Pancreatic adenocarcinoma (PDAC) comprises only 3% of all cancer diagnoses each year in the United States and yet accounts for nearly 8% of all cancer-related deaths due to its late symptom presentation and aggressive tumor biology.[1,2] At diagnosis, only 20% of patients have potentially resectable disease, while 40% have locally advanced tumors, and 40% have metastatic disease. For those with resectable disease, surgery remains the mainstay of treatment. However, resection alone is often not sufficient as studies of recurrence patterns demonstrate that approximately 50% to 60% of patients with PDAC will recur distantly, 20% to 25% will recur locally, and 15% to 20% of patients will recur both locally and distantly.[3–5] Isolated local recurrences most commonly arise within the perineurium of the autonomic nerves along the retroperitoneal margin of resection and are often challenging to treat. The frequent presentation at an advanced stage combined with this high rate of locoregional and distant recurrence result in a dismally low 5-year overall survival rate of 5% to 20% after resection, even with the use of adjuvant therapy.[6,7] Effective multimodal therapies are therefore urgently needed to systematically improve long-term outcomes in this disease, a feat that has not been accomplished in 25 years.
Radiation has been successfully integrated into the treatment armamentarium for other gastrointestinal malignancies with high risk of locoregional failure with the intention to reduce local recurrence rates and improve overall survival. In a neoadjuvant setting, the benefits conveyed by chemoradiotherapy have been proven most robustly for stage II or III rectal cancer based on the results of the German Rectal Cancer Study. This landmark trial demonstrated the superiority of preoperative vs postoperative chemoradiotherapy in terms of improved local control, increased rates of complete pathologic response, and greater chance of anal sphincter preservation at the time of surgery. Similarly, adjuvant chemoradiotherapy has demonstrated locoregional control benefits in gastroesophageal and rectal cancer trials, and these results have subsequently translated into improved overall survival.[9–11] Given these successes, radiation in both the neoadjuvant and adjuvant setting has been evaluated in PDAC and, unfortunately, studies have yielded mixed and inconclusive results.
Proponents of neoadjuvant chemoradiotherapy for PDAC favor this approach as it ensures delivery of therapy, may result in downstaging and conversion to resectable disease, facilitates a margin negative resection, and most importantly, allows for improved identification of patients that would not benefit from resection due to occult, micrometastatic disease that becomes evident during therapy.[12–15] In fact, in 2 recent trials of neoadjuvant therapy for patients with stages I and II PDAC, 30% of patients who began neoadjuvant therapy were not able to undergo resection as a result of disease progression, evolving medical comorbidities, or a decline in performance status.[16,17] These patients were therefore spared from a non-therapeutic pancreaticoduodenectomy or left-sided pancreatectomy despite the absence of systemic disease at the time of initial staging. However, critics of neoadjuvant chemoradiotherapy state that as conventional chemoradiotherapy is generally delivered over a period of 5.5 weeks followed by a 6-week treatment break, the systemic micrometastatic disease that is presumed to exist in all patients with PDAC may be suboptimally treated for nearly 3 to 4 months before resection. In the adjuvant setting, chemoradiotherapy is used to control microscopic local residual disease and further eradicate micrometastatic disease that is neither clinically nor radiographically apparent at the time of surgery and could result in local recurrence and distant metastases. The main challenge of adjuvant chemoradiation is delay or omission of treatment due to postoperative complications or reduced tolerance to chemotherapy.
In order to appropriately risk-stratify patients and select those who will most likely benefit from multimodal therapy with surgery, radiation and chemotherapy, careful staging is crucial particularly given the evidence that microscopic positive margins (R1) lead to median survival rates comparable to inoperable locally advanced pancreatic cancer. The most widely accepted definition of resectability was published by the Intergroup, a consortium of 3 cooperative clinical trial groups including the Alliance for Clinical Trials in Oncology, Southwest Oncology Group, and Eastern Cooperative Oncology Group and these guidelines have now been endorsed by the National Comprehensive Cancer Network (NCCN). According to the Intergroup definition, resectable PDAC is characterized by the absence of any vascular attachment, while borderline resectable PDAC includes distortion, narrowing or occlusion of the respective veins, a semicircumferential abutment (≤180°) of the superior mesenteric artery or an attachment at the hepatic artery without contact toward the celiac axis. The literature has demonstrated that these 2 categories have fundamental differences in outcomes as borderline resectable PDAC is associated with a much higher risk of positive resection margins, involves a more complex surgical resection procedure, and is associated with the presence of occult distant disease. Compared to patients with resectable PDAC, those with borderline resectable tumors are therefore more likely to benefit from a neoadjuvant treatment approach.[22,23] Unresectable PDAC is defined as a more extended involvement of the superior mesenteric artery, celiac axis, aorta, or inferior vena cava as well as a superior mesenteric vein or portal vein involvement without a possibility for surgical reconstruction (Table 1).
Radiation therapy for PDAC is currently delivered via 2 major modalities. External beam radiotherapy (EBRT) is delivered concurrently with chemosensitization, usually with 5-fluorouracil (5-FU) or gemcitabine. Although combining chemotherapy with radiation therapy can increase the risk of toxicity, chemoradiotherapy has been shown to be superior to EBRT alone at least in the setting of locally advanced PDAC. Administering concurrent chemotherapy also has the added potential benefit of eradicating micrometastatic disease. One major challenge with the use of EBRT in pancreatic cancer is the potential toxicity to adjacent structures such as the stomach, small bowel and kidneys which limit the dosage that can be delivered. Thus, the maximally tolerated doses using this technique are 45.0 to 50.4 Gy. Modern radiation delivery techniques, such as intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) permit dose escalation while minimizing the risk of radiation treatment-related toxicities. IMRT optimally assigns non-uniform intensities to tiny subdivisions of beams thus enabling custom design of the dose distribution and protecting critical surrounding organs. SBRT delivers 1 to 5 ablative doses of radiation to a small area only including gross disease with a tight margin. This radiation approach appears to be better tolerated than longer standard fractionation radiation treatment regimens, and is easily combined with other modalities by limiting delays in chemotherapy and time to surgery. Lastly, intraoperative radiation (IORT) is a technique that also allows for delivery of high doses of radiation therapy with minimal toxicity and has been associated with favorable oncologic and survival outocmes. All data regarding its use, however, are limited to retrospective studies and its role in the management of pancreatic cancer remains poorly defined. In resectable disease, IORT has proven beneficial for patients with positive microscopic margins on frozen section. For patients with locally advanced or unresectable disease, IORT may be used for pain relief and to improve local control.[30,31] This review aims to highlight the historical trials and studies that have defined the potential benefits for radiation in PDAC using the aforementioned radiation techniques.
Neoadjuvant radiation in resectable and borderline resectable pancreatic cancer
Level I evidence for the use of neoadjuvant chemoradiotherapy in patients with resectable or borderline resectable PDAC is lacking, as the majority of the attempted clinical trials in the past have failed to complete target recruitment.[32,33] As a result, the relevant literature concerning neoadjuvant chemoradiotherapy in these 2 categories is predominantly single-institution and focused on the safety and feasibility of neoadjuvant radiation therapy (Table 2). In addition, the lack of a historical standard definition characterizing resectable and borderline resectable PDAC has confounded outcomes and made results difficult to generalize to current clinical practice. The section below summarizes the most recent data regarding neoadjuvant chemoradiotherapy for PDAC.
The first large-scale study to address the role of neoadjuvant chemoradiotherapy was the 2018 surgeon-initiated Korean phase II/III multicenter randomized controlled trial in patients with borderline resectable PDAC. In this trial, 58 patients were randomized to gemcitabine-based neoadjuvant chemoradiotherapy with 54 Gy followed by surgery or upfront surgery followed by chemoradiotherapy with the same regimen with a primary end-point of 2-year survival. Importantly, pre-determined radiographic criteria were used to define eligibility, and each patient's scans were reviewed by dedicated radiologists before enrollment. Only 63% of patients who initiated neoadjuvant chemoradiotherapy underwent subsequent pancreatectomy, largely due metastatic disease progression. In the intention-to-treat analysis, the 2-year survival and median survival were significantly improved in the neoadjuvant chemoradiotherapy group compared to the upfront surgery group (40.7%, 21 months vs 26.1%, 12 months, P = .028). R0 resection rate was also higher in the neoadjuvant chemoradiotherapy group than upfront surgery (51.8% vs 26.1%, P = .004). Despite this difference in survival and R0 resection, there was no difference in recurrence patterns further highlighting the continued need for effective systemic therapies in this disease.
These results are consistent with those of the concurrent Dutch PREOPANC-1 trial, a multicenter phase III trial which randomized 246 patients with resectable or borderline resectable PDAC to either neoadjuvant chemoradiotherapy followed by surgery and adjuvant gemcitabine or upfront surgery followed by adjuvant gemcitabine with a primary endpoint of overall survival. Preliminary findings were presented at the 2018 American Society of Clinical Oncology Annual Meeting and demonstrated that neoadjuvant chemoradiotherapy achieved a median overall survival of 17.1 months compared with 13.5 months with upfront surgery and adjuvant chemotherapy in the intention-to-treat analysis (hazard ratio [HR] 0.74; P = .047). On subgroup analysis of patients who were able to undergo resection, the median overall survival in the neoadjuvant therapy arm was 29.9 months compared with 16.8 months for those who had upfront surgery, likely due to improved selection of surgical candidates. In addition, 89% of patients were able to complete neoadjuvant treatment and achieve a complete resection rate of 65% compared to only 31% in those who underwent upfront surgery. Although results are certainly compelling, the study design drew significant criticism due to its large effect size and use of gemcitabine as adjuvant chemotherapy given the findings of the Unicancer GI Prodige study in which adjuvant therapy with a modified FOLFIRINOX (mFOLFIRINOX) regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer.[57,59] We currently await final results from this trial once target recruitment is achieved. The Alliance for Clinical Trials in Oncology Trial A02150 sought to compare the efficacy of neoadjuvant mFOLFIRINOX alone and neoadjuvant mFOLFIRINOX combined with hypofractionated SBRT in patients with borderline resectable PDAC with a primary endpoint of 18-month overall survival, but unfortunately accrual to the radiation arm was suspended in 2018 secondary to reaching the futility boundary of margin positive resections.
Before these 2 large-scale trials, multiple single-center trials were conducted at MD Anderson Cancer Center (MDACC) from 1997 to 2002 on patients with resectable PDAC with infusional 5-FU and conventional fractionation as well as hypofractionation and paclitaxel-based chemoradiotherapy.[14,60,61] A major shortcoming of these studies is that results predominantly focused on the low toxicity profile of neoadjuvant chemoradiotherapy in order to demonstrate the feasibility of this treatment paradigm. These early trials along with some data demonstrating the superiority of gemcitabine as a chemosensitizing agent led to a subsequently performed phase II trial of neoadjuvant gemcitabine-based chemoradiotherapy which enrolled 86 patients of which 74% underwent pancreaticoduodenectomy with an 89% R0 resection rate. Median overall survival was 34 months for patients who underwent resection and 7 months for the unresected patients (P < .001).[16,62] A subsequent trial by the same group expanded on this initial treatment regimen using neoadjuvant combination chemotherapy with gemcitabine and cisplatin before chemoradiotherapy with gemcitabine in an attempt to reduce distant metastasis and improve overall survival. Ninety patients were enrolled and 88% completed neoadjuvant treatment with a resection rate of 66%. Median survival was 17.4 months for all patients, 31 months for those who underwent resection, and 10.5 months in those who did not undergo surgical resection. Based on the results of their prior study, the investigators concluded that the addition of induction cisplatin and gemcitabine chemotherapy before neoadjuvant chemoradiotherapy did not improve long-term outcomes. Subsequent trials have also predominantly used gemcitabine-based chemotherapy and included patients with resectable or borderline resectable PDAC (Table 2). In these studies, a high R0 resection rate and survival rate are reported. Despite these data, the efficacy of radiation in this setting remains unclear due to lack of comparative arms. Other neoadjuvant agents have also been investigated as demonstrated by the 2013 phase II trial by Van Buren et al in which 59 patients with resectable and borderline-resectable PDAC were treated with full-dose gemcitabine and bevacizumab, a vascular endothelial growth factor inhibitor, followed by hypofractionated radiation (30 Gy in 10 fractions) and concurrent bevacizumab. Similar to prior studies, 73% of patients underwent resection and R0 resection was achieved in 88%. Median overall survival was 16.8 months for all patients and 19.7 months for those undergoing resection.
In terms of retrospective studies, a recent analysis from MDACC of 483 patients demonstrated that neoadjuvant chemoradiotherapy is associated with better local control when compared to neoadjuvant chemotherapy, though significant differences in survival were not found. Conversely, a recent SEER study compared neoadjuvant radiation to surgery alone or surgery with adjuvant radiation. Results demonstrated a median overall survival of 23 months with neoadjuvant radiation, 12 months with surgery alone, and 17 months with surgery and adjuvant radiation. Again, a major limitation of both of these studies is selection bias as they only included patients with radiographic resectable and borderline resectable disease who underwent definitive surgery. Based on the data presented here, neoadjuvant chemoradiotherapy provides a rational alternative to a surgery-first approach for resectable and borderline resectable PDAC as it may facilitate a margin negative resection and help identify patients who would not derive a survival benefit from resection.
With accepted resectability definitions in future studies, the contribution of chemoradiotherapy in the neoadjuvant setting will become better defined. Future studies will need to compare neoadjuvant chemotherapy with or without radiation over adjuvant treatment in resectable and borderline resectable PDAC.
Adjuvant radiation in resectable and borderline resectable pancreatic cancer
The role of adjuvant radiation after pancreaticoduodenectomy is controversial. This is largely due to lack of consensus in historical trials regarding its benefit and non-standardization of adjuvant radiation regimens and comparison groups, with some studies comparing radiation to adjuvant chemotherapy and others to surgery alone. The first randomized trial to investigate adjuvant radiation was performed by the Gastrointestinal Tumor Study Group (GTSG), in which 43 patients were randomized to receive adjuvant infusional 5-FU with 2 courses of 20-Gy radiation or surgery alone. Patients who received adjuvant therapy had a 2-month median disease-free survival advantage (11 vs 9 months, P = .04) compared to those who underwent surgery alone, a difference which was only evident 1 year postoperatively. In contrast, no survival difference was reported between patients who received adjuvant chemoradiotherapy and those who received surgery alone in a randomized trial from the European Organization for Research and Treatment of Cancer. However, these results must be interpreted with caution, as 20% of patients randomized to receive adjuvant therapy did not receive it due to a combination of postoperative complications and patient refusal. Furthermore, only 55% of patients had PDAC, while the remainder had other periampullary tumors, though the different histologies were distributed equally between treatment groups. On subgroup analysis including only 104 patients with PDAC, median overall survival for patients who received adjuvant chemoradiotherapy was 17.1 months compared to 12.6 months in patients who received surgery alone, a result that trended toward significance (P = .099) indicating a possible survival benefit of adjuvant chemoradiotherapy. Similar to the GTSG study, patients received adjuvant infusional 5-FU and a total of 40 Gy of radiation in a split course.
The European Study for Pancreatic Cancer-1 Trial, was the first randomized trial to compare adjuvant chemotherapy alone with adjuvant chemoradiotherapy, randomizing 289 patients from 11 countries into 4 groups: adjuvant chemotherapy (bolus intravenous leucovorin and 5-FU), adjuvant chemoradiotherapy (40-Gy radiation and bolus intravenous 5-FU), a combination of adjuvant chemotherapy and chemoradiotherapy, and surgery alone. There was no survival benefit reported in patients who received adjuvant chemoradiotherapy compared to those who did not, regardless of whether they did or did not receive adjuvant chemotherapy, while patients who received adjuvant chemotherapy did receive a survival benefit compared to those who did not, regardless of whether they did or did not receive adjuvant chemoradiotherapy. Median overall survival for patients who received surgery alone was 16.9 months, 13.9 months for patients who received adjuvant chemoradiotherapy, 21.6 months for patients who received adjuvant chemotherapy, and 14.2 months for patients who received both adjuvant chemotherapy and chemoradiotherapy, however the study was underpowered to directly compare these groups. The authors concluded that adjuvant chemotherapy provided a survival benefit for patients with resectable PDAC, while chemoradiotherapy not only fails to provide a benefit but reduces survival when given before adjuvant chemotherapy, presumably because of the delay in chemotherapy initiation. The results of this study were used to justify a shift toward using adjuvant chemotherapy alone; however, the interpretation and application of the results is complicated by selection bias (surgeons were allowed to choose the randomization), protocol violations (70% of patients assigned to chemoradiotherapy and 50% assigned to chemotherapy alone received it as specified in the protocol), and the use of a now historical chemotherapy regimen.
Historical study results have also been questioned due to utilization of suboptimal split course radiation dosing and archaic radiation techniques. In contrast, more recent studies have shown that modern treatment courses of adjuvant chemoradiotherapy are associated with acceptable toxicity and increased effectiveness.[68,69] In a retrospective review conducted by Johns Hopkins Hospital and Mayo Clinic, 2 high volume centers, patients who received adjuvant chemoradiotherapy, consisting of 50.4-Gy external beam radiation given in 1.8 Gy daily fractions with infusional 5-FU, were compared with those who received surgery alone. In propensity matched analysis, adjuvant chemoradiotherapy was associated with improved overall survival (21.9 vs 14.3 months, P < .001) and this association persisted amongst all subset analyses, including stratification by age, T-stage, and nodal and margin status. Data investigating outcomes with use of advanced radiation techniques, including SBRT, IMRT, and proton therapy, are thus far limited to retrospective series, however these results have been promising regarding toxicity and local control. Yovino et al analyzed 71 patients who received adjuvant chemoradiotherapy (IMRT to a median dose of 50.4 Gy and 5-FU or gemcitabine based chemotherapy) and found that only 19% of patients experienced local recurrence, 8% reported grade 3/4 nausea and vomiting, and the post treatment course for 6% was complicated by small bowel obstruction. Nichols et al[72,73] found that proton therapy reduced radiation exposure to the small bowel and stomach compared to IMRT and led to extremely low levels of gastrointestinal toxicity (0/22 patients). Finally, SBRT has also been found to have low rates of gastrointestinal toxicity. Rwigema et al evaluated 24 patients who received adjuvant SBRT following resection for PDAC; no patients experienced a grade 3 or 4 gastrointestinal toxicity, and only 5 patients had a grade 1 or 2 toxicity.
The Radiation Therapy Oncology Group (RTOG) is evaluating patient outcomes, including overall and disease-free survival, and toxicity profiles associated with adjuvant gemcitabine-based chemotherapy compared to adjuvant chemoradiotherapy using either IMRT or 3D conformal radiotherapy with capecitabine or 5-FU, in an ongoing randomized clinical trial, RTOG 0848 (NCT01013649), estimated to be completed in late 2020. We eagerly await the results of this trial, which hopes to clarify the role of adjuvant chemoradiotherapy for patients with resected PDAC.
Role of radiation in locally advanced pancreatic cancer
The current role of radiation in locally advanced pancreatic cancer is 2-fold: therapeutic and palliative. In patients with a poor performance status or whose comorbidities obviate the ability to tolerate combined chemoradiotherapy, radiation may be used as a single modality in the palliative setting for pain control.[20,76] Initial randomized trials reported contradictory results regarding the benefit of chemoradiation in combination with chemotherapy compared to chemotherapy alone.[77,78] Thus, the role of chemoradiation in locally advanced pancreatic cancer remained, and to some degree continues to remain, controversial. Currently, for patients with good performance status, chemotherapy remains first-line treatment for locally advanced PDAC, largely to identify patients with occult metastatic disease in whom a time-intensive local treatment associated with adverse events would be inappropriate.[76,79] This treatment strategy was first shown to be associated with improvements in survival by Krishnan et al who retrospectively analyzed patients who received chemoradiation alone and those who received induction chemotherapy followed by consolidation chemoradiotherapy. They found induction chemotherapy to be associated with decreased risk of death and disease progression on both univariate and multivariable analysis [overall survival: HR 0.53, 95% confidence interval (CI) 0.38–0.71, P < .001; progression-free survival: HR 0.60, 95% CI 0.45–0.78, P < .001], with a median overall survival difference of 3.4 months (induction chemotherapy: 11.9 months vs chemoradiation alone: 8.5 months, P < .001).
The paradigm of induction chemotherapy followed by chemoradiation was subsequently implemented by the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) that treated patients with 3 months of induction chemotherapy and determined eligibility for chemoradiation based on the presence or absence of local or metastatic disease progression during this time. Randomization was not performed; the investigator made the decision to administer chemoradiation or to continue chemotherapy alone for each patient. Among 128 patients, 56% received chemoradiation and 44% continued chemotherapy alone. Patients who received chemoradiation were found to have longer progression-free and overall survival (10.8 vs 7.4 months, P = .005 and 15.0 vs 11.7 months, P = .009, respectively) compared to those who received chemotherapy alone. While there is obvious risk of selection bias due to lack of randomization, patients were well matched in terms of age, gender, performance status, response to chemotherapy, performance status changes after induction chemotherapy, and weight loss during chemotherapy. To validate these results, GERCOR conducted an international randomized trial, LAP07, in which 269 patients without progression after 4 months of gemcitabine based induction chemotherapy were randomized to continue chemotherapy or to receive chemoradiotherapy. There was no significant difference in overall survival between the 2 groups (chemotherapy: 16.5 months vs chemoradiotherapy: 15.9 months, P = .83), though chemoradiotherapy was associated with decreased rates of local progression (32% vs 46%, P = .003).
Efforts to determine the optimal treatment for patients with locally advanced pancreatic cancer remain ongoing, including investigation of novel radiation modalities, such as SBRT. Current guidelines from the NCCN recommend chemotherapy alone or induction chemotherapy followed by chemoradiotherapy for patients with good performance status, or chemoradiotherapy or SBRT for patients who are not candidates for combination chemotherapy. Palliative radiation is recommended for patients with poor performance status. Active clinical trials investigating the role of radiation in patients with locally advanced PDAC are presented in Table 3 .
Given its aggressive nature, delayed symptom presentation, and high rate of recurrence, pancreatic cancer requires multidisciplinary care and a full armamentarium of treatment strategies. Though the optimal role of radiation for pancreatic cancer in the neoadjuvant, adjuvant, and locally advanced settings is unknown, great strides have been made in the past 3 decades, in our understanding of the disease, refining treatment paradigms, and in radiation techniques and technology. As novel radiation techniques and systemic treatment regimens continue to evolve, new studies will be needed to define the role of radiation in improving outcomes while limiting toxicity for patients with pancreatic ductal adenocarcinoma.
Supported in part by the Katz Foundation.
Conflicts of interest
The authors declare no conflicts of interest.
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