pancreatic head tumors. b Authors reported lack of statistically significant difference in disease-free survival, but did not report the data. c A third arm (observation alone) was closed due to results of ESPAC-1, which demonstrated inferiority of surgery alone. Two large series studies of RAPD are worth highlighting. Giulianotti et al 11 reported the results of 60 RAPDs performed by a single surgeon (27 for PDAC). After a mean follow-up period of 16.8 months, 8 patients were lost, 2 died in the perioperative period, 5 died within 2 years of disease recurrence, 3 were alive but had their cancer recur after 1 year, and 9 were disease-free. The authors did not report the number of patients who received adjuvant therapy. Zeh et al 12 reported outcomes of 50 RAPDs performed for periampullary tumors (37 malignant lesions, including 14 cases of PDAC). Based on oncologic quality parameters, 87% of procedures resulted in an R0 resection, a median of 18 lymph nodes were collected, and 73% of eligible patients received adjuvant chemotherapy; long-term survival data were not reported. Collectively, studies of minimally invasive pancreatic surgery have indicated acceptable perioperative outcomes, including reduced blood loss and shorter hospital stays, despite longer operating times (at least for right-sided lesions), without compromising quantifiable parameters generally associated with the quality of oncologic surgery. However, the stringent selection of patients for these studies and publication bias must be recognized. Minimally invasive pancreatic cancer surgery is a new procedure, so its long-term effects on cancer outcomes are unclear and must be the focus of future studies. Nonetheless, improvements in perioperative outcomes directly affect delivery of therapy and survival time. Greater loss of blood and transfusion requirements have been associated with worse patient outcomes and higher mortality rates. 13 In addition, quicker recovery (shorter hospital stays and fewer complications) can reduce the time to adjuvant therapy; this is important because nearly 25% of patients never receive their intended adjuvant therapy after PD because of their prolonged recoveries. Conversely, patients must be carefully selected for minimally invasive surgery because conversions are often associated with greater morbidity than planned open operations. Unfortunately, minimally invasive approaches will be assimilated into the treatment of pancreatic cancer before randomized controlled trials can establish their noninferiority to open surgery (especially with regard to longterm oncologic outcomes). Ideally, until minimally invasive approaches are accepted as standard of care, they should be performed according to rigorously designed protocols that have been approved by Institutional Review Boards. Adjuvant and Neoadjuvant Therapy Five-year survival rates after surgery for pancreatic cancer remain low, ranging from 15% to 20%; most patients die from metastatic disease and/or locoregional recurrences. These statistics indicate the inadequacy of surgery as the only therapy and the need for additional treatments. Adjuvant therapy. In 1985, the Gastrointestinal Tumor Study Group reported increased survival among patients who received adjuvant therapy with 5-fluorouracil (5-FU) and 5-FU based chemoradiation. 14 Patients randomly assigned to receive adjuvant therapy had significantly longer median survival times (20 months) than those who received only surgery (11 months). These findings, however, were not confirmed by the European Organization for Research and Treatment of Cancer or European Study Group for Pancreatic Cancer (ES- PAC)-1 trials, which concluded that adjuvant chemoradiation actually reduced, and 5-FU adjuvant chemotherapy alone increased, survival time. 16 In light of these contradictory reports, the role of adjuvant therapy remained in question until the recent publication of results from several adjuvant therapy trials (Table 2). The Charité Onkologie Clinical Studies in Gastrointestinal Cancers-001 reported results from 354 patients who were randomly assigned to receive adjuvant gemcitabine or undergo observation after curative surgery. 17 Patients given adjuvant gemcitabine had significantly longer median times of disease-free survival (13.4 months vs 6.9 months) and overall survival time (22.8 months vs 20.2 months) than patients that did not receive the drug. The magnitude of the difference in overall survival observed might have been reduced because nearly all patients in the observation arm received gemcitabine upon disease relapse. The ESPAC-3 trial compared the effects of 5-FU with that of gemcitabine as adjuvants. 18 A third arm, observation alone, was closed early, in light of the final results

4 May 2013 THERAPEUTIC ADVANCES IN PANCREATIC CANCER 1319 from ESPAC-1. In the ESPAC-3 trial, 1088 patients who underwent surgery for pancreatic cancer were randomly assigned to groups given 6 cycles of either 5-FU/folinic acid or gemcitabine. No differences were detected between groups in median survival time (23.0 months for 5-FU vs 23.6 months for gemcitabine), progression-free survival (14.1 months vs 14.3 months), or quality of life. Gemcitabine therapy, however, was associated with significantly fewer serious adverse events. In the Radiation Therapy Oncology Group trial, 451 patients with resected PDAC received either gemcitabine or 5-FU chemotherapy before and after 5-FU based chemoradiation. 19 Among patients with cancer of the pancreatic head, median survival time was 20.5 months for those that received gemcitabine and 16.9 months for those that received 5-FU. Multivariate analysis revealed a significant trend toward longer overall survival times among patients who received gemcitabine. Other studies assessed combinations of chemotherapy and chemoradiation because of the high rate of locoregional recurrence after pancreatic cancer resection. Hsu et al 20 published a large retrospective analysis of the effects of combined adjuvant chemoradiation, based on data collected from Johns Hopkins University Medical Center and the Mayo Clinic. Patients who received 5-FU based chemoradiation after resection for pancreatic cancer had significantly longer overall survival times than patients who did not receive the adjuvant chemoradiation (21.1 months vs 15.5 months). Because of the limited efficacy of 5-FU based chemoradiation, the American College of Surgeons Oncology Group examined the efficacy of interferon-based chemoradiation. 21 In the Z5031 trial, patients with resected PDAC were treated with the combination of interferon alfa2b, cisplatin, and 5-FU, along with concurrent external beam radiation. Median time of disease-free survival was 14.1 months, and the overall time of survival was 25.4 months; 69% of patients met the study s primary end point, 18-month overall survival, surpassing the threshold of 65% set as a positive outcome. Although the rate of toxicity was high (95% of patients experienced all-cause, grade 3 or 4 toxicity), there were no long-term toxic effects or toxicity-related mortalities. These results indicate that it might be possible to improve the outcomes of patients with pancreatic cancer by combining cytotoxic chemotherapeutic agents, if manageable levels of toxicity can be achieved. A phase III trial (Radiation Therapy Oncology Group 0848) is examining the effects of adjuvant radiation therapy in patients who have no evidence of disease progression after 5 months of gemcitabine-based adjuvant chemotherapy. The study is the first to include American and European investigators (from the European Organization for Research and Treatment of Cancer), and is also testing whether patients benefit from receiving erlotinib in addition to gemcitabine. Neoadjuvant therapy. Although trials of adjuvant therapies have provided important information, the results have been disappointing, showing marginal clinical benefit and frequent and rapid disease recurrence. These issues led to development of neoadjuvant treatment strategies. The rationale for neoadjuvant therapy includes the ability to provide early treatment of occult, micrometastatic disease, to deliver therapy to a tumor that is undisturbed and well-vascularized (which could increase rates of R0 resection), and the ability to assess drug activity in vivo, during surgery. Neoadjuvant treatment provides a window of biologic assessment to insure that patients with rapidly progressive disease are spared a nontherapeutic, morbid operation. Finally, neoadjuvant therapy also increases the chances for patients to receive all aspects of multimodal therapy; many patients, under the surgeryfirst strategy, have either significant delays to adjuvant therapy or never recover enough to receive it. Neoadjuvant therapy, however, can only be administered once a diagnosis has been made based on analysis of tissue samples, and generally necessitates biliary decompression. During the past 20 years, results have been published from numerous phase II neoadjuvant chemoradiation trials for resectable pancreatic cancer, with the most notable series coming from the MD Anderson Cancer Center (MDACC). Successive studies investigated various treatment regimens, including 5-FU, paclitaxel, and gemcitabine Thanks to the consistency in the definition of resectability and techniques for surgical and pathology analyses, results from these studies can be compared directly. Overall, the MDACC trials demonstrated that patients whose disease did not progress upon completion of neoadjuvant chemoradiation had higher rates of R0 resection, leading to lower rates of local recurrence, and increased rates of survival compared with historical data. Importantly, the effects of neoadjuvant chemoradiation clearly identified patients who were unlikely to benefit from surgery patients with disease progression through neoadjuvant therapy who, therefore, did not undergo surgery. In a comparison of the different regimens, more patients responded to gemcitabine-based neoadjuvant chemoradiation and therefore underwent surgery. These patients had a higher rate of R0 resection, better results from pathology analyses, and longer survival times than patients that received 5-FU or paclitaxel-based chemoradiation. The addition of cisplatin to gemcitabine-based chemoradiation as neoadjuvant therapy did not improve outcomes. 26 Estrella et al 27 reviewed clinicopathologic features of patients receiving neoadjuvant therapy at MDACC. Among 240 patients who received neoadjuvant chemoradiation and PD, the median time of disease-free survival was 15.1 months and median time of overall survival was 33.5 months. Post-treatment American Joint Commission on Cancer stage, based on pathology analysis, and number of tumor-positive lymph nodes were independent predictors of disease-free and overall survival, and margin status and degree of differentiation were independent predictors of disease-free survival only.

5 1320 PAULSON ET AL GASTROENTEROLOGY Vol. 144, No. 6 Borderline Resectable Pancreatic Cancer A major development in the clinical management of pancreatic cancer over the last several years has been the recognition of a subset of tumors that cannot be clearly categorized as resectable or locally unresectable. These borderline resectable pancreatic tumors might technically be resectable, but have a high likelihood for positive margins with upfront surgery. A consistent, objective, and standardized definition of borderline resectable pancreatic cancer is required to design and conduct meaningful clinical trials. However, variations of this definition have made it a challenge to compare data from published trials or retrospective analyses. In 2006, Varadhachary et al 28 introduced the MDACC definition of borderline resectable pancreatic cancer based on a number of criteria from computed tomography in the absence of metastatic disease. The criteria are as follows: superior mesenteric artery abutment, with 180 involvement of the circumference of the vessel; common hepatic artery abutment or short segment encasement that is amenable to vascular resection and reconstruction; and superior mesenteric vein (SMV), portal vein, or superior mesenteric portal vein confluence short segment occlusion, with a suitable option for venous reconstruction due to the presence of normal portal vein above and SMV below the area of tumor involvement. The National Comprehensive Cancer Network has endorsed a modified version described in a consensus statement from the Americas Hepatopancreatobiliary Association, Society of Surgical Oncology, and Society for Surgery of the Alimentary Tract. 29 Despite minor differences in the definitions, there is increasing consensus that patients with borderline resectable tumors should be treated with induction chemotherapy, followed by chemoradiation and restaging (based on results from computed tomography), before they receive surgery, preferably in the context of a clinical trial. This strategy could increase rates of R0 resection and also provide patients with the benefits of neoadjuvant therapy. However, the ideal neoadjuvant regimen has yet to be determined. Katz et al 30 have used this strategy and published results from the largest series of borderline resectable pancreatic cancers. In their study, 160 of 2454 patients had PDACs that were classified as borderline resectable 84 because they fit the anatomic imaging criteria (type A), 44 because of concern for, but not confirmation of, metastatic disease (type B), and 32 because of poor performance status (type C). These patients were treated initially with chemotherapy, chemoradiation, or both; 125 completed neoadjuvant therapy and their tumors were restaged. Based on restaging, 79 patients went to surgery and 66 had their tumors surgically resected. Among these, 18 required vascular resection; the R0 rate was 94%, and pathologic evidence of treatment response was identified in 37 specimens. Median survival time was 40 months for patients who completed all therapy vs 13 months for the 94 patients who did not undergo surgery. Although neoadjuvant therapy was at least partly responsible for the high R0 rate, it was unlikely to downstage the tumor in anatomic terms. In a separate study, Katz et al 31 found that only 1 of 122 patients with borderline resectable cancer who received neoadjuvant therapy had a tumor that was downstaged to resectable status. An Intergroup Trial led by the Alliance for Clinical Trials in Oncology, National Cancer Institute cooperative group is planning a pilot study to test the feasibility of induction therapy with FOLFIRINOX (ie, 5-FU, leucovorin, oxaliplatin, and irinotecan) and 5-FU based chemoradiation for patients with borderline resectable PDAC. This will be the first multi-institutional study of patients with this disease stage. In this trial, the following definition of borderline resectable pancreatic cancer will be used: tumor abutment of the SMV or portal vein exceeding 180 ; and/or short-segment occlusion of the SMV or portal vein with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction; and/or gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; and/or tumor abutment of the SMA not to exceed 180 of the circumference of the vessel wall. Locally Advanced and Metastatic Disease Most patients (80%) present with advanced tumors that cannot be removed by surgery; their management is a significant unmet challenge. More than 50% of patients come to clinical attention with metastatic disease, and an additional 30% 40% present with locally advanced tumors. 32,33 The prognosis for these patients is poor. Patients with locally advanced disease have a median survival time of 8 12 months, and patients with distant metastases have significantly worse outcomes, with a median survival time of 3 6 months. 33,34 Recent improvements in combination chemotherapy, as well as strategies to select patients most likely to benefit from radiation, have provided incremental advances for these patients. Increased understanding of the complex microenvironment and network of signaling pathways that maintain tumor progression has led to the identification of new therapeutic targets. Advances in Chemotherapy for Metastatic Disease The development of improved systemic treatments is a high priority for pancreatic cancer. In 1997, gemcitabine monotherapy was established as standard of care because it was shown to have greater clinical benefit than weekly 5-FU therapy. 35 Since then, gemcitabine chemotherapy combinations have been intensely evaluated. Despite frequently encouraging early-phase data, phase III

6 May 2013 THERAPEUTIC ADVANCES IN PANCREATIC CANCER 1321 Table 3. Trials of Chemotherapy for Metastatic Disease First author, year Regimen Study phase No. of patients enrolled Median survival (mo) Conroy, FOLFIRINOX vs gemcitabine III vs 6.8 (P.001; HR 0.57) Von Hoff, Gemcitabine plus nab-paclitaxel I/II Poplin, Gemcitabine vs gemcitabine FDR vs gemcitabine and oxaliplatin III vs 6.2 (P.04; HR 0.83) vs 5.9 (P.22; HR 0.88) Cunningham, Gemcitabine and capecitabine vs III vs 6.2 (P.08; HR 0.86) gemcitabine Pelzer, Oxaliplatin and 5-FU (OFF) vs best III vs 2.3 (P.008; HR 0.45) supportive care (2 nd line) LEAP trial CO-101 vs gemcitabine III 367 (planned) Unknown HR, hazard ratio. trials of such combinations have yet to demonstrate a statistically significant survival benefit over gemcitabine alone (Table 3). These combinations have included irinotecan, 36 fluorouracil, 37 cisplatin, 38,39 oxaliplatin, 40,41 and capecitabine. 42,43 Although they do not prolong survival, gemcitabine combinations are commonly used because studies of response rates and progression-free survival have supported their effects for some cases. In addition, 3 separate meta-analyses reported a statistically significant survival advantage of combination therapy compared with gemcitabine only; platinum- and capecitabine-based combinations have produced the most benefit The benefit of adding cisplatin could be greater for patients with hereditary forms of pancreatic cancer, based on retrospective analysis of patients treated at a single center. 46 A recent phase I/II study of combination therapy with nab-paclitaxel and gemcitabine reported significant activity. Of 44 patients with metastatic pancreatic adenocarcinoma treated in the phase II portion of the study, 48% had a response, with a median survival time of 12.2 months, and 48% survived for 1 year. 47 This combination is now in a phase III trial (compared with gemcitabine monotherapy), and results are expected by the end of Retrospective analyses of the combination of fixeddose rate gemcitabine, docetaxel, and capecitabine have demonstrated prolonged survival times (median overall survival times of 11.2 months and 11.3 months in 2 separate studies). 48,49 These data have supported the continued use of gemcitabine combinations for patients with good performance status, as described in the National Comprehensive Cancer Network Guidelines. 50 Additional efforts to optimize use of gemcitabine have focused on increasing its intracellular delivery. Fixed-dose rate infusions, although developed based on positive preclinical and early-stage clinical data, 51 failed to meet the thresholds set for clinically significant survival and response rate end points in a phase III trial and were associated with higher rates of hematologic toxicity. 41 Nucleoside transporters, such as human equilibrative nucleoside transporter 1 (hent1), are thought to promote transport of gemcitabine into cells, and have received considerable attention as mechanisms of drug sensitivity and resistance. 52,53 High levels of hent1 expression in pancreatic tumor samples were associated with increased overall and disease-free survival when patients were treated with gemcitabine therapy in a prospective, randomized trial of adjuvant therapy. 54 Similar results were not seen in the group that received 5-FU based therapy, indicating that hent1 could be a biomarker to identify patients most likely to respond to gemcitabine therapy. The LEAP (Low hent1 and Adenocarcinoma of the Pancreas) trial is investigating hent1 expression and outcomes in patients receiving either gemcitabine or a novel gemcitabine compound, CO-101, which is thought to bypass this transport mechanism altogether. 55 Accrual was complete late in Patients whose cancer progresses after receiving a gemcitabine regimen are often treated with a fluorinated pyrimidine and oxaliplatin, based on results from the Charité Onkologie Clinical Studies in Gastrointestinal Cancers-003 study and others that have supported this approach as second-line vs best supportive care. 56,57 Arguably the most important advance in recent years, however, has come from the first-line application of fluorouracil combined with irinotecan and oxaliplatin (the FOLFIRI- NOX regimen). After promising rates of response in phase I/II trials, 58 a phase III trial randomly assigned 342 patients to groups that received either FOLFIRINOX or gemcitabine alone as first-line therapies. Patients with an Eastern Cooperative Oncology Group performance status 1 or a total level of bilirubin 1.5-fold the upper limit of normal were excluded (therefore, the proportion of patients with biliary stents was relatively low, at 14.3%). The FOLFIRINOX group had significantly higher rates of objective response (32% vs 9%) and times of progressionfree (6.4 months vs 3.3 months) and overall survival (11.1 months vs 6.8 months) than patients that received gemcitabine only. However, FOLFIRINOX also had greater toxicity; patients had significantly more grade 3 or 4 neutropenia, febrile neutropenia, thrombocytopenia, diarrhea, neuropathy, vomiting, and fatigue. For this reason, the regimen is reserved for patients younger than 76 years old, with high performance status and good hepatobiliary function. 59 FOLFIRINOX is being modified to increase its tolerability and for use in patients with locally advanced cancer or as a neoadjuvant. 55,59

7 1322 PAULSON ET AL GASTROENTEROLOGY Vol. 144, No. 6 Table 4. Trials of Targeted Therapy for Advanced-Stage Pancreatic Cancer First author, year Regimen Target Moore, Philip, Van Cutsem, Kindler, Van Cutsem, Gemcitabine vs gemcitabine and erlotinib Gemcitabine vs gemcitabine and cetuximab Gemcitabine and erlotinib vs gemcitabine, erlotinib, and bevacizumab Gemcitabine vs gemcitabine and bevacizumab Gemcitabine vs gemcitabine and tipifarnib Study phase No. of patients enrolled Median survival (mo) EGFR III vs 5.9 (P.038; HR 0.82) EGFR III vs 5.9 (HR 1.06; P.23) EGFR, VEGF III vs 6.0 (HR 0.89; P.21) VEGF III vs 5.9 (P.95) Farnesyl-transferase III vs 6.1 (P.75) EGFR, endothelial growth factor receptor; HR, hazard ratio; VEGF, vascular endothelial growth factor. Advances in Targeted Therapy Our increased understanding of the molecular and genetic changes associated with tumorigenesis has led to the development of agents that specifically target these alterations. Targets have included KRAS and downstream factors, such as mitogen-activated protein kinase, epidermal growth factor receptor, vascular endothelial growth factor A, and type I receptor for insulin-like growth factor. 60 The characteristically dense stroma and desmoplastic reaction surrounding most pancreatic adenocarcinomas has led to approaches to increase vascular supply and drug delivery, and reduce resistance to chemotherapy. Matrix metalloproteinases, hyaluronan, and the Hedgehog signaling pathway have received considerable attention as therapeutic targets. However, the epidermal growth factor receptor inhibitor erlotinib has been the only one of these reagents found to significantly prolong survival in phase III trials (Table 4). 61 In a double-blind, placebo-controlled study, 569 patients with metastatic or locally advanced cancer received either erlotinib with gemcitabine or gemcitabine with placebo. The erlotinib combination produced a modest but statistically significant benefit, prolonging survival by 2 weeks (6.2 vs 5.9 months for patients that received gemcitabine with placebo), which led to its approval by the Food and Drug Administration for treatment of metastatic pancreatic cancer. Integration into clinical practice has been slow, however, because of the cost and the mild but noteworthy side effects of erlotinib (primarily rash and diarrhea). 62 Additional studies of reagents that target epidermal growth factor receptor have failed to show benefits; a combination of gemcitabine and cetuximab produced the same results as gemcitabine monotherapy in a trial of 745 patients. 63 A number of other targeted approaches have been investigated, but were not found to prolong survival in phase III trials. Reagents that target vascular endothelial growth factor signaling, such as bevacizumab, axitinib, sorafenib, and aflibercept, in combination with gemcitabine, have not been shown to have statistically significant effects on survival compared with gemcitabine alone Activating mutations in KRAS are frequently detected in pancreatic cancer (in 70% 90% of cases) and correlate with the degree of dysplasia in precursor lesions. 69 However, the unique conformation of KRAS and its position in the cell membrane make it a challenge to inhibit. 70 Attempts to manipulate its processing with the farnesyltransferase inhibitor tipifarnib showed no benefits in phase III trials, despite encouraging preclinical data. 71 Efforts to target the Ras pathway have therefore focused on downstream effectors of KRAS activation, such as Raf and mitogen-activated protein kinase. The mitogen-activated protein kinase inhibitor selumetinib has shown results similar to capecitabine in phase II studies, 72 and is currently being tested in combination with erlotinib; blocking multiple pathways could have synergistic effects against tumors. 55 A distinctive feature of pancreatic adenocarcinoma is the dense, fibroinflammatory stroma that surrounds cancer cells. This desmoplastic reaction is thought to impair drug delivery by restricting blood supply and reducing diffusion of drugs while supporting the aggressive behavior of tumors. 73 Researchers are investigating the effects of removing the glyosaminoglycan polymer hyaluronan from the matrix to decrease interstitial pressure. In a genetically engineered mouse model of pancreatic cancer, administration of the hyaluronan-degrading enzyme PEGPH20, in combination with gemcitabine, increased tumor blood flow, reduced interstitial pressure, and prolonged survival. 74 The reagent is currently in development for testing in clinical trials. The Hedgehog signaling pathway has been reported to promote desmoplasia. Inhibitors of this pathway have been shown to increase delivery of cytotoxic agents to tumors in mice. 75 Studies are underway to determine if these drugs have similar effects in patients. Locally Advanced Disease There are few data from randomized, controlled trials to indicate the best treatment approaches for patients with locally advanced disease. A number of trials have been performed during the past 30 years, often

8 May 2013 THERAPEUTIC ADVANCES IN PANCREATIC CANCER 1323 assessing some combination of chemotherapy and radiation. However, it has been difficult to draw conclusions from these studies because of variations in the dose and methods of radiation, use of radiosensitizers, and chemotherapy controls. Combined chemoradiotherapy clearly prolongs survival for patients with locally advanced tumors, compared with radiation or supportive care, 34,44 but it has not been established whether chemoradiation improves outcomes compared with chemotherapy alone. Randomized trials to compare chemoradiation with gemcitabine monotherapy have produced conflicting results, 76,77 and 2 separate meta-analyses have found that combined therapy does not prolong survival, despite its increased toxicity. 34,44 Because of these conflicting results and the improved activity of newer chemotherapeutic regimens, it is not clear how best to combine chemo- and radiation therapies. A strategy of first providing chemotherapy, followed by consolidative chemoradiation, in patients that have not developed metastases, might be a rational approach. Two retrospective series studies have led to increased acceptance of this strategy. One series analyzed data from 128 patients with locally advanced disease who had started gemcitabine-based chemotherapy (either alone or in combination with 5-FU or oxaliplatin) and not progressed after 3 months of therapy. 78 Patients then received 5-FU based chemoradiation or continued to receive chemotherapy alone. The combination of chemotherapy and chemoradiation significantly increased survival time compared with chemotherapy alone (15 months vs 11.7 months). A separate study of 323 patients produced similar results; 247 patients received initial chemoradiotherapy and were compared with 76 patients who had received a median of 2.5 months of gemcitabine-based induction therapy before radiotherapy. 79 Median overall survival times were significantly longer for patients that received the gemcitabine-based therapy before radiation (11.9 months vs 8.5 months). In a small phase II study, 25 patients received 6 cycles of fixed-dose gemcitabine plus cisplatin; those that did not progress to extrapancreatic disease received capecitabinesensitized radiation. 80 Median survival time for all patients was 13.5 months, and the median survival time for patients that completed radiation therapy (48%) was 17.5 months. 70 This approach appears to protect patients with rapid tumor progression and metastatic disease from the toxicities of radiation therapy; only patients most likely to benefit receive radiation treatment. A phase III study is underway. 55 There is no ideal radiosensitizing agent for patients with locally advanced disease. Gemcitabine and continuous infusion of 5-FU have been most frequently studied in trials. Direct comparisons of these 2 regimens have failed to produce any strong conclusions because the studies included small numbers of patients or were retrospective analyses. 34 Capecitabine has gained acceptance as a radiosensitizer in treatment of other malignancies, 81 as well as in several early-phase studies of pancreatic cancer. 82,83 Its use spares patients from carrying an infusion pump throughout weeks of radiation. Taxanes might also be promising radiosensitizers, 84 and trials with paclitaxel and nab-paclitaxel are underway. 55 Through selection of patients and improved combination therapy, chemoradiation will have a continued and important role in the treatment of patients with unresectable disease. 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