Neoadjuvant vs Adjuvant Therapy for Resectable Pancreatic Cancer: The Evolving Role of Radiation Sarah Hoffe, MD, Nikhil Rao, MD, and Ravi Shridhar, MD, PhD A major challenge with pancreatic cancer management is in the discrimination of clearly resectable tumors from those that would likely be accompanied by a positive resection margin if upfront surgery was attempted. The standard of care for clearly resectable pancreatic cancer remains surgery followed by adjuvant therapy, but there is considerable controversy over whether such therapeutic adjuvant strategies should include radiotherapy. Furthermore, in a malignancy with such high rates of distant metastasis, investigators are now exploring the feasibility and outcomes of delivering therapy in the neoadjuvant setting, both for clearly resectable as well as borderline resectable tumors. In this review, we explore the current standard of care of upfront surgery for clearly resectable cancers followed by adjuvant therapy, focusing on the role of radiotherapy. We highlight the difficulties in interpreting a literature fraught with inconsistencies in how resectable vs borderline resectable cancers are defined and treated. Finally, we explore the role of neoadjuvant strategies in the modern era. Semin Radiat Oncol 24:113-125 C 2014 Elsevier Inc. All rights reserved.

P

ancreatic cancer (PCA) remains one of the most lethal malignancies. Over the past 30 years, little progress has been demonstrated in regard to long-term survival, with the overall 5-year survival of all patients with PCA in the 5% range.1 Unfortunately, most patients present with advanced disease, with only 10%-20% of patients presenting with disease amenable to resection.2 Of those patients who undergo resection, 5-year survival rates are 15%-20%.3 Autopsy series reveal that rates of metastasis are high, even with small tumors less than 2 cm and that patients often have multiple tumors within the pancreas, indicating either multicentric disease or intraparenchymal metastasis.4 Moreover, the retroperitoneal location of the pancreas adjacent to major abdominal blood vessels and autonomic ganglia makes surgery difficult. With microscopic involvement of the ganglia surrounding the celiac and superior mesenteric arteries, tumors have a high potential for local recurrence.5 Yet it is far more than anatomical location that has led to such poor outcomes. Indeed, the biological aggressiveness of human PCAs is firmly entrenched in a milieu of stromal proliferation, decreased vascular density, and immune

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL. The authors declare no conflict of interest. Address reprint requests to Sarah Hoffe, MD, Department of Radiation Oncology, Moffitt Cancer Center, 33612 Magnolia Drive, Tampa, FL 33612. E-mail: Sarah.hoffe@moffitt.org

1053-4296/14/$-see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semradonc.2013.11.002

suppression.6 These molecular features contribute to therapeutic resistance in a disease in which patients often present with advanced age, cachexia, pancreatic insufficiency, biliary obstruction, infection, and a hypercoagulable state. When Allen Whipple published his landmark report in 1935, few diagnostic techniques were available to aid in the initial evaluation of a patient with a pancreatic mass, and hospital mortality rates from pancreatic tumor resections were 425%.7 Fortunately, mortality rates have improved significantly since that time. Turaga et al8 analyzed outcomes based on nearly 50,000 pancreatectomies that were performed between 1996 and 2004, noting a morbidity rate of 35%. The national mortality rate was 9% with an average length of hospital stay of 15 days. Larger hospital size and high-volume center have been reported to decrease mortality.9 Contemporary surgical series now range from the techniques of robot assisted and laparoscopic to the traditional open approach. Strijker et al10 reviewed 251 reports of robotassisted pancreaticoduodenectomy. The rate of conversion to open was 16.4% with an overall morbidity of 30.7%, most commonly involving development of a pancreatic fistula. However, negative margins were obtained in 92.9% of patients.

Initial Staging We have certainly progressed diagnostically since the time when exploratory surgery was the recommendation for 113

114 patients presenting with a pancreatic mass. Multidetector computed tomography (CT) has a sensitivity of 86%-97% in PCA.11 Imaging obtained during the peak pancreatic parenchymal phase can be utilized to delineate the usual hypoenhancing primary tumor and peak liver portal venous enhancement phase to determine tumor involvement of the liver and venous structures.12 These thin-cut images allow clinicians to see the relationship of the primary tumor with the adjacent vasculature. Radiologists also have the ability to provide reformatted images with curved multiplanar reconstructions along the common bile duct, pancreatic duct, and mesenteric vessels, which may help improve sensitivity for tumor detection over axial images alone.13 Although the technology has improved dramatically, pancreatic imaging still falls short in identifying involved regional nodes and peritoneal implants. Valls et al14 reported that only 3 of 18 patients (16.7%), who had pathologically proven nodal disease, had been identified preoperatively when a size criterion of 41.5 cm was used. Data for identifying involved nodes on positron emission tomography (PET)/CT have shown sensitivities of 46%-71% and specificities of 63%100%.15,16 PET/CT as part of initial staging had a sensitivity of 73% of detecting extrapancreatic metastatic disease and changing clinical management in 11%-22% of patients.17,18 All imaging modalities have limited efficacy in detecting small peritoneal metastases. Although staging laparoscopy should be more effective at detecting peritoneal disease not seen on imaging, a 2001 meta-analysis did not show significant benefit, noting it changed management in only 4%-15% of patients after a thin-section pancreatic protocol CT.19 Despite these limitations of PET/CT, there is still an interest in integrating this modality into the management of PCA, if it can yield reliable prognostic information. In the locally advanced setting, Schellenberg et al20 found that clinical standardized uptake value (SUVmax) was an independent predictor for overall survival and progression-free survival. In addition to prognostic information in the initial staging setting, there is also interest in exploring the value of molecular changes from the initial staging to restaging setting as a radiographic biomarker. In other gastrointestinal (GI) sites, such as esophageal cancer, spatial-temporal PET features were found to be useful predictors of pathologic tumor response to neoadjuvant chemoradiation therapy (CRT).21

Defining Clearly Resectable Tumors One of the challenges with PCA management is in the discrimination of clearly resectable tumors from those that would likely be accompanied by a positive resection margin (R1) if upfront surgery was attempted. Imaging criteria of tumors with an increased likelihood of R1 initial resection were first described by Mehta et al.22 This designation emerged after series were reported showing that concomitant vein resection could increase the rate of margin-negative resection.23 These studies led the American Joint Committee on Cancer Staging in 2002 to change the criteria for T category so that involvement of arteries rather than veins

S. Hoffe, N. Rao, and R. Shridhar changed the designation from a T3 to T4 tumor.24 Indeed, resection of the superior mesenteric artery is not advised as survival is poor.25,26 By 2006, the National Comprehensive Cancer Network had adopted the term “borderline resectable” to describe localized cancers that would be at high risk for marginpositive resection with surgery alone (Figs. 1 and 2).27 Yet, standard criteria for defining borderline resectable PCA (BRPC) are lacking and there is no “standard of care” option for neoadjuvant management. Patient factors in the borderline designation in addition to radiographic tumor criteria have been suggested by Katz et al.28 In a review of 2454 patients with PCA at MD Anderson Cancer Center (MDACC), 160 (7%) tumors were deemed to be borderline resectable and were then divided into 3 groups. The first group of patients was categorized as BRPC based on radiographic criteria. The second group, however, was included in this category because of findings suspicious, but not diagnostic, for metastases. The third group had a performance status deemed marginal for surgery. Of the 160 patients, 125 (78%) were able to complete the neoadjuvant therapy and underwent reevaluation for surgery. Of these patients, 41% underwent surgery with 18 of 66 patients (27%) requiring vascular resection and 62 (94%) ultimately having R0 resections. Outcome data showed that the 66 patients who completed all therapy had a median survival of 40 vs 13 months for the 94 patients who were not able to undergo surgery (P o 0.001). Investigators from Johns Hopkins created an early mortality risk score (EMRS) that suggests that it may be possible to preoperatively identify patients who are less likely to benefit from upfront surgery.29 Records of 740 patients who underwent upfront curative resection were analyzed to identify predictors of early mortality, defined as death at 9 and 12 months. EMRS factors were age 475 years, tumor size Z 3 cm, poor differentiation, and comorbid diseases. EMRS was associated with early mortality, both in those who received adjuvant therapy (P ¼ 0.038) and in those who did not (P o 0.001). Prospective validation of the EMRS is needed.

Upfront Resection: Outcomes and Prognostic Factors For patients who have clearly resectable tumors, proceeding directly to surgery remains the standard of care. Cameron et al30 reported the largest consecutive series of a single surgeon over a time period from 1969-2003 with 1000 patients who underwent upfront pancreatic resection with a surgical mortality rate of 1%. The 5-year overall survival rate was 18%; for patients with negative lymph nodes, the 5-year survival rate was 32%, and for patients who had both node- and marginnegative resections, it was 42%. Even with a R0 resection, only 15%-20% of patients are long-term survivors.31 Hishinuma et al32 reported recurrence patterns after curative intent resection, discovering patterns characterized as local, hepatic, peritoneal, para-aortic, and other distant sites. In this small series of 24 patients, 75% had a local recurrence, 50% had hepatic metastasis, and 46% had both. In 4 of the patients with recurrence, the findings were not

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115

Figure 1 Initial staging pancreatic protocol CT showing pancreatic head adenocarcinoma that is borderline resectable by virtue of venous abutment next to the superior mesenteric vein (SMV).

visible by CT because of their infiltration without forming a mass. Data from a rapid autopsy series at Johns Hopkins suggested that there may be 2 distinct subsets of patients with advanced PCA: those who die of metastatic disease and those who die primarily of locoregional tumor; 30% of patients were documented to have died of a locally destructive PCA vs 70% of metastatic disease.33 Additional series of upfront resection suggest the importance of multiple prognostic factors. Garcea et al reviewed all of the English-language publications for studies of patients who underwent pancreatic resection from 1980 to the present; the review included 154 studies reporting on over 25,000 patients,

Figure 2 Same patient after neoadjuvant therapy, restaging pancreatic protocol CT before surgery shows improvement.

which showed that patients with tumors o2 cm in size, negative resection margins, lymph node–negative tumors, well-differentiated tumors, and the absence of perineural or blood vessel invasion have improved survival.34 The median number of lymph node–negative tumors was 42.4%, with a range of 11.4%-72%. Survival of patients with lymph node– negative tumors was 25 months as opposed to 13.6 months for lymph node–positive tumors (P o 0.001). Lymph node ratio (LNR), the number of involved lymph nodes relative to the number of examined lymph nodes, is a strong independent prognostic factor after PCA resection.35 In this study by Riediger, 70% of patients had positive lymph nodes. The median number of examined nodes was 16 and the median number of involved nodes was 1. The median LNR was 0.1. On multivariate analysis, an LNR Z 0.2 or 0.3, a R1, and poor differentiation were all associated with poorer survival. Similarly, in a study of 905 patients who underwent tumor resection, reported by Pawlik et al,36 the median overall survival decreased as the LNR increased (LNR ¼ 0, 25.3 months; LNR 4 0-0.2, 21.7 months; LNR 4 0.2-0.4, 15.3 months; LNR 4 0.4, 12.2 months; P ¼ 0.001). Underlying patient factors also have prognostic significance. La Torre et al37 reported that the modified Glasgow prognostic score is an independent predictor of survival. The modified Glasgow prognostic score is a measure of the host's systemic inflammatory response that is derived from the value of the circulating levels of C-reactive protein and albumin. Cannon et al38 reported that preoperative diabetes mellitus (DM) status can help stratify patients in terms of overall

S. Hoffe, N. Rao, and R. Shridhar

116 survival and disease-free survival (DFS). In this study, preoperative DM, tumor size Z 2 cm, LNR 4 0.1, and a R1 were all independently associated with worse overall survival, whereas DM, LNR 4 0.1, and a positive margin were associated with decreased DFS. Other investigators, including Sperti et al39 and Chu et al,40 have also reported an association with DM and outcomes. It has been suggested that diabetics, with higher serum levels of insulin, could have worse survival because malignant tumors can overexpress receptors for insulin and insulinlike growth factor.41,42 Furthermore, patients with obesity with a body mass index of more than 35 are more likely to have nodepositive PCA and decreased survival after surgical resection.43

Adjuvant Chemoradiation Data Given the high rates of local and distant failure following curative resection, adjuvant strategies have been used to improve outcomes (Tables 1 and 2). The first randomized study in the adjuvant setting utilizing chemoradiation was reported by the Gastrointestinal Tumor Study Group, noting

that 22 patients who underwent observation had a median survival of 11 months compared with 21 patients who received adjuvant chemoradiation with a median survival of 20 months (P ¼ 0.035).44 Two-year survival rates also improved with CRT, with 42% vs 15% in the observation group. In this study, the radiation was delivered along with 5-fluorouracil (5-FU) chemotherapy at 2 Gy per fraction over 5 days a week for 2 weeks followed by a 2-week break. For 3 days of each course, 5-FU was delivered at 500 mg/m2 and then was continued as maintenance for 2 years or until progression. Subsequent analysis of patients who were not randomized but were treated according to the experimental arm also showed a survival similar to the adjuvant CRT group (median overall survival of 18 months with 2-year survival of 46%), thus laying the foundation for future trials evaluating CRT strategies.45 European investigators sought to confirm these findings in an European Organisation for Research and Treatment of Cancer trial randomizing patients to adjuvant CRT vs observation but were unable to do so46; however, only 55% of their patients had PCA and the remainder had periampullary cancers. Eligibility criteria included both node-negative and regional node-positive tumors: patients with PCA were eligible

Table 1 Adjuvant Series Investigating Radiation Questions as well as Chemotherapy Questions Arm

N

RT (Y/N)

Dose

GITSG

Observation CRT

22 21

N Y

40 (s)

EORTC

Observation CRT

54 60

N Y

40 (s)

Observation CRT Observation Chemotherapy

144 145 142 147

N Y N N

Observation CRT Observation Chemotherapy

178 175 235 238

N Y N N

Gemcitabine Gemcitabine þ CRT

45 45

N Y

50.4

24 24

RTOG 9704

CRT þ 5-FU CRT þ Gemcitabine

230 221

Y Y

50.4 50.4

17.1 20.5

18 22

0.08

CONKO-001

Observation Gemcitabine

161 133

N N

20.2 22.8

9 21

0.005

ESPAC-3

5-FU Gemcitabine

551 537

N N

23 23.6

Study

5-y OS

P

11 20

5 19

S

12.6 17.1

22 25

NS

MS (m)

RT question

ESPAC-1 (2  2)

ESPAC-1 (pooled)

GERCOR

20 10 9 21

40 (s)

40 (s)

16.1 15.5 14 19.7

0.009 0.05

0.24 0.0005

NS

Chemotherapy question

0.39

Abbreviations: EORTC, European Organisation for Research and Treatment of Cancer; GERCOR, Groupe Coordinateur Multidisciplinaire en Oncologie; GITSG, Gastrointestinal Tumor Study Group; MS, median survival; NS, not statistically significant; OS, overall survival; S, statistically significant; (s), split course.

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117

Table 2 Comparison of CONKO-001 Chemotherapy Alone vs RTOG 9704 Study CONKO-001 9704 all 9704 all o90 9704 all o90 with QA 9704 head o90 9704 head o90 with QA

Median Survival

5-y Overall Survival

22.8 19 21 23 22

21 21 24 32 25

24

34

Abbreviation: QA, quality assurance.

if the cancer was categorized as T1-2 and patients with periampullary cancer if categorized as T1-3. The median survival for the observation group was 19.0 months compared with 24.5 months in the treatment group (log-rank P ¼ 0.208). There was no local control benefit seen with CRT. The European Study Group subsequently designed the ESPAC (European Organisation for Research and Treatment of Cancer)-1 trial to compare observation alone with adjuvant strategies of either chemoradiation alone or chemotherapy in a 2  2 study design.47,48 The trial recruited 541 patients. The treatment arms were as follows: (1) chemoradiation with 40 Gy split course along with a bolus 5-FU at 500 mg/m2 on days 1-3 of each course followed by 2 years of systemic 5-FU, (2) adjuvant chemotherapy for 6 months with 5-FU at 425 mg/m2 and leucovorin at 20 mg/m2 delivered on days 1-5 every 28 days, (3) chemoradiation alone, and (4) observation. Results showed that adjuvant chemotherapy was superior to observation, with a 20-month vs 15-month median survival and a 2-year survival rate of 40%-30% (P ¼ 0.009). Moreover, chemoradiation was inferior, with a median survival of 16 vs 18 months for those who did not receive chemoradiation and a 2-year survival inferior outcome of 29% vs 40% (P ¼ 0.05). Many criticisms have been lobbied at the ESPAC-1 trial.49,50 These include the lack of quality assurance and the split-course treatment techniques. The study allowed radiation oncologists to choose their dose from a range of 40-60 Gy. In addition, the modifications to the trial resulted in there being essentially 3 internal studies with discretion up to the treating clinician as to which treatment parameters to follow. Moreover, the trial had a high rate of local failure (462%), and only 53% of patients enrolled in the study were included in the final analysis. Lack of quality assurance in adjuvant therapy trials transcends more than just problems with the delivery of radiotherapy. For example, Katz et al51 have assessed the degree of adherence to protocol criteria in a U.S. national trial. Only 34% of pathology reports met criteria as per the College of American Pathologists. Katz concluded that trials of adjuvant therapy following pancreaticoduodenectomy suffer from a lack of standardization and quality control before patient enrollment, no doubt muddying the adjuvant trial landscape and adding to the difficulty in discriminating the true effect of each modality upon outcomes. After ESPAC-1 was reported as showing inferior outcomes with chemoradiation, the Charite Onkologie Clinical (CONKO-001) trial evaluated single-agent

adjuvant gemcitabine compared with observation.52,53 Each gemcitabine cycle was given as a weekly infusion of 1000 mg/m2 over 30 minutes for 3 weeks followed by a 1-week break; this regimen was continued for 6 cycles. This trial involving 368 patients demonstrated the benefit of gemcitabine across all subgroups of disease, doubling DFS to 13.4 vs 6.9 months (P ¼ 0.001) in the initial report and a median survival of 22.8 vs 20.2 months (P ¼ 0.005) in a later analysis. Stocken et al54 reported a meta-analysis of 5 randomized controlled trials that yielded further support, reporting that chemotherapy, but not CRT, is effective adjuvant treatment in PCA. Further data on chemotherapy alone were reported from ESPAC investigators with publication of the ESPAC-3 trial. The trial was initially devised as comparing 6 monthly cycles of 5FU vs 6 months of gemcitabine vs observation. The reported results from 1088 patients showed a median survival of 23.6 vs 23 months comparing gemcitabine vs 5-FU or leucovorin (hazard ratio ¼ 0.94, P ¼ 0.7) but with low grade 3-4 toxicity in the gemcitabine arm (7.5% vs 14%, P o 0.01).55 These investigators thus recommended gemcitabine as the preferred regimen given equivalent efficacy. In the United States, investigators have still been incorporating CRT into the adjuvant treatment armamentarium, with Abrams et al noting that the European Organisation for Research and Treatment of Cancer trial, which was described as a negative trial, may perhaps be better viewed as an underpowered positive trial.50 In the 1990s, Radiation Therapy Oncology Group (RTOG) investigators designed the RTOG 9704 trial to explore the outcomes of systemic therapy in addition to a standard CRT arm.56 This protocol differed from the previous Gastrointestinal Tumor Study Group trial as patients were randomized to receive either gemcitabine (1000 mg/m2 weekly for 3 weeks followed by a 1-week break) or 5-FU (250 mg/m2 per day for 3 weeks) preceding the chemoradiation for 1 cycle. The radiation was no longer split course but delivered in a continuous fashion to a total dose of 50.4 Gy along with a continuous infusion 5-FU given at dose of 250 mg/m2. Then, 3-5 weeks after the completion of CRT, additional chemotherapy was delivered, either as 3 months of 5-FU (4 weeks continuous infusion at 250 mg/m2 followed by 2 weeks off for 2 cycles) or as 3 months of gemcitabine. The initial report of 451 patients showed a nonstatistically significant trend for patients with pancreatic head tumors to have improved 3-year survival if they were treated with adjuvant gemcitabine instead of 5-FU. The updated 5-year report of RTOG 9704 showed a trend on multivariate analysis toward improved overall survival on the gemcitabine arm, P ¼ 0.08, with a median overall survival of 20.5 months compared with 17.1 months and 5-year overall survival of 22% compared with 18%.57 The dominant first site of relapse was distant in 73% compared with 28% first local recurrence. Moreover, the number of positive nodes, the total nodes examined, and the LNR were associated with overall survival and DFS, and LNR 433% was associated with worse outcomes.58 Patients with postresection CA 19-9 values Z 90 U/mL had a significantly worse survival.59 Patients with

118 pancreatic head tumors treated with gemcitabine and with a CA 19-9 serum level o90 U/mL, with radiation therapy (RT) delivered according to protocol guidelines, had a survival similar to that seen in the CONKO-001 trial.60 Given the results of a distant dominant pattern of first failure, the current RTOG 0848 study has a design of adjuvant chemotherapy alone following resection, randomizing patients to 5 cycles of either gemcitabine vs gemcitabine or erlotinib, and if no progression, then a second randomization is performed so that patients either receive an additional cycle of the previous chemotherapy or an additional cycle of the same chemotherapy followed by CRT to 50.4 Gy along with 5-FU (www. rtog.org). RTOG 9704 was the first trial to report the effect of adherence to protocol guidelines for radiation field design.61 Failure to adhere to specified radiotherapy guidelines was associated with reduced survival. In fact, nearly 50% of the radiotherapy plans deviated from protocol guidelines. As the appropriate contouring of the postoperative abdomen has been difficult for clinicians, there are now consensus panel guidelines to delineate the clinical target volume.62 When the noncentrally reviewed ESPAC-1 radiotherapy results are viewed within the context of the 9704 data, it is apparent there were variations in field design and treatment technique, which undoubtedly could have negatively affected the survival outcomes of the CRT arms reported in that trial. Nonrandomized, retrospective series in the era of modern radiation dosing and delivery continue to report benefits of adjuvant CRT, unlike the ESPAC-1 results that deemed the receipt of RT to be associated with worse survival. Hattangadi et al63 reported outcomes of 86 patients with PCA who were treated with CRT. Most patients were treated with Z50.4 Gy with 3-dimensional conformal radiation and concurrent continuous infusion of 5-FU, and nearly half of the patients went on to receive adjuvant gemcitabine. A total of 75 (87%) patients had disease recurrence with the majority at distant sites, with peritoneal (55%) or liver (53%) metastases. Overall, 81% of tumors were categorized as T3 and 66% had involved nodes, with node-negative patients trending toward a lower rate of distant failure (P ¼ 0.60). The median DFS was 10 months for all patients; treatment with gemcitabine (P ¼ 0.044) and the receipt of any chemotherapy (P ¼ 0.47) were significant predictors of DFS. Similarly, Corsini et al64 reported the Mayo experience of 466 patients, which excluded patients with positive margins. Compared with the observation arm with a median survival of 19.2 months, adjuvant CRT was associated with a 25.2-month survival (P ¼ 0.001). Interestingly, patients receiving adjuvant therapy had more adverse prognostic factors than those not receiving therapy (P ¼ 0.001), suggesting a possible selection bias. Indeed, other investigators have reported that the rates of adjuvant therapy use may be influenced by age 470 years, major postoperative complications, distal pancreatectomy, absence of nodal metastases, and absence of perineural invasion, with up to one-third of the patients not receiving adjuvant therapy.65 Another large series of 616 patients at Johns Hopkins Hospital was reported by Herman et al66 with similar findings.

S. Hoffe, N. Rao, and R. Shridhar Patients who received adjuvant chemoradiation had an improved median, 2-year, and 5-year survival compared with surgery alone (21.2 vs 14.4 months, 43.9% vs 31.9%, 20.1% vs 15.4%; P o 0.001). Patients in the observation group were older (median age ¼ 70 years) and had higher rates of complications. Finally, most patients in this study had node(80.2%) and margin-positive resections (44.6%). In an attempt to control for selection bias, the Mayo and Hopkins data of 1045 patients with resected PCA were combined in a report from Hsu et al67 using a matched-pair and propensity score analysis. When compared with observation, patients receiving adjuvant CRT had improved overall survival in all subgroups, regardless of grade, age, size, and margin or nodal status. Few data are yet available comparing chemotherapy alone with chemotherapy followed by CRT in the adjuvant setting. In a European Cooperative Group (ECOG) phase II study, 90 patients were randomized to receive either 4 cycles of gemcitabine alone or gemcitabine for 2 cycles (given as earlier on days 1, 8, 15, 29, 36, and 43) followed by weekly gemcitabine (300 mg/ m2 by 30-minute infusion once a week) 4 hours before concurrent radiation of 50.4 Gy.68 Greater grade 3 toxicity was found in the chemoradiation arm. The median DFS was 12 months in the chemoradiation arm and 11 months in the control arm, with a median overall survival of 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% vs 24%) with a similar rate of distant progression (40% vs 42%). There are also data supporting the role of radiotherapy as part of the adjuvant therapy regimen from large populationbased series. Kooby et al69 reported an analysis of data from 11,526 patients who underwent resection for PCA from 19982002. Patients receiving CRT had the best overall survival (hazard ratio ¼ 0.70, 95% CI: 0.61-0.80) compared with chemotherapy only (hazard ratio ¼ 1.04, 95% CI: 0.93-1.18) and no adjuvant therapy. Similarly, Hazard et al70 reported outcomes from the Surveillance, Epidemiology, and End Results registry data in 3008 patients who underwent surgery for PCA. There was an improved median survival of 17 months and a 5-year survival of 13% in those patients who received radiation as part of their adjuvant therapy compared with 12 months and 9.7% for those who did not (P o 0.0001).

New Advances in Adjuvant Therapy Differentiating which tumors are destined to have higher rates of distant failure vs local failure may be possible with biomarkers, therefore allowing investigators to select an adjuvant therapy strategy based on the tumor's biological genotype. Although validation is ongoing, a promising biomarker appears to be the tumor suppressor, DPC4, which is a mediator in the TGF-β pathway.71 Patients with intact SMAD4 (DPC4) on immunohistochemistry were more likely to die of a locally destructive PCA vs those with loss of SMAD4 who were more likely to die of metastatic disease. In patients with locally advanced disease, Crane et al72 reported that 73% of patients with intact SMAD4 had a local dominant pattern of

The evolving role of radiation progression, whereas 70% with loss of this gene demonstrated a distant dominant pattern. Determinations of DPC4 status at diagnosis may be helpful to stratify patients into treatment regimens personalized to individual risks of local vs systemic disease progression. CXCR4 is a strong independent prognostic biomarker associated with distant metastatic spread, which could be explored in the postoperative setting.73 Marechal et al noted that the metabolizing gemcitabine protein (the human equilibrative nucleoside transporter 1 and the deoxycytidine kinase) can predict the benefit of gemcitabine-based therapy in patients who underwent tumor resection.74 Finally, S100A2 has been shown to be a predictive biomarker of adjuvant therapy benefit.75 Harnessing the immune system is also promising in improving adjuvant outcomes although few data are available. The types of vaccines evaluated to date include peptide vaccines, recombinant microorganism, and whole-cell vaccines along with anticytotoxic T-lymphocyte antigen 4 blockade and anti-CD40 strategies.49 A promising report of vaccine integration has been noted by Hardacre et al76 with improved outcomes associated with the addition of a “hyperacute” vaccine to the adjuvant therapy regimen. This strategy involves the transplantation concept of “hyperacute” rejection such that live allogeneic irradiated whole PCA cells genetically modified from mouse genes lead to foreign protein recognition in patients and an ensuing acute rejection with recruitment of antigen-presenting cells and complement-mediated cell lysis.77 This report revealed a 12-month DFS of 62% and 12-month overall survival of 86% with vaccine in conjunction with 5-FU and 50.4 Gy CRT preceded and followed by gemcitabine employed as per the RTOG 9704 trial.

Neoadjuvant vs Adjuvant Strategies In multiple GI tumor sites, neoadjuvant strategies have become the standard of care, raising the potential for a significant paradigm shift in resectable PCA as well. Lessons from the randomized German trial reported by Sauer et al78 showed improved local control as well as significantly less acute and late toxicity in the preoperative setting. At this time, there are no randomized preoperative vs postoperative data available in resectable PCA so we have examined the data reported to date. Katz et al79 evaluated 329 consecutive patients at MDACC with PCA between 1990 and 2002 who underwent resection. Preresection or postresection therapy was routine; 91% of patients received neoadjuvant or adjuvant therapy. The median overall and disease-specific survivals were 23.9 and 26.5 months, respectively. A total of 88 patients (27%) survived a minimum of 5 years. Among the long-term survivors, 24% experienced a recurrence, with 8% of these occurring after 5 years. Small studies provide some interesting comparisons. A retrospective analysis of 236 patients with head of pancreas cancer considered resectable by imaging criteria and treated between 1999 and 2007 evaluated patients receiving

119 preoperative therapy vs those proceeding directly to resection.80 The results suggest that preoperative treatment optimized patient selection, with median overall survival of 27 months in the resected group that received preoperative therapy vs 17 months in the upfront resection setting (P ¼ 0.04). Similar findings were demonstrated in a retrospective study of 100 patients who underwent resection at Fox Chase in which 47% received adjuvant therapy and 53% received neoadjuvant therapy.81 In the neoadjuvant therapy group, 7.5% had more than 1 positive margin vs 44.7% of those without preoperative therapy (P o 0.001) with a significant increase in survival of margin-negative patients (P ¼ 0.02). As there is no clearly defined optimal sequence of treatment modalities in this disease, cost-effectiveness is an important consideration. Abbott et al82 showed that surgery plus adjuvant therapy for resectable head of pancreas cancer extends survival but at considerable expense. A decision analytical model was constructed and reported for the neoadjuvant population.83 Abbott et al showed that neoadjuvant therapy strategies identify patients with early metastases or poor performance status who can be spared surgery and are associated with improved survival at significantly lower cost than a surgery-first approach. The surgery-first approach costs $46,830 with a survival of 8.7 quality-adjusted life-months compared with neoadjuvant therapy that costs $36,583 with a survival of 18.8 quality-adjusted life-months. In addition to cost benefits, delivery of treatment in the preoperative setting has many other potential advantages, such as increased local control, increased access to therapy, addressing systemic disease recurrence risk without delay, and optimal patient selection for surgery through exclusion of patients with rapidly progressive metastatic disease.84 Moreover, preoperative therapy can improve quality of life. Heinrich et al85 reported the results of a prospective phase II trial of 28 patients that showed serum prealbumin levels significantly improved after chemotherapy. In this study, the R0 rate was 80% and the quality of life score improved in 2 items. Gillen et al86 reported a meta-analysis in the preoperative setting. They demonstrated that in patients with initially resectable tumors, resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Additionally, approximately one third of patients with nonresectable tumors, who were initially categorized, would be expected to have resectable tumors following neoadjuvant therapy with survival comparable to those with initially resectable tumors. Katz et al87 clarify, however, that 53% of the studies in the metaanalysis did not state the criteria to categorize disease and only 40% enumerated the criteria used to measure treatment response. This may be more an artifact of variability in staging and in criteria used to indicate operative intervention. Using objective imaging response criteria, only 12% of 129 patients with tumors judged borderline resectable had reduction in size sufficient to meet the definition of Response Evaluation Criteria in Solid Tumors (RECIST) response, and only 1 patient was downstaged by imaging to resectable; however, 66% of patients had an R0 resection, and vascular resection was required in 60% of all resections.

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120

Neoadjuvant Experience Treatment in the neoadjuvant setting was explored by the Eastern Cooperative Oncology Study Group in the 1990s.88 Investigators evaluated radiotherapy delivered in continuous course to a total dose of 50.4 Gy along with concurrent chemotherapy of a 96-hour infusion of 5-FU at 1000 mg/m2 on days 2-5 and 29-32 along with mitomycin C at 10 mg/m2 on day 2. A total of 53 patients were evaluable for analysis; of these, 12 did not proceed to surgery. At the time of resection, 17 of 41 patients did not undergo resection owing to hepatic or peritoneal metastasis or both (11/17) or local extension (6/17). Tumor resection was successfully performed in 24 of 41 patients. The median survival for the entire group vs those patients who underwent successful resection was 9.7 vs 15.7 months. Owing to the time during which this study was done, advanced CT imaging for uniform surgical classification was not available and more advanced tumors were likely included in this trial. In 2006, Mornex et al89 reported the European experience of 41 patients treated with a preoperative approach. The radiation was to 50 Gy and included the tumor plus elective nodes. The chemotherapy consisted of 5-FU at 300 mg/m2/ day for 5 days a week during radiation therapy along with cisplatin at 20 mg/m2 on days 1-5 and 29-33. Among 40 evaluable patients, 27 (67.5%) were successfully treated with the full radiation dose and at least 75% of the prescribed chemotherapy, and no grade 4 nonhematologic toxicity was reported. Overall, 63% of patients underwent resection with curative intent and 80.7% had R0 resection.90 Overall, 50% (13/26) of specimens had a major pathologic response with at least 80% of severely degenerated cancer cells. The local recurrence and 2-year survival rates were 4% and 32%, respectively. The largest experience with neoadjuvant therapy for resectable PCA has been conducted since 1988 by investigators from MDACC.91 Uniform CT-based staging criteria, histopathologic diagnosis, and a standardized system for evaluating pathologic response have been reported. These trials have evolved over time from 50.4 Gy over 5.5 weeks with concurrent infusion of 5-FU to 30 Gy in 10 fractions along with concurrent gemcitabine. Importantly, the MDACC group has evolved a strategy of delivery of systemic therapy with gemcitabine followed by CRT. The ideal sequencing of such therapies is not known, but studies in the locally advanced setting have suggested that systemic therapy followed by CRT for nondistant disease progression may enhance survival.92-95 In the MDACC experience of 240 consecutive patients treated with neoadjuvant chemotherapy or radiation or both,91

the treated group was compared with 60 patients who underwent upfront pancreaticoduodenectomy. Of 240 patients, 233 received either 5-FU-based or gemcitabine-based CRT. Of these, 119 patients (50%) were treated with CRT only and 47% received systemic chemotherapy preceding the CRT. Only 7 patients (3%) did not receive CRT and were treated with chemotherapy alone. There was no significant survival difference among the different neoadjuvant regimens but there were differences in outcome based on pathologic changes. In 223 specimens from the patients who received neoadjuvant chemoradiation and surgery, the extent of residual tumor was graded using both the College of American Pathologists and the Evans grading systems (Table 3).96 Pathologic complete response (pCR) or minimal residual tumor in posttreatment specimens correlated with better survival in patients who received neoadjuvant therapy. Overall, 2.7% of patients showed pCR, 16.1% minimal residual tumor, 55.6% moderate response, and 25.6% poor response. Group 1 (pCR and minimal residual) had lower posttherapy tumor and American Joint Committee on Cancer stages, lower rates of lymph node metastases, lower rates of positive margins, and lower recurrence or metastasis. Grading the extent of residual tumor was an independent prognostic factor of overall survival in multivariate analysis.

Postoperative Complications After Neoadjuvant Therapy Some investigators have expressed concern about the potential for a higher rate of complications following neoadjuvant therapy for PCA. For example, Tsuruga et al97 have reported an increased rate of extrahepatic portal vein stenosis following neoadjuvant CRT. In their report of 18 patients, 3 had portal vein stenosis compared with no cases of portal vein stenosis among 22 patients operated with portal vein resection without neoadjuvant CRT. Araujo et al,98 however, have reported the postoperative morbidity of 29 patients who underwent surgery following neoadjuvant therapy and noted no increase when compared with matched controls who underwent upfront resection. The use of preoperative chemoradiation may actually reduce the risk for pancreatic leak after pancreatic reconstruction.5,99 In a series from 1987-2000 of 116 patients who underwent resection, 53% of whom received neoadjuvant therapy, treatment was associated with high rates of tumor fibrosis and low rates of positive margins. The administration of neoadjuvant therapy resulted in greater fibrosis (73%) compared with

Table 3 Tumor Regression Grading With the College of American Pathologists (CAP) System Compared With the Evans System Utilized in the MDACC Neoadjuvant Series Evans IV: no viable residual tumor Evans III: o10% viable-appearing cells Evans IIA: destruction of 51%-90% of tumor cells Evans IIB: destruction of 10%-50% of tumor cells CAP 3: poor response with minimal or no tumor kill, extensive residual cancer Evans I: o10% of tumor cell destruction CAP 0: complete response CAP 1: moderate response with single cells or small groups of cancer cells CAP 2: minimal response with residual cancer cells outgrown by fibrosis

The evolving role of radiation preoperative treatment (38%) (P ¼ 0.0001). Higher mean fibrosis levels were observed in patients with negative nodes (P ¼ 0.0006) and negative margins (P ¼ 0.05). Factors associated with improved survival included negative margins (P ¼ 0.001), negative nodes (P ¼ 0.03), and the use of neoadjuvant therapy (P ¼ 0.03).

Personalizing Therapy Posttherapy pathologic stage, lymph node status, the number of positive regional lymph nodes, the histologic grading of residual viable tumor, and tumor invasion into muscular vessels are independent prognostic factors in the neoadjuvant setting.95,96,100 The therapeutic goal is clearly to optimize the “right” modalities in the “right” sequence to match the molecular profile of the individual tumor. With the data suggesting that a tumor's propensity for local vs metastatic disease growth pattern can be identified at initial diagnosis, we then must consider knowledge about the tumor's existing sensitivity to chemotherapy and radiation. Chemosensitivity has been correlated with some specific genetic profiles in work done at John Hopkins.101 All pancreatic cell lines were sensitive to triptolide and docetaxel, most were also sensitive to gemcitabine and mitomycin C, and most were not sensitive to cisplatin, irinotecan, and a PARP1 inhibitor. DPC4/SMAD4 inactivation sensitized PCA cells to cisplatin and irinotecan by 2-4 fold but they were modestly less sensitive to gemcitabine. A novel genomics-based molecular assay has been developed at Moffitt Cancer Center to predict tumor radiosensitivity (RSI).102 RSI has been validated in patients with esophageal and rectal cancer, with responders to preoperative CRT having a significantly lower RSI score indicating greater RSI. These promising techniques are encouraging and may guide personalized treatment selection for incorporation of local modalities in the near future.

Radiation Field Design: Neoadjuvant vs Adjuvant In the modern era, treatment techniques in the setting of an intact pancreas have become increasingly conformal to target gross disease only and the volume irradiated has decreased from the time when large fields including elective volumes were common. Prior studies reported options ranging from radiation to the tumor bed and adjacent nodes vs an intensive regimen with whole-liver dose of 2340-2700 cGy followed by a higher dose to the tumor bed of 5040-5760 cGy.103 The question thus becomes what is the optimal field design, dose, and volume for future preoperative trials in the clearly resectable setting? Are there data to support an extended elective nodal target volume preoperatively to mirror the postoperative consensus volume that includes para-aortic nodes? If we extrapolate from our surgical colleagues, we might question whether elective nodal irradiation in the preoperative setting would be of benefit, as extended lymphadenectomy has

121 not led to improved survival.104 Portal vein resection has increased the number of patients amenable to resection with survival rates equivalent to those of standard resections but there has been no survival benefit with a more extensive dissection. As discussed earlier, currently available imaging options to characterize positive nodes are neither sensitive nor specific. Tracers other than fluorodeoxyglucose are being explored to image physiological processes, such as hypoxia, proliferation, amino acid accumulation, apoptosis, and receptor expression.105 In the future, perhaps we will be better able to delineate not only the primary pancreatic tumor but also involved regional nodes. Minimizing the volume irradiated would be desired and may lead to lower rates of acute and chronic toxicity. The question of optimal radiation dose remains. There is no dose-response data in the neoadjuvant setting, but there may be an optimal dose in the adjuvant setting. Recent outcome data reported by Hall et al from the National Cancer Data Base in 1385 patients noted that an adjuvant radiation dose of o40 Gy, 40 to o50 Gy, and Z55 Gy were associated with inferior overall survival.106 This suggests that the recommended adjuvant dose should be 50 to r55 Gy, although the data from such retrospective studies must be interpreted with caution.

Neoadjuvant: A Novel Setting to Exploit Biological Modifications With Radiation? Another area worthy of investigation is whether preoperative radiotherapy can produce an immunologic effect that will influence survival. Zitvogel et al107 have indicated that radiation can induce specific immune responses that can lead to cancer cell death or to immunostimulatory effects. This report is provocative and suggests the potential for the elimination of residual cancer cells or, perhaps, a suspension of micrometastases in a state of dormancy. As previously noted, PCA provides investigators with epithelial as well as stromal targets. Traditional radiobiology has espoused the goal of epithelial cell destruction. However, radiation oncologists may consider expanding this focus to stromal targets, similar to the exploration of sonic hedgehog inhibitors performed by medical oncologists.108 Though studies with sonic hedgehog inhibitors have been negative, integration with radiation therapy may be more effective. The PCA stroma is, in fact, its own microenvironment composed of leukocytes, fibroblasts, endothelial cells, neuronal cells, collagen, and hyaluronan.6 This neighborhood of cells forms a dense desmoplastic cocoon that limits the penetrance of systemic therapy. Moreover, this cellular matrix enables propagation of an immune-suppressed fortress, which is nearly devoid of T lymphocytes. Interestingly, it is the epithelial tumor component that overexpresses sonic hedgehog, which activates the stromal fibroblasts to proliferate.

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122 A question for radiation oncologists thus can be readily identified; is there an opportunity to exploit advanced radiation strategies to specifically damage the stroma, perhaps before systemic therapy, in an attempt to increase perfusion and enable enhanced delivery of cytotoxic drugs? The hypothesis is an attractive one that may now be appropriate for clinical trial design given the potential use of stereotactic ablative radiation therapy (SABR) or stereotactic body radiation therapy as a more effective local control modality. Indeed, data from other tumor sites, such as medically inoperable early-stage non–small cell lung cancer, have shown clinical superiority compared with conventional radiation, but the biological advantages are incompletely understood.109 Current data suggest that SABR can induce immune changes in the tumor microenvironment that can promote increased penetration of immune effector cells.110 There are also laboratory data that vascular endothelial cell apoptosis is rapidly activated above 10 Gy per fraction, thus reinforcing the possibility that tumor stroma plays a significant role in the response to SABR at higher daily doses of radiation.111 Perhaps innovative techniques to target the tumor stroma with SABR neoadjuvantly hold promise. If this modality can be integrated into the resectable setting where the treated disease will be removed surgically, limiting the potential for late toxicity, researchers will need to determine how best to sequence such treatment. Given its relatively low potential for acute toxicity, it could be introduced before systemic therapy, in an attempt to optimize the microenvironment for enhanced drug delivery. Further insights will await clinical trials. In terms of available data, few studies report outcomes on resected PCA treated with neoadjuvant higher dose radiation. Kozak et al112 reported on the feasibility of a short course of proton beam radiation for treatment of PCA. They compared 9 proton plans with intensity-modulated radiation therapy plans. Improved dose conformality was provided by the protons with significant sparing of kidneys, liver, and small bowel. Subsequently, using this approach, a phase I clinical trial of 15 previously untreated patients with pancreatic head adenocarcinoma showed feasibility, with doses ranging from 3 GyE  10 to 5 GyE per fraction for 5 fractions along with oral capecitabine at 1650 mg/m2 administered twice daily.113 The target coverage included elective nodal coverage including the celiac, porta hepatic, superior mesenteric artery and vein, and para-aortic nodes. Of the 15 patients, 11 went on to surgical resection, 3 patients had metastases, and 1 was unresectable. Of 11 patients, 9 (82%) had R0 resections with 10 of 11 patients (91%) displaying positive lymph nodes. Overall survival at 1 year was 75%, with 53% developing metastatic disease. To our knowledge, no data have been reported for SABR with photons in the clearly resectable setting. Chuong et al114 have, however, reported a series of 32 patients with BRPC who underwent neoadjuvant gemcitabine-based chemotherapy for 3 cycles followed by SABR with a median dose of 35 Gy to the area of vessel involvement and 25 Gy to the gross tumor. Of 32 patients, 31 (97%) underwent R0 resection, with a 10% rate of pCR. The median overall survival was 16.4 months, with a 1year overall and progression-free survival of 72% and 43%, respectively. Those borderline patients who underwent R0

resection had an overall survival of 19.3 months, with a 1-year overall and progression-free survival of 84% and 57%, respectively, and a low rate of grade Z 3 toxicity.

Conclusions In many GI tumor sites, neoadjuvant chemoradiation is the dominant strategy, yet the standard of care for clearly resectable PCA remains surgery followed by adjuvant therapy. For pancreatic head primary lesions, RTOG 9704 supports the integration of adjuvant CRT into the treatment regimen, with the strongest data for node-positive patients. Biomarker validation to predict an individual tumor's predilection for local vs systemic disease as well as its intrinsic sensitivity to chemotherapy and radiation therapy is ongoing. If confirmed, postoperative radiation delivered according to consensus guideline specifications could be indicated for those tumors with a locoregional phenotype. For clearly resectable tumors, a neoadjuvant approach may be preferred. The ability to improve patient selection and avoid unnecessary surgery in patients with systemic disease progression is supported by the present data. Pathologic response rates seem to be high, with significantly fewer patients harboring positive margins and positive nodes. With the current health care economic landscape shifting so rapidly, the effect of the decision analyses citing cost-effectiveness of a neoadjuvant approach resonates strongly. Further studies are needed to determine whether there is truly a difference in outcomes, perhaps with a randomized preoperative vs postoperative design.

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