Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: Beyond the Abstract

Pancreatic cancer is the fourth most common cause of cancer-related death in the United States, with the American Cancer Society estimating approximately 53,670 new cases and 43,090 deaths in 2017 [1]. The preferred treatment for patients with resectable pancreatic adenocarcinoma is complete surgical resection with curative intent. However, due to the unavailability of regular screening modalities for this malignancy, many patients with pancreatic adenocarcinoma present late in the course of the disease, often with locally advanced or metastatic disease. The standard of care for patients with widely metastatic disease is chemotherapy [2,3]. However, the treatment guidelines for locally advanced, non-metastatic disease vary. 

Based on the American College of Radiology (ACR) Appropriateness Criteria for borderline and unresectable pancreatic cancer, the treatment of choice for locally advanced pancreatic adenocarcinoma has historically been chemotherapy +/-chemoradiotherapy (CRT).  CRT is commonly reserved for those who do not develop metastatic disease, as CRT has been shown to improve local control in the locally advanced setting [3]. Systemic therapy has been established as an important part of management, as treatment failure in pancreatic cancer is often attributed to distant sites of failure [4]. Current National Cancer Comprehensive Network (NCCN) guidelines recommend CRT following a course of systemic therapy for patients who do not progress [5]. The role of local therapy has been shown to decrease the rate of local progression for a subset of patients with intact expression of the tumor suppressor SMAD4 [6]. A prospective phase II trial studying SMAD4 expression in patients with locally advanced pancreatic adenocarcinoma found that SMAD4+ patients had a local dominant pattern of progression, whereas SMAD4- patients had a distant dominant pattern of progression [7]. Future studies may aim to further elucidate the mechanism underlying these distinct patterns of progression in locally advanced disease as well as develop treatment strategies tailored to progression pattern.

In terms of the potential survival benefit that may be conferred with the use of RT, while data from randomized trials performed by the Eastern Cooperative Oncology Group (ECOG) and Gastrointestinal Tumor Study Group (GITSG) demonstrated a survival benefit from the addition of radiotherapy (RT) to chemotherapy [3,8,9], other studies have demonstrated no survival benefit from the addition of RT [10]. The recently published LAP07 phase III multicenter trial studied 269 patients with locally advanced disease randomized between CRT and chemotherapy alone and found that, while the addition of RT did not confer an overall survival benefit, patients receiving CRT had significantly less local tumor progression and a significantly longer median time without treatment as compared to chemotherapy alone (34% vs 65%, p<0.0001). [11]. Furthermore, even in the absence of an established survival benefit with the addition of RT, CRT allows for better pain management. Local progression may often lead to pain secondary to tumor invasion of the celiac and mesenteric plexi that may be difficult to manage with pain control strategies such as opioids and anesthetic blocks [12]. Such pain may be often be relieved by the addition of RT to systemic therapy, as was demonstrated in a feasibility study delivering high-dose conformal RT to patients with locally advanced disease [13]. 

Gemcitabine is a chemotherapeutic agent commonly employed in CRT for pancreatic adenocarcinoma because it is a known potent radiosensitizer [4,14]. Early trials exploring the safety and efficacy of gemcitabine with concurrent full-dose RT found unacceptable toxicity requiring a reduction in the dose of gemcitabine, which thereby reduced the efficacy of systemic therapy [14]. Recently, phase II trials published by Small et al. in 2008 and 2010 demonstrated the safety and efficacy of full-dose gemcitabine with concurrent attenuated 3D conformal RT (3D-CRT), both with and without the use of the anti-vascular endothelial growth factor antibody (VEGF) bevacizumab [4,14]. On the other hand, various trials have also demonstrated that the addition of 5-fluorouracil (5-FU) to RT conveys an overall survival benefit [8,15]. The current NCCN guidelines recommend either hypofractionated RT with concurrent gemcitabine or standard fractionation RT with concurrent 5-FU [5]. Therefore, as both of these CRT regimens have been commonly used, Rakhra et al. decided to compare these two treatment regimens’ overall survival (OS), distant metastasis free survival (DMFS), and toxicity profiles in patients with locally advanced, non-metastatic pancreatic cancer [16].  

While traditional RT has consisted of five to six weeks of fractionation with concurrent 5-FU or gemcitabine, the results published by Rakhra et al. support the hypofractionated regimen as the preferred approach for patient management. The study showed that treatment with hypofractionated RT using 3D-CRT with full-dose gemcitabine had OS rates of 52% and 14% at 1 and 2 years, respectively, as compared to rates of 36% and 6%, respectively, for patients receiving standard fractionation RT with 5-FU (p=0.02). The RT/gemcitabine group yielded significantly greater DMFS rates as well. Not only did the hypofractionated regimen demonstrate better OS, the shorter treatment course is more pragmatic from a patient care standpoint. There has been a shift in oncology care to hypofractionated regimens in the treatment of non-gastrointestinal malignancies as well, with hypofractionation being utilized in lung, prostate and breast cancer [17].

In terms of toxicity, Rakhra et al. found no significant difference in the cumulative incidence of acute toxicities (<90 days from start of radiation) or late toxicities (>90 days from start of radiation) for both grades 1-2 GI toxicities and grades 3-4 GI toxicities [16]. Though not significant, the RT/gemcitabine group demonstrated better late toxicities overall as compared to the RT/5-FU group – the cumulative incidence of grade 3-4 late GI toxicity was 19% in the RT-5 FU group and 12% for the RT/gemcitabine group. Additionally, other studies have demonstrated that there is possibly a better toxicity profile associated with hypofractionation. A report by Elhammali et al. assessing late gastrointestinal tissue effects after hypofractionated RT of the pancreas compiled the toxicity data from 16 studies examining a total of 1,160 patients and found that the median late grade 3-4 GI toxicity rate among all studies was 7.4% [18]. The improved efficacy and reduced toxicity of hypofractionated regimens calls into question the traditional radiobiological assumptions made in the treatment of pancreatic cancer. It is possible that the tumor maybe more responsive to larger fractions while minimizing associated toxicity. 

Overall, in addition to providing evidence for better outcomes with hypofractionation as compared to standard fractionation RT, this study conducted by multiple major centers underscores the concept established by Small et al. that a shortened course of RT allowed for the delivery of full-dose gemcitabine, which provides significant systemic treatment [4]. This trial also provides evidence that the requisite radiation treatment field need only encompass the gross tumor [19]. Treating elective nodal regions, as was done in the RT/5-FU group, does not appear to confer additional benefit in the treatment of locally advanced pancreatic adenocarcinoma. All patients included in the study by Rakhra et al. were treated prior to the emergence of more active systemic chemotherapy regimens such as FOLFIRINOX (5-FU, oxaliplatin, irinotecan) and gemcitabine/nab-paclitaxel. However, even in the era of more active systemic therapy, patients with locally advanced disease are at risk of local progression leading to symptoms that are often difficult to manage. The approach outlined by Rakhra et al. can be sequenced with more active systemic chemotherapy regimens to achieve better control of the primary tumor site for those patients who do not rapidly progress on systemic therapy [20, 21]. Alas, it is important to note that the hypofractionated RT schedule limits the time off of these preferred chemotherapy regimens. 

Written by: Amishi Bajaj, BA*, Asha Dhanarajan, MD**, Sam G. Pappas, MD+, Dr. Tarita O. Thomas, MD, PhD, MBA*, William Small, Jr., MD, FACRO, FACR, FASTRO*

*Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL, USA
**Division of Hematology/Oncology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA
+Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA

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