Role of Chemoradiotherapy in the Adjuvant and Neoadjuvant Settings for Resectable Pancreatic Cancer

Clinical Oncology 26 (2014) 551e559 Contents lists available at ScienceDirect

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Overview

Role of Chemoradiotherapy in the Adjuvant and Neoadjuvant Settings for Resectable Pancreatic Cancer N. Sen *, S. Falk y, R.A. Abrams * * Department y

of Radiation Oncology, Rush University Medical Center, Chicago, USA Department of Oncology, Bristol Haematology and Oncology Centre, Bristol, UK

Received 5 February 2014; received in revised form 21 March 2014; accepted 5 June 2014

Abstract Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death. Worldwide, the mortality incidence ratio approaches 98%. Although only 15e20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm. Despite advances in surgical technique, peri-operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20e25%. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies. Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

Key words: Adjuvant; cancer; chemoradiation; neoadjuvant; pancreatic

Statement of Search Strategies Used and Sources of Information A broad search was carried out to include primary and review articles containing the key words ‘pancreatic adenocarcinoma’, ‘adjuvant therapy’, ‘pancreatic cancer radiation’, ‘neoadjuvant therapy pancreatic cancer’, ‘pancreatic cancer chemotherapy’, ‘pancreatic cancer survival’ and ‘randomised trial pancreatic cancer’. From this, a list of references encompassing relevant data pertaining to adjuvant therapy, neoadjuvant therapy and natural history of disease was generated. This list was supplemented by additional articles known to us from past experience.

Author for correspondence: N. Sen, Department of Radiation Oncology, Rush University Medical Center, 500 South Paulina Ave, Chicago, IL 60612, USA. Tel: þ1-312-942-5751. E-mail address: [email protected] (N. Sen).

Introduction and Overview Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death [1]. Worldwide, the mortality incidence ratio approaches 98% [2]. Although only 15e20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm [3]. Despite advances in surgical technique, peri-operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20e25% [4e8]. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term

http://dx.doi.org/10.1016/j.clon.2014.06.003 0936-6555/Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

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survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies.

gemcitabine versus 5-fluorouracil (5-FU)-based sandwich chemoradiotherapy], postoperative CA 19-9 was highly predictive of survival (hazard ratio of 3.4 for 90 U/ml); no patients with postoperative levels greater than 180 U/ml survived longer than 2 years (see Figure 1). This highlights postoperative CA 19-9 as an independent prognostic factor. These findings provide rationale for stratifying enrolment on clinical trials by factors such as CA 19-9, lymph node status and margin resection status. In addition, this significantly complicates comparison of existing randomised data as enrolment was not historically stratified according to these criteria.

Patterns of Failure Without Adjuvant Therapy

Role of Adjuvant Therapy for Resected Pancreatic Adenocarcinoma

Historical series have shown that local recurrence rates after macroscopic excision alone are as high as 80% [9,10]. Distant failure or distant failure in conjunction with a locoregional failure is more common than an isolated locoregional recurrence after resection alone (see Table 1). Although local recurrence has not been shown to predict survival, it is associated with considerable morbidity [9]. A Japanese autopsy study of 27 patients treated with curative resection showed that 75% had recurred locally at the time of death [14]. Prognostic Factors for Survival after Surgical Resection Cure rates after surgery alone are low, with median survival generally less than 18 months and 5 year overall survival between 5 and 15% (see Table 2). Interpretation of data regarding adjuvant treatment for pancreatic cancer is complicated by a wide spectrum of factors that influence survival independent of therapy. A series from the University of Pennsylvania showed that in patients treated with adjuvant chemoradiotherapy, the number of positive lymph nodes, age less than or equal to 60 years and a microscopically margin negative resection were all independently highly associated with improved survival on multivariate analysis [19]. A similar series of 204 patients showed that lymph node ratio (positive to total dissected) may be a more significant prognostic factor than the number of positive lymph nodes alone [20]. Obtaining negative margins provides rationale for neoadjuvant therapy in cases of borderline resectability, as discussed below. On secondary analysis of RTOG 9704 [a phase III trial designed to evaluate

Role of Adjuvant Chemotherapy for Resected Pancreatic Adenocarcinoma Death due to metastatic disease comprises the majority of cancer-specific mortality from pancreatic cancer [14]. This provides a rationale for early systemic therapy. Multiple treatment regimens incorporating adjuvant chemotherapy have been shown in randomised settings to improve survival when compared with observation [2,15,22]. The historical adjuvant paradigm incorporated 5-FUbased chemotherapy with local-regional radiotherapy. The evolution of this paradigm from animal model to clinic was recently reviewed [23]. The first of these trials was carried out by the Gastrointestinal Tumor Study Group (GITSG 9173) in which patients were randomised to adjuvant 5-FUbased chemoradiotherapy versus observation. Although this trial has been criticised for its small sample size (42 patients in the initial study), there was a clear survival benefit for adjuvant 5-FU-based therapy over observation alone, with a median overall survival of 20 months versus 11 months [15]. The ESPAC-1 study confirmed a survival benefit for 5-FU-based chemotherapy versus observation alone, but has been criticised for its design, as described below [4]. Intra-arterial (celiac axis) chemotherapy has also been explored. In a single institution trial from Erasmus MC, 120 patients with resected cancer of the pancreas were randomised to intra-arterial mitoxantrone, 5-FU, leucovorin and cisplatin  6 with radiotherapy (54 Gy in 30 fractions) after the first cycle versus observation. Forty-eight per cent

Table 1 Patterns of first failure after resection without adjuvant therapies Series (no. patients)

Locoregional only

Distant only

Both

Reference

MGH (31) University of Pennsylvania (72) University of Kansas (26) University of Leuven (145) CONKO-001 (175) Westerdahl (74)

50% e 19% 17% e 8%

13% e 7% 60% 49% 14%

37% 85%* 73% 23% 41%* 78%

[9] [10] [11] [12] [7] [13]

*

Recurrence reported as locoregional with or without distant recurrence.

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Table 2 Survival after curative intent surgery alone Series (no. patients)

Median survival

5 year survival

Reference

ESPAC-1 (69) GITSG (22) Johns Hopkins (616) MSKCC (118) University Hospital Kuala Lumpur (236) EORTC (54) CONKO-001 (175)*

16.9 months 11 months 14.4 months 14.3 months 14.3 months 12.6 months 20.2 months

11% 5% 15.1% 10.2% 10.2% 10% 11.5%

[4] [15] [16] [17] [18] [6] [5]

*

All patients enrolled had postoperative CA 19-9 < 2.5 upper limit of normal.

of these patients had peri-ampullary cancers. There was no benefit in overall survival with the addition of chemotherapy and radiation, but there was a benefit in terms of progression-free survival [24] In addition, on quality of life analysis, patients in the chemoradiotherapy arm had less pain, nausea and vomiting than their counterparts in the observational arm [25]. Recent trials have centred on identifying alternative chemotherapeutic options other than gemcitabine. The ESPAC-3 trial compared gemcitabine to bolus 5-FU for peri-

ampullary and pancreatic ductal cancers. In the pancreatic ductal subset there was an improved toxicity profile, but no survival advantage to gemcitabine [26]. The current preeminence of gemcitabine was established by the CONKO001 study, which compared adjuvant gemcitabine versus observation alone for macroscopically resected adenocarcinoma of the pancreas. Of note, patients were required to have postoperative CA 19-9 levels < 2.5 times the upper limit of normal (92.5 U/ml) for enrolment. The long-term results were recently published and there is a clear survival benefit to chemotherapy versus observation, with 5 year overall survival 20.7% versus 10.4% and 10 year overall survival 12.2% versus 7.7% [5] Importantly, the median disease-free survival was also significantly improved with the addition of gemcitabine (13.4 versus 6.7 months). Operationally, this probably confirms that the adjuvant use of gemcitabine is superior to gemcitabine at recurrence in this context. RTOG 9704 also provides support for the inclusion of gemcitabine in the adjuvant setting. In this trial, patients with resected adenocarcinoma of the pancreas were randomised to adjuvant gemcitabine followed by 5FU-based chemoradiotherapy and maintenance gemcitabine versus 5-FU-based therapy alone. On planned multivariate analysis there was an overall survival benefit for gemcitabine before and after 5-FU-based chemoradiation when administered to patients with resected cancer of the head of pancreas, with a median overall survival of 20.5 months versus 16.9 months [22]. ESPAC-4 is currently open to enrolment and aims to investigate whether the addition of capecitabine to gemcitabine improves survival in the adjuvant setting.

Role of Adjuvant Radiotherapy for Resected Pancreatic Adenocarcinoma

Fig 1. Overall survival in RTOG 9704 according to postoperative CA 19-9. Survival curves compare favourably with those seen in CONKO001 (with enrolment criteria postoperative CA 19-9 < 2.5 upper limit of normal or about 92.5). Adapted from [21].

The role of adjuvant chemotherapy for resected cancer of the pancreas is well established. The rationale for the addition of radiotherapy includes the theoretical advantage of radiation sensitisation, high local recurrence rate with surgery alone as described above and extrapolation from treatment paradigms for other solid malignancies where there is a concurrent risk of locoregional and distant failure [27,28]. To date, there are no randomised data demonstrating the superiority of the addition of radiotherapy with modern delivery techniques to adjuvant chemotherapy alone. GITSG

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9173 randomised patients with resected cancers of the pancreas to adjuvant chemoradiotherapy versus observation alone, showing a survival benefit to chemoradiotherapy. This trial has been criticised for its small sample size and prolonged accrual. Nevertheless, the median overall survival of 20 months and 5 year overall survival of 15% is almost comparable with rates seen in modern series [15]. The European Organization for Research and Treatment of Cancer (EORTC) subsequently evaluated the role for adjuvant chemoradiotherapy in the first European multiinstitutional trial [29]. In a trial where 218 patients with resected cancer of the pancreas were randomised to adjuvant 5-FU-based chemoradiotherapy versus observation, there was no survival benefit seen with the addition of chemoradiotherapy. Importantly, 45% of enrolees had periampullary cancer. The median overall survival in the pancreas tumour subset was 17 months versus 13 months (not significant). This trial has been criticised for its design. The radiotherapy was split course (40 Gy in 20 fractions), as prescribed in the seminal GITSG trial, but there was no maintenance chemotherapy. In addition, 20% of patients assigned to the chemoradiotherapy arm did not receive treatment as prescribed. After the GITSG study, the next American multicentre trial to evaluate the role for radiotherapy in the adjuvant setting was RTOG 9704. In this trial, 451 patients with gross total resection of cancer of the pancreas were randomised to 5-FU-based chemoradiotherapy to a dose of 50.4 Gy in 28 fractions with 5-FU versus gemcitabine before and after chemoradiotherapy. Seventy-five per cent had T3 disease, 66% were node positive and 60% had unknown or microscopically positive margins. The first site of recurrence was local in 28% versus distant in 73%. On initial univariate analysis, there was no statistically significant difference in survival between the 5-FU and gemcitabine arms (17 versus 20 months median overall survival, P ¼ 0.09). On multivariate analysis of all enrolled patients, there was a trend towards improved survival with the addition of gemcitabine. On analysis of cancers of the pancreatic head (periampullary tumours), there was a statistically significant improvement seen with the addition of gemcitabine

(P ¼ 0.05). A per protocol analysis showed that the median and 3 year survival for patients receiving gemcitabine before and after radiotherapy were 25.2 months and 46%, respectively (see Figure 2). In RTOG 9704, CA 19-9 was measured but not used to define eligibility and included patients with values well above the cut-off used in CONKO001. Without appropriate selection or stratification for postoperative CA 19-9, any survival benefit from the addition of radiation to chemotherapy was probably confounded. ESPAC-1 was carried out in Europe [4]. This trial was intended to evaluate adjuvant 5-FU-based chemotherapy in comparison with adjuvant 5-FU-based chemoradiation. Initially, this was planned as a 2  2 design, but two additional randomisations ( chemoradiotherapy,  chemotherapy alone) were added to improve accrual. In total, 541 patients were enrolled, all were status post-macroscopically resected cancer of the pancreas (19% R1). Physicians were allowed to choose a randomisation and ‘background’ therapy (including radiotherapy and/or chemotherapy) was permitted. Radiotherapy was prescribed using the GITSG regimen (split course 40 Gy in 20 fractions), although up to 60 Gy was permitted. Radiation fields and planning techniques were not delineated. Concurrent bolus 5-FU (500 mg/m2) þ leucovorin þ adjuvant 5-FU 425 mg/ m2  6 months was prescribed. There was no central audit carried out as part of the trial design and as such there was significant heterogeneity in radiation treatment fields and volumes. On initial analysis, there was no improvement in survival with adjuvant chemoradiotherapy versus observation (median overall survival 15 versus 16 months, not significant) and there was an improvement in median survival with chemotherapy alone versus observation (20 months versus 14 months, statistically significant (SS). A subsequent subset analysis of the 2  2 factorial showed a detrimental survival effect of chemoradiotherapy in comparison with observation alone [4]. From this, it is concluded that adjuvant chemotherapy confers a benefit in overall survival and the addition of radiation may in fact be detrimental. However, there are several aspects of the trial design that may complicate this conclusion. First, the radiotherapy field and dose specifications were not clearly

Fig 2. Per protocol analysis of RTOG 9704. The results show a statistically significant benefit to the addition of gemcitabine on per protocol analysis. Adapted from [30].

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delineated. In addition, machine and beam energy specifications were also lacking. A dose of 60 Gy using twodimensional planning with large AP/PA fields (as was standard before three-dimensional planning techniques) was potentially allowed and if/when used probably caused significant normal tissue toxicity, which may have directly led to treatment-related mortality. In addition, the mean time from surgery to chemotherapy was 48 days versus 61 days for chemoradiotherapy, with no analysis of time to initiation of therapy. Recurrences were not well defined and it is unclear whether they occurred within the radiation portals. Lastly, survival statistics in the observational arms suggest that background therapies may have significantly impacted on outcome, as a median overall survival of 16 months for surgery without adjuvant therapy is much higher than reported in other series. The results of this trial have impacted on the design of subsequent ESPAC trials, which do not include adjuvant radiation as a component of therapy. Interpretation of randomised historical data with respect to the utility of radiation therapy in the modern adjuvant setting is complicated by considerable advances in treatment planning and delivery. Accurate localisation of the tumour bed and draining lymphatics is enhanced by computed tomography simulation. In addition, threedimensional planning techniques and intensity-modulated radiotherapy (IMRT) have allowed for more conformal target coverage and considerably less normal tissue toxicity. Two-dimensional planning techniques with large fields were used in ESPAC-1 and GITSG 9173. As a result, doselimiting structures in the upper abdomen did not allow for safe dose escalation or continuous chemoradiotherapy. Although there is concern for the potential for geographic miss with IMRT, locoregional control with IMRT in the adjuvant setting is promising, with rates of failure as low as 14% [31]. In addition, the dose to critical organs can be considerably lowered with inverse planning and IMRT has shown improved acute toxicity in comparison with threedimensional planning techniques [32,33]. These developments underscore the critical importance of specifying target volumes and planning techniques, as well as having a central review process as part of a modern clinical trial incorporating radiotherapy. There are several large retrospective analyses investigating the addition of chemoradiotherapy in the adjuvant setting. A series of 616 patients from Johns Hopkins suggests that adjuvant chemoradiotherapy improves survival over postoperative observation alone. In this population, 44% received adjuvant 5-FU-based chemoradiotherapy (median dose 50 Gy) þ 2e6 months of maintenance 5-FU and 56% received no adjuvant therapy. The 5 year overall survival for patients receiving chemoradiotherapy was 20.1% versus 15.1% for those who were observed. Of note, patients receiving chemoradiotherapy were younger, had less comorbid disease and fewer peri-operative complications. On multivariate analysis (MVA) for competing risk factors, chemoradiotherapy still showed a beneficial effect [34]. A similar series of patients from the Mayo Clinic also suggests that chemoradiotherapy improves survival after

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surgical resection. This study only included patients with R0 resection. At a median follow-up of 32.4 months, the 5 year overall survival with chemoradiotherapy was 28% versus 17% for those who were observed. Patients receiving chemoradiotherapy were more likely to be node positive and on MVA lack of adjuvant therapy was a negative prognostic factor [35]. Given the mixed prospective randomised data for adjuvant chemoradiotherapy and the retrospective data suggesting a benefit in terms of survival, there is a need for randomised data with adequate study design comparing adjuvant chemoradiotherapy using modern radiation techniques to adjuvant chemotherapy alone. RTOG 0848 is open to accrual and aims to address this comparison. In this study, patients with resectable pancreatic cancer status after macroscopic resection were initially enrolled in a two-step randomisation. First, they were randomised to gemcitabine  5 versus gemcitabine þ erlotinib  5 with clinical re-assessment. With no progression, patients were randomised to one additional cycle of chemotherapy versus one additional cycle of chemotherapy followed by chemoradiotherapy to 50.4 Gy using modern planning techniques (three-dimensional conformal or IMRT) with capecitabine or 5-FU. Based on the preliminary results of LAP07, which did not show a survival benefit to the addition of erlotinib to gemcitabine in the adjuvant setting, RTOG 0848 has since been amended such that all patients receive five cycles of adjuvant gemcitabine followed by randomisation to chemotherapy  radiotherapy with 5-FU or capecitabine. There are several aspects of RTOG 0848 that may help clarify the optimal role of chemoradiotherapy in the adjuvant setting. First, a secondary analysis of RTOG 9704 showed that 200 of 416 patients analysed for radiotherapy quality assurance (RTQA) were less than protocol. Based on per protocol delivery, survival was significantly increased and there was a trend towards fewer grade 3 and 4 toxicities. Based on this, RTOG 0848 has prospective radiation quality control built into the trial (prospective central review of all computed tomography-based contours including normal structures, clinical target volumes including draining nodal stations and dosimetric data before the initiation of radiotherapy). Second, although adenocarcinomas of the pancreas may arise in sites other than the head, these may be biologically different with a higher propensity for earlier micrometastatic disease. In support of this, RTOG 9704 showed a survival benefit with gemcitabine for patients with pancreatic head cancers. As such, enrolment of patients on RTOG 0848 is limited to those with cancers of the head of pancreas. Third, as described above, secondary analysis of RTOG 9704 showed that postoperative CA 19-9 is highly predictive of survival. In addition, about 25% of patients in RTOG 9704 had unknown margin status. As described above, margin status and nodal involvement at presentation have considerable prognostic implications. As such, these have been incorporated into the stratification criteria for enrolment on RTOG 0848. Fourth, radiation treatment volumes in RTOG 0848 are well described and

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reproducible. A step by step guide to clinical target volume delineation is outlined such that the target volume encompasses the celiac axis, superior mesenteric artery, porta hepatis, surgical bed and pancreaticojejunostomy (http://www.rtog.org/LinkClick.aspx?fileticket¼CLd11PWZek¼).

exploratory laparotomy and possible resection without neoadjuvant radiotherapy, there was no difference in 5 year overall survival (22 versus 26%, not significant). Patients who received preoperative radiotherapy had significantly fewer deaths due to regional recurrence within the first 1.5 years, with significantly higher hepatic metastases after 1 year.

Adjuvant Treatment Summary Role of Neoadjuvant Chemoradiotherapy Randomised trials have shown superiority of chemotherapy over observation alone in terms of survival after potentially curative surgery. Worldwide, the role of radiation therapy as a component of adjuvant therapy remains controversial. No randomised phase III prospective data exist for adjuvant chemotherapy alone versus chemoradiotherapy using modern radiotherapy techniques. RTOG 0848 seeks to evaluate the role for modern radiotherapy in an adjuvant treatment paradigm.

Role of Neoadjuvant Therapy for Resectable Pancreatic Adenocarcinoma Although all major multicentre randomised data for the curative-intent treatment of resected cancer of the pancreas has been carried out in the adjuvant setting, there is considerable interest in investigating a neoadjuvant treatment paradigm. Theoretical benefits include increasing the likelihood for resectability (i.e. borderline cancers) and R0 resection, obtaining a higher proportion of patients receiving prescription dose chemotherapy/radiotherapy, the early treatment of micrometastatic disease and the opportunity for clinically localised disease to declare metastatic potential, thereby sparing the patient of a morbid operation for low clinical benefit. To date, studies incorporating neoadjuvant treatment are varied with respect to the definition of resectability and the inclusion of patients with varying levels of resectability. This complicates comparison between studies. Here, we will review neoadjuvant chemoradiotherapy and novel radiotherapeutic approaches. Although neoadjuvant chemotherapy is also under investigation it is outside the remit of this review. Role of Neoadjvuant Radiotherapy There are retrospective data from Japan evaluating the role of neoadjuvant radiotherapy alone [36]. In one series comparing 23 patients who received neoadjuvant radiotherapy (50 Gy) followed by exploratory laparotomy and possible resection and 31 patients who underwent

The largest published single institution collection of data on neoadjuvant treatment for resectable pancreatic cancer has been collected at MD Anderson. To date, six phase II trials for neoadjvuant chemoradiotherapy for resectable pancreatic cancer have been carried out there. All six trials define resectable cancer as disease confined to the pancreas without extension to the superior mesenteric artery or celiac axis, and tumour abutment and encasement of the superior mesenteric vein in the absence of overt occlusion. This definition incorporates more advanced disease than other definitions of resectability (see Table 3). Given that the definition of resectability has been uniform across all studies performed at MD Anderson, an internal comparison of outcomes with various therapies is facilitated. Preoperative gemcitabine has been associated with lower rates of R1 resection, rates of postoperative local recurrence and improved overall survival in comparison with 5-FU- or taxane-based regimens. The most recent publication evaluating neoadjuvant gemcitabine-based chemoradiotherapy (30 Gy in 10 fractions) reports a median survival of 34 months for resected patients and a 5 year overall survival of 36%. This compares favourably with adjuvant data, although it is important to note that those who were resected did not progress on neoadjuvant therapy. This provides the framework for an attractive treatment paradigm in which a potentially morbid operation is reserved only for patients who are responsive to systemic therapy [37]. To date, there is only one randomised controlled trial comparing immediate resection with neoadjuvant chemoradiotherapy followed by resection. In this phase II trial, patients with histologically proven adenocarcinoma of the pancreatic head with <180 degree contact to peripancreatic vessels were randomised to primary surgery versus neoadjuvant chemoradiotherapy (55.4 Gy with concurrent gemcitabine/cisplatin) followed by surgery 6 weeks later. The results have been published in abstract form. There was a trend towards improved R0 resection rate (90% versus 67%, P ¼ 0.08) as well as a trend towards improved median survival (17.4 versus 14.4 months, not significant) with neoadjuvant therapy [38].

Table 3 Definitions of borderline resectability Structure

National Comprehensive Cancer Network

MD Anderson

Superior mesenteric vein/portal vein

Abutment, encasement, or occlusion amenable to resection and reconstruction Abutment < 180 degrees No abutment or encasement

Short segment occlusion

Superior mesenteric artery Celiac trunk

Abutment Abutment

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Future directions include ESPAC-5, which is a proposed phase II study that aims to evaluate the role for neoadjuvant therapy in a multicentre, prospective, randomised setting. This trial aims to accrue 100 patients and will randomise them to one of four arms: (A) immediate surgery with adjuvant gemcitabine or 5-FU for six cycles (control), (B) neoadjuvant gemcitabine þ capecitabine followed by restaging computed tomography and surgery if no evidence of progression, (C) neoadjuvant FOLFIRINOX followed by restaging computed tomography and surgery if no evidence of progression and (D) neoadjuvant chemoradiotherapy (50.4 Gy in 28 fractions with concurrent capecitabine daily) followed by restaging computed tomography and surgery if no evidence of progression. Novel Neoadjuvant Radiotherapeutic Approaches Proton therapy in the neoadjuvant setting has been evaluated in a phase I trial [39]. In this dose-escalation study, 15 patients with localised cancers of the pancreatic head were treated with concurrent capecitabine 825 mg/m2 BID  10 days. Level 1 was 30 Gy in 10 fractions, level 2 was 25 Gy in five fractions over 2 weeks, level 3 was 25 Gy in five fractions over 1.5 weeks and level 4 was 25 Gy in five fractions in 1 week. There were no dose-limiting toxicities and surgical resection was carried out as planned in 11/15 patients. Neoadjuvant radiation for borderline tumours with photon-based stereotactic body radiotherapy (SBRT) has also been evaluated in a series of 73 patients with nonmetastatic borderline resectable (by National Comprehensive Cancer Network definition) pancreatic cancer [40]. After induction gemcitabine-based chemotherapy, five-fraction SBRT was delivered with intent to deliver 30e40 Gy to the tumourevessel interface and up to 30 Gy to the remainder of gross disease. This treatment was well tolerated and no patients experienced grade 3 toxicities during SBRT. After restaging, 32 patients underwent surgery with 31 undergoing an R0 resection. Those who underwent an R0 resection had a median overall survival of 19.3 months versus the rest of the cohort (12.3 months, P ¼ 0.03). Breath hold techniques and four-dimensional planning have allowed for dose escalation in the neoadjuvant setting. In one phase I/II trial in which 50 patients with radiographically unresectable tumours were enrolled, a dose of 55 Gy in 25 fractions with concurrent gemcitabine resulted in a dose-limiting toxicity (gastrointestinal grade 3, neutropenic fever, deterioration of performance status to  3) rate of 24%. Twelve patients underwent resection and 10 underwent R0 resection [41]. Meta-analyses of Neoadjuvant Studies Three large meta-analyses of neoadjuvant therapy have been published [42,43]. In the first, 14 prospective phase II trials were included, comprising 536 patients. Eighty-five per cent received chemoradiotherapy and 15% received chemotherapy alone. Seventy-five per cent of patients were resectable at presentation. An 11% local recurrence rate was found after pooling data from eight trials that reported local recurrence (LR), which is lower than autopsy series as

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reported above. As expected, there was a higher resection rate (65.8%) for those who presented with resectable disease at presentation versus borderline or unresectable disease (31.6%). In a second meta-analysis, 111 retrospective and phase I/II prospective studies incorporating neoadjuvant chemoradiotherapy, radiotherapy or chemotherapy alone were evaluated. Studies were subdivided into resectable tumours and unresectable/borderline tumours at presentation. Response rates after neoadjuvant therapy were comparable in both groups (with a pathological complete response rate of about 4%). The median overall survival with resection was 23.3 months versus 8.4 months without resection, which is comparable with published data for adjuvant therapy. In a third meta-analysis, 10 studies with 182 participants enrolled in prospective trials limited to borderline resectability (four used National Comprehensive Cancer Network criteria and the rest used similar but other well-defined criteria) were analysed [44]. Sixtynine per cent of patients were brought to surgery and 80% of those were resected. Eighty-three per cent of resected patients achieved R0 resections. After completion of neoadjuvant therapy, only 16% had complete or partial response by computed tomography evaluation.

Conclusions In summary, there is strong evidence for increased survival with chemotherapy in the adjuvant setting for resected cancer of the pancreas. Gemcitabine-based therapy for 6 months is the current standard of care. There are no available randomised multicentre data comparing adjuvant chemoradiotherapy with chemotherapy alone using appropriate study design, precise and appropriate definition of modern radiation techniques and prospective quality assurance of radiotherapy. Interpretation and comparison of existing data are complicated by independent prognostic factors, such as margin status, postoperative CA 19-9 levels, lymph node involvement and the location of the tumour within the pancreas. RTOG 0848 aims to address these issues. Given available data, adjuvant chemoradiotherapy is an alternative to adjuvant chemotherapy alone and may be of particular benefit in patients who are at a high risk of locoregional failure without excess competing distant risk as per the consensus of the National Comprehensive Cancer Network [33]. An adjuvant dose of 50.4e54 Gy with concurrent 5-FUbased chemotherapy using conventional fractionation and three-dimensional planning techniques is recommended. Neoadjuvant chemoradiotherapy provides several theoretical advantages, including the early initiation of systemic therapy and the identification of a subset of patients for whom resection will not offer a survival benefit. In addition, it has been shown in phase II settings to provide reasonable long-term survival in those who proceed to resection. However, a direct comparison of results from neoadjuvant trials with adjuvant trials is difficult due to the lack of surgical staging before chemotherapy or chemoradiotherapy and the inherent selection process that occurs with a surgery last rather than surgery first approach.

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