Radiotherapy in locally advanced pancreatic cancer



  1. Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  2. Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  3. Medical Oncology, St John of God Hospital, Subiaco, Western Australia, Australia.
  4. Gastroenterology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
  5. General Surgery, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.


While radiotherapy was considered an important treatment modality in locally advanced pancreatic cancer for several decades, the presentation of the LAP 07 trial results have impressed a concept that radiotherapy provides no benefit in this patient group. Further analysis however, revealed that the use of radiotherapy in the LAP 07 trial was associated with better local control and a greater chemotherapy-free interval, both meaningful palliation benefits. Further, the initiation of radiation was delayed by a four month period of induction treatment that employed a drug with only an 8% response rate, and progression free survival control of 3.1 months. A detailed review of the literature to date demonstrates that modern radiotherapy in locally advanced pancreatic cancer has a significant local effect, is well tolerated and associated with improved quality of life through providing durable local control, and in a subset population, resulting in long-term survival. Perhaps the most important conclusion of the LAP 07 study, which was very well conducted, is that delaying a local therapy for four months is not an effective sequencing strategy when the induction treatment is of borderline efficacy in a cancer with a rapid progression characteristic. While newer agents are improving survival, the outlook remains dismal. Optimising the integration of radiation needs to be a priority to define how this modality can assist the modest gains that have come about from a very large number of chemotherapy sequencing studies.

Pancreatic cancer is the tenth most common cancer diagnosed in Australian men and women, but is the fourth most common cause of cancer mortality.1 At diagnosis, approximately one third of patients present with locally advanced disease and approximately half with metastatic disease, leaving only 10 to 20% suitable for resection.2 As a group, locally advanced pancreatic cancers (LAPCs) tend to be characterised by their proximity to critical vascular structures, rendering them unsuitable for resection, even in the absence of gross metastatic disease. LAPC is associated with poor survival, approximately 5 to 11 months.3

LAP 07

LAP 07 trial design and endpoints

The results of the LAP 07 trial were presented at the 2013 American Society of Clinical Oncology Annual Meeting. In this large trial, patients of good performance status with LAPC (n = 442) were first randomised to four months of gemcitabine (1000mg/m2/week x3) with or without erlotinib (100mg/day). Patients who did not have disease progression were further randomised to radiotherapy treatment of 54 Gy, with concurrent capecitabine (1600mg/m2/day), or two additional months of the same chemotherapy.4 Patients who received erlotinib at first randomisation continued with this drug from the completion of protocol until further disease progression. The primary objective was to assess whether chemoradiotherapy increased overall survival.

LAP 07 shortcomings

A widely reported outcome from the study, median overall survival for the chemotherapy only arm was 16.5 months, appeared very good. This is misleading however, as it relates to the outcome for the selected 61% of patients who remained eligible to progress to the four month second randomisation point. Two thirds of the patients who did not proceed to second randomisation (26% of all patients) had disease progression, and one tenth had treatment toxicity.

At the time of the LAP 07 trial development, single agent gemcitabine was the standard of care for metastatic pancreatic cancer. This stems from an initial landmark study that showed improved median survival with gemcitabine compared to 5-fluorouracil (5-FU) by approximately five weeks (5.6 months versus 4.4 months), and improved clinical benefit (based on a non-validated health-related quality of life tool) in patients with advanced pancreatic cancer.5 Multiple other studies have replicated the additional but modest benefit of this drug in locally advanced and metastatic pancreatic cancer, including progression-free survival of 3.1 months and a response rate of 8.2%.6

The LAP 07’s investigation of the role of erlotinib concluded that its use was not beneficial in LAPC. The added toxicity was quite substantial, with 37.3%, 32.9%, 24.5% and 6.6% experiencing grade 3 or 4 neutropaenia, coughing, dyspnoea and diarrhoea respectively. This is in contrast to just 5.9% of patients treated with radiotherapy experiencing grade 3 or 4 nausea.

Common induction program practices prior to the study employed neoadjuvant periods of 1-2 months, as it was recognised that occult metastatic disease could present quite quickly in this condition. It was hypothesised that extending the neoadjuvant period might improve the selection of patients who would benefit from the addition of radiotherapy. However, no benefit to survival was observed by extending the period to four months, which exceeded the median progression-free survival of 3.1 months.

Evidence that modern radiotherapy is effective

Radiotherapy has a useful response rate and increases R0 rates

Multiple phase 1 and 2 trials (summarised in table 1) demonstrate improved response rates and increased R0 resection rates with neoadjuvant chemoradiotherapy. In one retrospective study of patients with borderline and LAPC (n = 41), investigators attempted to compare the relative contributions of neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy to outcomes.7 Patients receiving radiotherapy (58.5%) were treated to a dose of 45 Gy to 50.4 Gy, with concurrent gemcitabine, cisplatin or capecitabine at radiosensitising doses. Patients treated with chemotherapy only received gemcitabine alone, or gemcitabine in combination with capecitabine or oxaliplatin. A complete pathological response was only attained in patients receiving radiotherapy – 12% of patients vs 0% for chemotherapy alone. The addition of radiotherapy significantly increased the likelihood of a partial response – 46% vs 17% (P = 0.03). The use of radiotherapy more than doubled the R0 surgical resection rate – 96% vs 35% (P < 0.0001).

Table_Studies on neoadjuvant chemoradiotherapy-small

Radiotherapy reduces local failure

Huguet et al in a recent review of the role of chemoradiotherapy in LAPC, identified three-dimensional (3D) -conformal radiotherapy as an ‘active, well-tolerated regimen’, and given that LAPC was rarely downstaged with contemporary treatment programs, the goal of treatment should be palliative with aims of prolonging survival, disease control and symptom palliation.8 The palliative benefits of chemoradiotherapy compared to no chemoradiotherapy in LAPC were demonstrated in one prospective trial (n = 31), with improved Karnofsky’s performance status (77.1 vs 65.5, P < 0.0001), reduced days in hospital (12.3 days vs 19.0 days, P < 0.05) and pain relief (response rate 80%, median duration 5.2 months).9 This was in addition to a survival benefit (median survival 6.4 months vs 13.2 months, P = 0.0009). Closer analysis of the LAP 07 data reveals reduced local progression with radiotherapy.10 With improved local control there would be potential to avoid biliary or gastric outlet obstruction, and hence avoid stenting or surgical procedures.

Radiotherapy improves chemotherapy free interval

Patients in the LAP 07 trial who received chemoradiotherapy achieved a greater chemotherapy-free interval than those who did not receive radiotherapy.10 The median time to re-introduction of chemotherapy was 5.2 months versus 3.2 months.

Radiotherapy is associated with long-term survivors

The notion that we should include the presence of a tail of longer term survival as an endpoint in pancreatic cancer was emphasised at the recent American Society of Clinical Oncology plenary update of a randomised phase 3 study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone, in patients with metastatic adenocarcinoma of the pancreas (MPACT).11 Longer-term follow-up of this study, which has established the combination of nab-Paclitaxel and gemcitabine as a new standard of therapy for locally advanced and metastatic cancer, emphasised three year survival of 4%. The authors’ experience (manuscript in preparation) of 124 patients with histologically confirmed locally advanced inoperable pancreatic cancer, employing only one cycle neoadjuvant gemcitabine prior to 3D-conformal radiotherapy (54 Gy with concurrent 5-FU), found three year survival of 13% and five year survival of 6%. Prospective randomised control trials of chemoradiotherapy in LAPC to date have generally not reported on survival rates beyond 1-2 years. The identification of a small but not insignificant ‘tail’ of long-term survivors is only apparent if we look.

All radiation isn’t the same radiation

Radiation technique is vital

The importance of consistent technical expertise is recognised in the surgical literature. The same applies to any radiotherapy technique. A good example of this is seen in the European Study Group for Pancreatic Cancer (ESPAC) 1 study, a randomised trial of adjuvant chemoradiotherapy and chemotherapy after resection of pancreatic cancer, where the median survival of patients assigned to chemoradiotherapy was worse than those assigned to observation – 13.9 months vs 16.9 months.12 At that time, radiation was rarely, if ever, employed at most centres and there was very little engagement with expertise. There was no funding to undertake radiation technique quality assurance, and the protocol description was confined to a brief paragraph that referred to a crude Gastrointestinal Tumor Study Group radiation technique developed in the 1970s.13 This was in contrast to the robust contemporary standards of surgical practice that were well developed, as well as the widespread familiarity of chemotherapy protocols. Their minimalist approach to radiation quality assurance appears to have resulted in poor survival, worse than no treatment at all.14 Bydder and Spry further suggested that the observed detriment to survival might be accounted for by inadvertent coverage of the kidneys in close proximity, leading to their later and premature failure.14 With such confounding factors, this study does not exclude the role of radiotherapy in this setting. Rather, it suggests the ESPAC-1 radiotherapy technique should not be employed and further highlights the great need to develop safe future radiotherapy techniques and robust quality assurance processes.

Improved results with advances in modern techniques

Contemporary anatomically targeted radiation programs have now been set up to be safe and avoid adverse late renal or hepatic damage.15,16,17

We have previously identified the importance of ‘dummy run’ testing of new centres, which exposed unexpected misunderstandings of protocol writing, allowing them to be addressed.17 Additionally, development of quality assurance assessment tools address the very complex data sets that represent modern computer planning.18

Intensity-modulated radiotherapy (IMRT) is a technique which uses multiple non-coplanar beams of non-uniform intensity, leading to better conformality of dose to the target volume, and less dose to adjacent critical structures, thereby reducing potential toxicities and allowing for dose escalation. This was used in a recent LAPC trial to a dose of 55 Gy to 60 Gy, in 25 fractions;19 even with concurrent full dose gemcitabine, this combined treatment was well tolerated and achieved a median survival of 14.8 months and two year overall survival of 30%. Superior dosimetry is achievable with volumetric-modulated arc radiotherapy, a type of IMRT in the treatment of pancreatic cancer, which may translate to better toxicity profiles and the potential for dose escalation.20

Diaphragmatic movement is transmitted to the pancreas hence this target moves during the treatment; the limits of this motion increase the size of the target needed to be treated and thereby increase treatment toxicity. Four-dimensional computed tomography (CT) can reliably reduce the margin necessary for treating pancreatic cancer, reducing dose to adjacent organs.21 Until recently, the radiation target was determined by a CT-defined target based on CT abnormality and standard anatomical risk patterns. Positron emission tomography (PET) in other cancer situations e.g. lung, has already changed the approach to target delineation. While current PET tracers are only uncommonly useful, we are likely to see more confident target delineations with future development, which will improve treatment efficacy, possibly allowing radiotherapy dose escalation and simultaneous normal tissue toxicity reduction.22,23

Changing landscape

Impact of stage migration from improved imaging

In the last two decades, increased utilisation of CT, improvements in multidetector CT technology, and increased utilisation and expertise in reporting of magnetic resonance imaging (MRI) and PET in pancreatic cancer have led to improved detection of smaller primary disease, hence earlier detection. Furthermore, improvement in the assessment of the vascular involvement selects out truly inoperable patients along with the better assessments of previously occult metastatic diseases.24 The impact of better staging not only helps our patient selection, it improves outcome even when there has been no true treatment effect by this better selection. This is the process of stage migration (the Will Rogers phenomenon*);25 patients that would not have been identified as having gross distant metastases are now identified and treated as metastatic cancer patients, thereby improving the outcomes in non-metastatic and metastatic populations. In the 1990s, phase 3 trial data found gemcitabine achieved a median overall survival for non-operable patients of 5.6 months,5 contrasting with more recent improved outcomes, employing the same regimen of 6.6 months.11 It is likely that the Will Rogers effect is a major contributor to this survival improvement.

*In the Will Rogers Phenomenon, stage migration and new diagnostic techniques are recognised as a source of misleading statistics for survival in cancer. Patients who previously would have been classified in a “good” stage migrate to a “bad stage” with the new identification of metastases with improved techniques. The prognosis of those migrated (although worse than those in the good-stage group) is better than those in the bad-stage group; thereby improving the survival rates of both groups without improvement of individual outcomes.

So how do we best integrate treatment?

Importance of durable local control with improving systemic treatments

Multiagent nab-paclitaxel and FOLFIRINOX has resulted in improved survival compared to gemcitabine alone in metastatic pancreatic cancer, 8.7 months vs 6.6 months, and 11.1 months vs 6.8 months respectively.11,26 As in other tumour sites, the role of local control in improving overall survival may become evident as systemic treatment improves.  

The vast experience from breast cancer research has demonstrated improved systemic treatments leading to improved survival for localised disease.27 With the arrival of effective systemic treatments in breast cancer, achieving local control was thought to have limited impact on survival because of the view that a local recurrence could be treated, and that local recurrence was not thought to lead to metastatic disease. The evidence however, shows that improved local control in non-metastatic breast cancer actually improves overall survival.27 In the Early Breast Cancer Trialists’ Collaborative Group meta-analysis of local therapy, for every four local recurrences prevented by loco-regional radiotherapy, one death from breast cancer was avoided.28 In the setting of LAPC and improving effectiveness of systemic treatment, improving local control will become an important factor in improving survival.

Paucity of radiotherapy data

There have been huge resources employed to study the effect of minor variations to drug sequencing and combinations using the clinical trial method. These collaborations have encouraged the rapid development of widespread familiarity with and expertise in the safe and effective use of systemic agents in this condition. In contrast, there have been very few resources employed to develop the optimal utilisation of radiotherapy, hence expertise is rare and largely confined to few centres who publish their own data.

A search of the PUBMED database from 1950 until October 2015, combining the MESH terms ‘pancreatic neoplasms’ with ‘chemotherapy’, ‘biological agents’ or ‘immunotherapy’, and limiting search to human phase 2 or 3 trials, excluding irrelevant trials (focused only on resectable, borderline resectable or metastatic disease), yields 338 trials, 42 of which were phase III. A similar search combining MESH terms ‘pancreatic neoplasms’ with ‘radiotherapy’, but excluding trials on stereotactic body radiotherapy and intraoperative radiotherapy, yields 53 trials, making up less than 15% of the available data for management of LAPC. While few of the systemic treatment studies have changed systemic treatment directly, the knowledge base has helped optimise schedules and sequencing, and helped foster expertise and familiarity. This contrasts with the paucity of data to define how to sequence and integrate radiotherapy in LAPC.

A summary of what LAP 07 showed us

The LAP 07 experience showed us that a program that delays the commencement of radiation by four months in patients with locally advanced disease does not improve overall survival. The induction period had been extended in this study from a common one month period to four months, based on a belief that this would identify occult liver metastases and hence improve selection. The progression-free survival for the drug was 3.1 months, however, less than the induction period, matched by a response rate of 8%. Nonetheless, the study did establish the safety and protocol compliance of study collaborators (radiation therapy quality assessment identifying on 18% of major deviations from radiotherapy protocol).4 It also confirmed that the radiation program was minimally toxic and there were clear palliative benefits of improved local control, and beneficial delay to time of recommencement of chemotherapy.10


Locally advanced pancreatic cancer has a poor outlook. Advances in radiotherapy technique and expertise in locally advanced pancreatic cancer have resulted in improved tolerance and benefits in palliation, such as improved local control and increasing time off chemotherapy. Furthermore, in a small but not insignificant number the potential for long-term survival has been observed. With the introduction of more effective systemic treatments, more studies are needed to identify the optimal integration of radiotherapy and further define the most effective sequencing strategy to improve quality of life and survival.


  1. Australian Institute of Health and Welfare: Cancer in Australia 2014: Actual incidence data from 1982 to 2011 and mortality data from 1982 to 2012 with projections to 2014. Asia Pc J Clin Oncol. 2015;11:208-220.
  2. Tucker ON, Rela M. Controversies in the Management of Borderline Resectable Proximal Pancreatic Adenocarcinoma with Vascular Involvement. HPB Surgery. 2008;2008:8.
  3. Yeo TP, Hruban RH, Leach SD, et al. Pancreatic Cancer. Curr Probl Cancer. 2002;26(4):176-275.
  4. Hammel P, Huguet F, Van Laethem J-L, et al. Randomized multicenter phase III study in patients with locally advanced adenocarcinoma of the pancreas: gemcitabine with or without chemoradiotherapy and with or without erlotinib LAP 07 study. J Clin Oncol. 2013;31(suppl):abstr LBA4003.
  5. Burris 3rd HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403–2413.
  6. Heinemann V, Quietzsch D, Gieseler F, et al. Randomised phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006;24:3946-3952.
  7. Barugola G, Partelli S, Crippa S, et al. Outcomes after resection of locally advanced or borderline resectable pancreatic cancer after neoadjuvant therapy. Am J Surg. 2012;203(2):132-139.
  8. Huguet F, Mukherjee S, Javle M. Locally advanced pancreatic cancer: The role of definitive chemoradiotherapy. Clin Oncol. 2014;26(9):560-568.
  9. Shinchi H, Takao S, Noma H, et al. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2002;53:146-150.
  10. Huguet F, Hammel P, Vernerey D, et al. Impact of chemoradiotherapy (CRT) on local control and time without treatment in patients with locally advanced pancreatic cancer (LAPC) included in the international phase III LAP 07 study. J Clin Oncol. 2014;32(suppl):abstr LBA4001.
  11. Goldstein D, El-Maraghi RH, Hammel P, et al. nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015;107(2).
  12. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–1210.
  13. Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899-903.
  14. Bydder S, Spry N. Chemotherapy for pancreatic cancer. N Engl J Med. 2004; 350(26):2713–2715.
  15. Osborne C, Bydder SA, Ebert MA, et al. Comparison of non-coplanar and coplanar irradiation techniques to treat cancer of the pancreas. Australas Radiol. 2006;50(5):463-467.
  16. Goldstein D, Van Hazel G, Walpole E, et al. Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer. Br J Cancer. 2007;97(4):464-471.
  17. Spry N, Harvey J, MacLeod C, et al. 3D radiotherapy can be safely combined with sandwich systemic gemcitabine chemotherapy in the management of pancreatic cancer: factors influencing outcome. Int J Radiat Oncol Biol Phys. 2008;70(5):1438-1446.
  18. Spry N, Bydder S, Harvey J, et al. Accrediting radiation technique in a multicentre trial of chemoradiation for pancreatic cancer. J Med Imaging Radiat Oncol. 2008;52(6):598-604.
  19. Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2012;84(5):1166–1171.
  20. Nabavizadeh N, Simeonova AO, Waller JG, et al. Volumetric-modulated arc radiotherapy for pancreatic malignancies: dosimetric comparison with sliding-window intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy. Med Dosim. 2014;39(3):256-260.
  21. Huguet F, Yorke ED, Davidson M, et al. Modeling pancreatic tumor motion using 4-dimensional computed tomography and surrogate markers. Int J Radiat Oncol Biol Phys. 2015;91(3):579-587.
  22. Li XX, Lui NB, Zhu L, et al. Consequences of additional use of contrast-enhanced (18)F-FDG PET/CT in target volume delineation and dose distribution for pancreatic cancer.Br J Radiol. 2015;88(1051):20140590.
  23. Heerkens HD, van Vulpen M, van der Berg CA, et al. MRI-based tumor motion characterization and gating schemes for radiation therapy of pancreatic cancer. Radiother Oncol. 2014;111(2):252-257.
  24. Raman SP, Horton KM, Fishman EK. Multimodality imaging of pancreatic cancer-computed tomography, magnetic resonance imaging, and positron emission tomography. Cancer J. 2012;18(6):511-522.
  25. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med. 1985;312(25):1604-1608.
  26. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–1825. 

  27. Punglia RS, Morrow M, Winer EP, et al. Local Therapy and Survival in Breast Cancer. N Engl J Med. 2007;356:2399-2405.
  28. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366:2087-2106.
  29. Joensuu TK, Kiviluoto T, Karkkainen P, et al. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;60(2):444–452.
  30. Calvo FA, Matute R, Garcia-Sabrido JL, et al. Neoadjuvant chemoradiation with tegafur in cancer of the pancreas: initial analysis of clinical tolerance and outcome. Am J Clin Oncol. 2004;27(4):343–349. 

  31. Pipas JM, Barth RJ, Jr, Zaki B, et al. Docetaxel / gemcitabine followed by gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2005;12(12):995–1004. 

  32. Talamonti MS, Small W, Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol. 2006;13(2):150–158. 

  33. Brown KM, Siripurapu V, Davidson M, et al. Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am J Surg. 2008;195(3):318–321. 

  34. Varadhachary GR, Wolff RA, Crane CH, et al. Pre-operative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3487–3495. 

  35. Small W, Jr, Berlin J, Freedman GM, et al. Full-dose gemcitabine with concurrent radiation therapy in patients with nonmetastatic pancreatic cancer: a multicenter phase II trial. J Clin Oncol. 2008;26 (6):942–947. 

  36. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol. 2008;26(21):3496–3502. 

  37. Lind PA, Isaksson B, Almstrom M, et al. Efficacy of preoperative radiochemotherapy in patients with locally advanced pancreatic carcinoma. Acta Oncol. 2008;47(3):413–420.
  38. Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic cancer: The importance of this emerging stage of disease. J Am Coll Surg. 2008;206(5):833–846.
  39. Maximous DW, Abdel-Wanis ME, El-Sayed MI, et al. Preoperative gemcitabine based chemoradiotherapy in locally advanced non metastatic pancreatic adenocarcinoma. Int Arch Med. 2009;2(1):7-7682-2-7.
  40. Satoi S, Yanagimoto H, Toyokawa H, et al. Surgical results after preoperative chemoradiation therapy for patients with pancreatic cancer. Pancreas. 2009;38(3):282–288. 

  41. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience. Oncology. 2009;76(6):413–419. 

  42. Landry J, Catalano PJ, Staley C, et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010;101(7):587–592.
  43. Piperdi M, McDade TP, Shim JK, et al. A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: Lessons from a single-institution database. HPB (Oxford). 2010;12(3):204–210.
  44. Turrini O, Ychou M, Moureau-Zabotto L, et al. Neoadjuvant docetaxel-based chemoradiation for resect-able adenocarcinoma of the pancreas: new neoadjuvant regimen was safe and provided an interesting pathologic response. Eur J Surg Oncol. 2010;36(10):987–92. 

  45. Chun YS, Milestone BN, Watson JC, et al. Defining venous involvement in borderline resectable pancreatic cancer. Ann Surg Oncol. 2010;17(11):2832–2838. 

  46. Stokes JB, Nolan NJ, Stelow EB, et al. Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer. Ann Surg Oncol. 2011;18(3):619–627.
  47. Patel M, Hoffe S, Malafa M, et al. Neoadjuvant GTX chemotherapy and IMRT-based chemoradiation for borderline resectable pancreatic cancer. J Surg Oncol. 2011;104(2):155–161. 

  48. Chuong MD, Hayman TJ, Patel MR, et al. Comparison of 1-, 2-, and 3-dimensional tumor response assessment after neoadjuvant GTX-RT in borderline-resectable pancreatic cancer. Gastrointest Cancer Res. 2011;4(4):128–134. 

  49. Leone F, Gatti M, Massucco P, et al. Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience. Cancer. 2013;119(2):277–284.
  50. Pipas JM, Zaki BI, McGowan MM, et al. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol. 2012;23(11):2820–2827. 

  51. Habermehl D, Kessel K, Welzel T, et al. Neoadjuvant chemoradiation with gemcitabine for locally advanced pancreatic cancer. Radiat Oncol. 2012;7:28-717X-7-28.
  52. Papalezova KT, Tyler DS, Blazer DG, 3rd, et al. Does preoperative therapy optimize outcomes in patients 
with resectable pancreatic cancer? J Surg Oncol. 2012;106(1):111–118.

  53. Estrella JS, Rashid A, Fleming JB, et al. Post-therapy pathologic stage and survival in patients with pancreatic ductal adenocarcinoma treated with neoadjuvant chemoradiation. Cancer. 2012;118(1):268–277.
  54. Arvold ND, Ryan DP, Niemierko A, et al. Long-term outcomes of neoadjuvant chemotherapy before chemoradiation for locally advanced pancreatic cancer. Cancer. 2012;118(12):3026–3035. 

  55. Kang CM, Chung YE, Park JY, et al. Potential contribution of preoperative neoadjuvant concurrent chemoradiation therapy on margin-negative resection in borderline resectable pancreatic cancer. J Gastrointest Surg. 2012;16(3):509–517. 

  56. Katz MH, Fleming JB, Bhosale P, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer. 2012;118(23):5749–5756. 

  57. Satoi S, Toyokawa H, Yanagimoto H, et al. Neoadjuvant chemoradiation therapy using S-1 followed by surgical resection in patients with pancreatic cancer. J Gastrointest Surg. 2012;16(4):784–792. 

  58. Sho M, Akahori T, Tanaka T, et al. Pathological and clinical impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer. J Hepatobiliary Pancreat Sci. 2013;20(2):197–205. 

  59. Dholakia AS, Hacker-Prietz A, Wild AT, et al. Resection of borderline resectable pancreatic cancer after neoadjuvant chemoradiation does not depend on improved radiographic appearance of tumor-vessel relationships. J Radiat Oncol. 2013;2(4):413–425. 

  60. Kim EJ, Ben-Josef E, Herman JM, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer. 2013;119(15):2692–2700.
  61. Takahashi H, Ohigashi H, Gotoh K, et al. Preoperative gemcitabine-based chemoradiation therapy for resectable and borderline resectable pancreatic cancer. Ann Surg. 2013;258(6):1040–1050.
  62. Van Buren G, 2nd, Ramanathan RK, Krasinskas AM, et al. Phase II study of induction fixed-dose rate gemcitabine and bevacizumab followed by 30 Gy radiotherapy as preoperative treatment for potentially resectable pancreatic adenocarcinoma. Ann Surg Oncol. 2013;20(12):3787–3793. 

  63. Eguchi H, Nagano H, Kobayashi S, et al. A phase I trial of combination therapy using gemcitabine and S-1 concurrent with full-dose radiation for resectable pancreatic cancer. Cancer Chemother Pharmacol. 2014;73(2):309–315.

Be the first to know when a new issue is online. Subscribe today.