Redefining the role of radiation therapy in pancreatic cancer management: innovations and future directions: A narrative review
Article information
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a major health issue worldwide. Recent advances in systemic treatment are expected to break away from the long period of stagnation and improve treatment outcomes for this disease. Radiation therapy (RT), one of the main treatments used in the field of oncology, has not shown clear clinical benefits. Development in RT techniques such as the adaptation of computed tomography in RT planning, the use of motion control, image guidance, and particle beams have enabled high-precision, high-dose radiation delivery to tumors without increasing the risk of RT toxicity. With the application of these technical advancements, it is possible to shorten the conventional RT period from approximately 4 to 6 weeks to less than a week. The shortened duration of RT minimizes the impact of systemic treatment interruption on PDAC management and raises expectations of clinical benefits from the use of RT in various clinical situations. In this review, we discuss innovations in RT and future directions for its role in the management of PDAC.
INTRODUCTION
Pancreatic cancer, despite ranking 12th in global incidence (511,000 cases, 2022 data), exhibits a higher incidence rate in Korea, placing it as the 8th most common cancer there (8,872 cases, 2021 data) [1,2]. It ranks, however, 6th globally (467,000 deaths, responsible for approximately 5% of all cancer deaths, 2022 data) and 5th in Korea (6,932 deaths, 2021 data) in terms of mortality rate in the same year [1,2]. In patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of pancreatic cancers, the median age at diagnosis is approximately 70 years [3,4]. Its morality rate is up to four times higher in countries with a very high or high Human Development Index (HDI) than in those with a medium or lower HDI [1,5]. According to the European Union data, there was an estimated 7% reduction in total cancer mortality rates in men and 5% in women between 2015 and 2021; there was no major decline in the pancreatic cancer mortality rate [6]. Furthermore, pancreatic cancer is estimated to surpass other types of cancer, except lung cancer, and become the leading cause of cancer-related deaths by 2030 in the United States [7].
These dismal outcomes of PDAC are primarily related to the fact that it is often diagnosed as advanced and unresectable due to its anatomical characteristics despite the introduction of an active screening program [8], and even in patients who have undergone surgery, aggressive recurrences, generally defined as occurring within 12 months after resection, occur in nearly half of the patients [9]. According to data available from Korea and Surveillance, Epidemiology, and End Results Program (SEER) staging, only 11.9% males and 14.0% females had localized PDAC at the time of diagnosis, 31.3% males and 30.9% females had regional, while 47.2% males and 42.6% females had metastatic disease in 2021 [10]. The 5-year overall survival (OS) rates for males and females with localized, regional, and metastatic PDAC are 46.6% and 47.9%, 20.6% and 21.4%, and 2.7% and 2.4%, respectively; these rates are poorer than those observed for other cancer types [2].
Recently, however, slightly but definite improvements in the treatment outcomes of PDAC have been reported with the progress in understanding the biological characteristics of tumors, development and introduction of imaging techniques and early screening systems, and advancements in surgery and systemic treatments [11]. Neoadjuvant treatment (NAT), particularly for borderline resectable (BR) PDAC [12-14] and efforts to distinguish high-risk biological groups from the low-risk biological groups are helping in the introduction of patient-specific customized treatment, even for anatomically resectable PDAC [15].
The role of radiation therapy (RT) in PDAC has been viewed with skepticism by many researchers and clinicians, and its use has been limited to the management of PDAC [3,4]. PDAC is anatomically adjacent to normal organs and can cause serious side effects from RT in the stomach, duodenum, small intestine, liver, kidneys, and spinal cord. Presently, oncologists face challenges while determining the radiation dose for treatment as high-dose RT is often considered necessary for control of radioresistant adenocarcinoma; however, it affects the surrounding radiosensitive normal organs [16]. To date, several prospective clinical trials have failed to confirm the efficacy and safety of RT for PDAC management [17]. However, with the remarkable advancement of RT and other imaging and treatment technologies, the application and effectiveness of RT in the treatment of PDAC is expected to increase [16].
This review summarizes the basis and evaluation of the role of RT in the treatment of PDAC to date, the status of RT in current PDAC treatment, and discusses future application strategies and necessary research regarding the disease extent and/or biological aggressiveness and technical advancement of RT.
ANATOMICAL AND BIOLOGICAL RESECTABILITY OF PDAC
In nonmetastatic localized tumors for which surgical resection is generally considered a priority, resectability stratification based on the criteria of radiologic characteristics in PDAC was first described by Mehta et al. [18] in 2001. Resectability was classified according to differences in postoperative mortality and/or severe morbidity while achieving margin-negative complete resection, which is one of the most important goals of oncological surgery [19,20]. Simultaneously, the theoretical basis for applying customized treatment, including NAT according to the status of resectability, is presented, followed by differences in the clinical results regarding the usefulness of the application.
Currently, one of the most widely used surgical resectability classifications using radiological criteria for PDAC is the classification according to the United States National Comprehensive Cancer Network (NCCN) guidelines [21]. According to these guidelines, tumors are classified according to the extent of the primary tumor and its relationship with the superior mesenteric artery (SMA), celiac axis, common hepatic artery (CHA), and variant arterial anatomy evaluated on contrast-enhanced computed tomography (CT) or magnetic resonance (MR) images at diagnosis, in consensus with multidisciplinary meetings/discussions. Among these criteria, BR (anatomical BR [BR-A]), which is currently the most clinically important, is defined as “solid tumor contact with CHA without extension to celiac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction, solid tumor contact with the SMA of ≤ 180°, solid tumor contact with variant arterial anatomy, and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning” for pancreatic head cancer, and “solid tumor contact with the celiac axis of ≤ 180°” in pancreatic body or tail cancer.
In addition, based on the early and aggressive recurrence after surgical resection of PDAC even in resectable case at diagnosis, and the improvement in treatment outcomes through the application of NAT for BR-A, the need for a more precise resectability classification system reflecting biological aggressiveness resectability has been raised. Through the international consensus based on the literature review, biological factors include clinical findings suspicious but not confirmed for distant metastases or regional lymph node (LN) metastases diagnosed by biopsy or positron emission tomography-CT, and a serum carbohydrate antigen 19-9 (CA19-9) level of more than 500 units/mL added as biological BR status (BR-B, BR-AB) [15]. Many studies, including randomized controlled trials (RCTs) to date, however, have presented evidence based on the resectability according to anatomical criteria without considering tumor biology. Therefore, direct application of the existing evidence in the management of BR to BR-B, where is limited information on prognosis and appropriate treatment, is challenging. Post hoc analyses of previously presented prospective trials, including RCTs and/or many other prospective/retrospective studies reflecting this patient group, are needed [22].
Recently, even in cases in which hematogenous metastases are considered systemic diseases, conversion to widespread metastasis has been prevented in some cases after appropriate resection and/or local ablative treatment (LAT) for several gross tumors, usually defined as five or fewer tumors [23]. As the number of cases in which micrometastatic tumors can be effectively controlled increases because of the rapid advancement of systemic treatments, especially targeted agents and immune check point inhibitors, interest in these tumor conditions so called “oligometastatic disease (OMD)” is further increasing. Studies have reported that this OMD condition may also exist in PDAC, and favorable clinical outcomes even in this dismal disease can be obtained through aggressive resection or LAT [24], this aspect should also be considered in the resectability classification of PDAC in the near future.
A schematic illustration of the different surgical resectability stages of PDAC that includes factors for biological aggressiveness and metastasis, in addition to the current standard anatomical criteria, is presented in Fig. 1.
Schematic illustrations of anatomical and biological resectability of pancreatic duct adenocarcinoma (PDAC). The resectability of PDAC is categorized into a spectrum. The categorization is based on anatomical factors (presence or absence of invasion into major surrounding arteries and veins) and biological factors (the degree of aggressiveness and extent of metastasis of the tumor). CA19-9, carbohydrate antigen 19-9; LN, lymph node.
HISTORICAL OVERVIEW OF RT FOR PDAC
Although surgical resection, including distal pancreatectomy and pancratoduodenectomy began to be successfully applied and became the mainstay of PDAC management, but treatment failure was common in the form of local recurrence in more than half of patients and distant metastasis in 30% to 40% of patients who underwent surgical resection [25,26]. Based on the high proportion of treatment failure and recurrence patterns of both frequent local recurrence and distant metastasis, RCTs on postoperative adjuvant treatment, including concurrent chemoradiotherapy (CRT) and chemotherapy, were mainly conducted in the 1980s and the 1990s.
The RCT conducted by the Gastrointestinal Tumor Study Group (GITSG) was terminated early owing to poor accrual; however, adjuvant CRT showed superior disease-free survival (DFS) and OS compared with surgery alone [27]. Additionally, RCT conducted by the European Organization for Research and Treatment of Cancer (EORTC) gastrointestinal tract cancer cooperative group, including PDAC and periampullary cancer, failed to confirm an overall significant oncological benefit of adjuvant CRT compared to surgery alone [28]. However, in the PDAC subgroup, the survival rate tended to be higher in the group that received adjuvant CRT, although this difference was not statistically significant. The European Study Group for Pancreatic Cancer 1 (ESPAC-1) trial attempted to simultaneously confirm the effects of adjuvant CRT and adjuvant chemotherapy through a two-by-two factorial design and reported that adjuvant CRT was associated with detrimental treatment outcomes [29]. Additionally, in the randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study, although adjuvant CRT was not associated with worse clinical outcomes than adjuvant chemotherapy, it failed to show superior clinical outcomes [30]. Based on the results of these RCTs, adjuvant CRT is not routinely recommended for completely resected PDAC. However, frequent local recurrence in more than half of patients, even after adjuvant chemotherapy after curative resection, standard treatment, and promising clinical outcomes from recent retrospective studies using cutting-edge RT techniques, rather than the unusual RT treatment method used in previous studies, require further research on effective treatments to enhance local control and survival outcomes [31]. In addition, the recent trend in PDAC management, including RT, is moving in the direction of NAT rather than adjuvant treatment in combination with surgical resection.
Another main axis of RT application in PDAC management is local control in unresectable, locally advanced (LA) cases [32]. In patients with LA PDAC whose metastasis was uncertain at the time of diagnosis, several prospective and/or RCT trials comparing RT alone or CRT with systemic treatment have been conducted with largely unsatisfactory results, with a median OS of approximately 10 months [16]. The RT technique used in the aforementioned studies has major limitations [33], such as the use of a split course that is no longer used without proper planned response evaluation, the inability to evaluate appropriate dose distribution, and a nonconformal technique that inevitably exposes more radiation to surrounding normal organs because planning CT is not used. Nevertheless, aggressive LAT, including RT, is difficult to recommend in routine clinical practice considering the aggressive biological characteristics of PDAC, including its widespread metastatic failure pattern. Potent multi-agent systemic therapy is preferentially recommended for advanced PDAC [21,34,35], and the importance of effective local control of the primary lesion continues to increase, with effective suppression of distant micrometastases in some patients [36]. In this subset of patients, favorable clinical outcomes can be expected by resolving primary tumor progression, and RT is being attempted as a neoadjuvant, definitive, or salvage approach with mainly hypofractionated, higher-dose with high-precision based on image guidance and respiration control.
RECENT TECHNICAL INNOVATIONS OF RT
Recent advancements in the field of RT have made it possible to safely and reliably deliver high-dose radiation to PDAC, overcoming previous concerns about the radiosensitive surrounding normal organs and achieving favorable local control. Moreover, many studies have demonstrated that utilizing these advanced RT techniques to safely increase radiation doses can improve OS as well as local control in PDAC [36-42]. Current and future radiotherapy techniques for PDAC as follows.
TECHNICAL DEVELOPMENT FOR CONFORMAL DOSE DELIVERY
Using three-dimensional (3D)-CRT, dose-volume histogram (DVH) of tumors and normal organs can be obtained, and the possibility of targeted local tumor control (tumor control probability) and toxicities of surrounding normal organs (normal tissue complication probability) can be predicted. Thus, 3D-CRT can increase the radiation dose while minimizing adverse events. Almost all RT techniques introduced in this article are based on planning CT and conduct a process of selecting the optimal RT plan through multiple trials and errors based on dose distribution and DVH.
Intensity-modulated radiation therapy (IMRT) uses beams in various directions based on CT planning, such as 3D-CRT. It is an optimized RT delivery technology that can accurately and precisely deliver radiation to tumors, with minimal radiation exposure to the surrounding normal organs [43]. While 3D-CRT finds the optimal dose distribution through trial and error by the person in charge of treatment planning, IMRT finds the optimal dose distribution with the minimum radiation dose to the surrounding normal organs through computer-based inverse treatment planning, and the radiation dose required for the tumor is delivered voxel-by-voxel like a mosaic using a multi-leaf collimator. The superiority of IMRT over 3D-CRT in PDAC has not yet been clearly confirmed in a prospective manner; however, dosimetric studies and acute toxicities have suggested that IMRT can be superior, at least when adjacent to important organs such as the gastrointestinal tract In particular, IMRT is possible to apply the simultaneous integrated boost (SIB) or simultaneous integrated protection (SIP) technique that differentiates the radiation dose to enhance local control or reduce radiation toxicities in high-risk areas, including extensive primary tumors or gastrointestinal toxicities, such as the duodenum, stomach, and/or liver [44]. Recently, trials using the SIP technique to increase the RT dose to the primary tumor without increasing gastroduodenal toxicities showed favorable and promising clinical outcomes for PDAC [45].
Stereotactic ablative radiation therapy (SABR), also known as stereotactic body RT, is a recently highlighted technique that uses a limited number of fractions, typically one to five, with a relatively higher single dose than that of conventional RT [46]. SABR is increasingly used as a valid alternative LAT method in various oncologic fields, like unresectable small primary and/or metastatic tumor in lung, liver, LN and/or other body part [47]. Despite the biological advantages of conventionally fractionated RT, the application of SABR is increasing due to improvements in precision and accuracy, and long-term side effects are not expected to increase or decrease [48]. SABR is even more spotlighted in the management of BR or LA PDAC, where systemic therapy is crucial, because it can be combined noninvasively in a short period of time with minimal effect on the use of systemic treatment [34].
RT TECHNIQUES SUPPORTING PRECISE AND RELIABLE DELIVERY (IMAGE-GUIDED RT, RESPIRATORY MOTION-CONTROLLED RT, ADAPTIVE RT)
While recent RT has enabled treatment dose distribution to be obtained with sub-millimeter precision, inappropriate radiation delivery situations may occur owing to changes in the positions or shapes of the tumor and normal organs daily according to the changes in body shape and/or the tumor itself during the treatment period. Even during the session, radiation is delivered according to respiratory and/or bowel motion [49]. The most recent common RT devices can be used for IMRT techniques, namely the linear accelerator (LINAC), which is equipped with an image guidance system that can identify tumor and normal organ locations through fluoroscopy images and cone beam or fan beam CT images immediately before or during treatment in the treatment room.
In PDAC, however, it is not easy to distinguish the tumor from the surrounding soft tissue of similar density and/or artifacts caused by bowel gas; therefore, additional attempts are being made to insert fiducial markers around the tumor that can reflect its location and movement. Furthermore, MR image-guided radiation therapy (IGRT) techniques have been introduced to enable more precise image-guided treatment by clearly distinguishing between tumors and normal organs in abdominal and pelvic tumors that are difficult to distinguish from the surrounding normal soft tissue [50], and are becoming increasingly used in the treatment of PDAC. Additionally, high-precision image guidance is advancing to enable adaptive radiation therapy (ART), one of the main parts of personalized RT, which appropriately changes RT strategies and treatment plans according to the RT response [51].
The thorax and abdomen are areas where movements related with respiration produce a phase difference of up to 5 cm or even more [52]. Respiration motion-controlled RT technique is designed to correct and adapt to the respiratory movements of the pancreas, tumor, and surrounding normal organs, thereby reducing radiation exposure to the surrounding normal organs. These techniques focus the radiation on the tumor and are provided in most current RT devices or are being developed to further improve precision. These methods involve acquiring planning CT images by reflecting the respiration cycle, holding breath at a specific cycle, delivering radiation by reflecting the change in tumor position according to the respiration cycle, or delivering radiation only at a specific cycle [53].
With the introduction and application of high-quality image guidance technology, including MR, it has become possible to identify changes in tumors and normal organs that may occur when radiation doses are delivered differently from the initial plan, even before or during radiation delivery. ART refers to the continuous adjustment of treatment plans according to changes in tumors and/or normal organs (changes in the location or shape of surrounding organs due to tumor improvement, volume changes due to weight loss, etc.) based on images acquired during the treatment period [51]. In PDAC, where there may be changes in the positions of tumors and normal organs depending on the intestinal contents or location as well as changes in position due to breathing, technology is being developed to modify the treatment plan within tens of minutes to reflect changes immediately before treatment. In this regard, MR guided RT devices clearly distinguish between tumors and normal soft tissues, and are expected to show notable results in the treatment of PDAC using daily ART planning (Fig. 2).
An example of magnetic resonance (MR) guided radiation therapy (RT) for pancreatic duct adenocarcinoma. (A) Initial RT plan in MR guided RT. (B) Adaptive RT planning considering the change of stomach shape. MR imaging provides a much higher ability to distinguish tumors and surrounding soft tissues than computed tomography, and based on this, it enables pre-treatment precise image-guided RT, real-time tumor location tracking, and adaptive RT reflects changes in the shape, size, and location of the tumor during inter- and intra-fractionation.
Personalized ultrafractionated stereotactic ART (PULSAR), a completely new dose scheme ablative RT technique distinct from SABR, which was previously conducted once every day or twice, is a plan to adjust the proceeding of RT, or ART plan by reflecting each patient’s RT response and tumor status through a period of several weeks or more to allow for potentially significant changes in the tumor after a single irradiation [54]. Through this completely different RT method, research is needed to improve treatment outcomes through effective local control in PDAC where systemic treatment is the mainstay. Considering the anatomy and intrafractional motion of PDAC, however, PULSAR may be applied preferentially in MR guidance [51], or by actively utilizing SIP techniques with advanced volumetric IGRT.
PARTICLE-BEAM RT
Recently, interest in particle-beam RT, including protons and heavy particles, has been growing, especially for gastrointestinal tumors, including PDAC [55-58]. The physical advantages of particle-beam RT were first reported in 1940. The introduction and application of particle-beam RT in the clinical setting, however, is largely restricted due to technical and cost limitations, and the construction and clinical purposes of proton and carbon ion beam therapy centers have begun to increase rapidly worldwide since the early 2000s [57]. Particle beam, usually proton or carbon ion has unique dose deposition at specific depth according to the its’ energy, called “Bragg peak” is the most important cause of the preference of particle beam in cancer treatment. Owing to the superiority of particle-beam RT in terms of reducing the surrounding normal tissue dose while delivering similar or even higher tumor doses, it is increasingly used in oncology. Based on these theoretical advantages, actually, reported results show that the application of proton beam or carbon ion in LA PDAC has achieved noteworthy outcomes, with median OS of approximately 20 to 30 months [58-62]. In addition, based on its excellent physical advantages, it may be considered a good alternative to surgery for some tumors, including OMD, in the near future.
An example comparing the dose distribution and DVH of 3D-CRT, IMRT and proton beam therapy plans in the definitive aim of PDAC is illustrated in Fig. 3.
An example comparing the dose distribution and dose-volume histogram (DVH) of (A) three-dimensional conformal radiation therapy (3D-CRT), (B) intensity-modulated radiation therapy (IMRT), and (C) proton beam therapy (PBT) plans in the definitive aim treatment of pancreatic duct adenocarcinoma. (D) Compared to 3D-CRT, IMRT shows a more appropriate dose distribution for high-risk areas (planning target volume [PTV]), and reduces the radiation dose exposed to surrounding normal organs. PBT can significantly reduce the moderate to low dose radiation exposure to normal organs, even in situations where higher doses are delivered compared to IMRT and 3D-CRT.
FUTURE DIRECTION FOR OPTIMAL RT INTEGRATION STRATEGIES FOR PDAC
As mentioned earlier, based on advanced RT techniques and their already established role in the oncology field, RT is being used in various situations in clinical settings for PDAC despite the lack of solid evidence limited to PDAC itself. Fig. 4 shows a schematic of the current standard of care for PDAC according to the disease extent and the areas where RT can be effectively combined in the management of PDAC based on future clinical research, which will be presented in the next paragraph.
Schematic illustration of current standard of care and potential radiation therapy (RT) combination in management. With the advancement of various medical technologies, systemic therapies, and RT techniques, the possibility of RT application and improving clinical outcomes of pancreatic duct adenocarcinoma in various clinical situations has been raised, and this should be confirmed through future researches. BR-A, anatomical borderline resectable; BR-B/AB, biological borderline resectable status; LA, locally advanced; CRT, concurrent chemoradiotherapy; SABR, stereotactic ablative radiation therapy; OMD, oligometastatic disease; CR, complete response; PR, partial response; SD, stable disease; LN, lymph node; PD, progressive disease; FFX, FOLFIRINOX; LAT, local ablative therapy; HR, high-risk; Sx (-), no symptom; DM, distant metastasis.
NEOADJUVANT
The application of NAT is increasingly being considered, even in anatomically resectable cases, as well as in BR or LA PDAC diagnosed due to rapid systemic and/or local progression even after aggressive surgical resection, including major vessel resection. Although the application of NAT has the disadvantage of possibly depriving the opportunity for surgery, it also has several theoretical advantages, including the opportunity for optimal surgical candidate selection with less aggressive tumor biology, early application of chemotherapy for the suppression of micrometastasis, and enhancement of anticancer effects through original vascular channels that are not destroyed by surgical resection of the primary tumor [63]. According to the results of systemic review and meta-analysis of RCTs to date [64], NAT compared with upfront surgery did increase the R0 resection rate (relative risk [RR], 1.53; 95% confidence interval [CI], 1.31 to 1.79; P< 0.00001) and OS (hazard ratio [HR], 0.68; 95% CI, 0.58 to 0.92; P= 0.012) without statistically significant difference of major surgical complication rate (RR, 0.96; 95% CI, 0.65 to 1.43; P= 0.85). NAT is now recommended in several guidelines based on these results [21,34,35]. There is little disagreement regarding the application of NAT for BR PDAC. However, in resectable cases, it is not yet clear whether benefits can be achieved. In addition, there is a lack of solid evidence for an appropriate NAT regimen, and the necessity of RT combination therapy for NAT remains controversial.
Several RCTs evaluating the efficacy of NAT and/or the optimal combination of NAT in resectable or BR PDAC have been conducted (Table 1). In a Korean multicenter study, gemcitabine-based neoadjuvant CRT (5,400 centigray [cGy] in 27 fractions, five times per week for a total of 6 weeks with intravenous gemcitabine an hour before RT at the start of each week) followed by surgery was compared with upfront surgery followed by CRT in the same regime as NAT in BR PDAC [13]. This study clearly demonstrated the benefit of NAT showing an outcome that was almost twice as high compared to the upfront surgery in terms of median OS (21 months vs. 12 months; HR, 1.495; 95% CI, 0.66 to 3.36; P= 0.028). The Dutch randomized Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer (PREOPANC) trial also showed that NAT, consisting of three cycles of gemcitabine combined with 3,600 cGy RT in 15 fractions during the second cycle of gemcitabine followed by surgery, resulted in statistically significantly better oncologic outcomes in both DFS (HR, 0.69; 95% CI, 0.53 to 0.91; P= 0.009) and OS (HR, 0.73; 95% CI, 0.56 to 0.96; P= 0.025) compared to upfront surgery [58]. Additionally, the beneficial effect of NAT was more evident for BR, with an HR of 0.67 than for resectable PDAC, with an HR of 0.79 [14,65]. Similarly, the clinical benefit of NAT was not definite in other RCT targeting resectable contrasts to BR PDAC, as presented in Table 1 [12-14,65-70].
Randomized controlled trials evaluating the efficacy of NAT including RT and/or optimal combination NAT in potentially resectable pancreatic adenocarcinoma
Even in BR PDAC, controversy continues regarding the necessity of RT as a combination treatment with NAT, despite the proven effects of NAT. Multicenter four arm phase II RCT (ESPAC-5) demonstrated that a short-course NAT of 8 weeks had a significant survival benefit compared with upfront surgery in BR PDAC, but the number of patients per NAT group and follow-up period were insufficient to compare clinical outcomes among the three groups according to NAT methods, including CRT [71]. Contrary to the general perception that oxaliplatin, irinotecan, leucovorin, and fluorouracil every 2 weeks (FOLFIRINOX), additionally, would be superior to CRT as NAT, the phase 3 multicenter RCT (PREOPANC-2) did not find any significant oncological differences between the two groups in patients with resectable or BR PDAC [69].
In the Alliance AO 21501 trial, however, a study comparing eight cycles of mFOLFIRINOX and seven cycles of mFOLFIRINOX followed by SABR (3,300 to 4,000 cGy in five fractions) or hypofractionated IGRT (2,500 cGy in five fractions) as NAT in BR PDAC showed that mFOLFIRINOX alone showed more favorable outcomes than the combined RT regimen. Although this study was randomly assigned and no statistical difference in baseline characteristics between the two groups was observed, the RT combination group included many patients who were numerically older, had higher levels of CA19-9, and had lower albumin levels, which are well-known poor prognostic factors [72]. Additionally, in contrast to many other studies, the R0 resection rate in the patients who received RT was lower than that in the control group in this study. Further research should be conducted to identify the necessity for RT combination and optimal indications based on various biological information, such as genome, proteome, and radiomics, as well as known clinical factors [73].
ADJUVANT
Despite the uncertainty in terms of improving the OS rate of adjuvant CRT for PDAC, the need for adjuvant CRT in patients at high-risk of local recurrence has been continuously increasing owing to frequent local recurrence after surgical resection and adjuvant chemotherapy [71]. Large retrospective studies have shown an improvement in the survival rate of patients who received adjuvant CRT, especially those with pathologic T3 and/or N1 [31,74,75]. Additionally, a recent retrospective study conducted on patients from the National Cancer Database found that CRT for PDAC patients who underwent curative resection after multi-agent NAT was associated with better outcomes in the multivariable model (HR, 0.75; 95% CI, 0.61 to 0.93; P= 0.008) after adjustment for confounders. This was especially true for patients with grade III tumors (HR, 0.53; 95% CI, 0.37 to 0.74) or tumors with positive lymphovascular invasion (HR, 0.58; 95% CI, 0.44 to 0.75) [76].
Given the strong necessity for effective local adjuvant treatment and the positive outcomes of large retrospective studies, the NRG/RTOG-0848 RCT evaluated the efficacy of CRT for patients with resected periampullary PDAC. This study showed that CRT improved both OS (HR, 2.34; 95% CI, 1.27 to 4.29; P= 0.0063) and DFS (HR, 2.05; 95% CI, 1.16 to 3.61; P= 0.014) in patients with LN-negative status rather than those with LN metastasis, without increasing grade 4–5 toxicities [77]. Interestingly, the opposite result was obtained compared with the general expectation that a greater effect in LA cases with LN metastasis might have a high possibility of systemic micrometastasis. This suggests that the local control effect of adjuvant CRT may increase if micrometastases are controlled. The focus of RT application is on NAT rather than adjuvant CRT, but future research on the optimal indications of sequential use of adjuvant RT with the current standard adjuvant FOLFIRINOX will be continued based on factors identified after surgical resection without neoadjuvant RT or CRT.
DEFINITIVE
In advanced PDAC, for which surgical resection is not indicated, multi-agent chemotherapy is the preferred initial treatment if the patient’s general performance status is feasible, even in localized cases, and RT is limited to cases that are not candidates for chemotherapy [21,34]. Considering the biological characteristics of PDAC, in which metastases are already common at the time of diagnosis and progress rapidly even after treatment, it is reasonable to postpone the application of the local modality until no tumor progression other than the primary lesion appears after a minimum of 4 to 6 months of chemotherapy [21]. For definitive management of the primary lesion is ultimately necessary, however, attempts to perform total NAT including RT and surgery are continuing. Retrospective and prospective studies that evaluated the efficacy of RT as a neoadjuvant or definitive modality for BR PDAC and LA PDAC are presented in Table 2 [51,60,78-85].
Studies evaluating the efficacy of RT in borderline resectable or locally advanced pancreatic adenocarcinoma
In the results of the Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib (LAP07) study, a randomized phase III study that compared the effectiveness of long course CRT in such clinical situations, no difference in OS (HR, 1.03; 95% CI, 0.79 to 1.34; P= 0.83) was observed between the CRT and the chemotherapy alone groups [78]. In terms of progression-free survival (PFS); however, the CRT group was numerically superior than chemotherapy alone, although there was no statistical difference (HR, 0.78; 95% CI, 0.61 to 1.01; P= 0.06). Additionally, locoregional progression was less frequent (32% vs. 46%, P= 0.03) and the period until treatment reintroduction was longer in the CRT group. In the German randomized Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for non-resectable locally advanced pancreatic cancer (CONKO-007) trial, an open-label, multicenter, randomized phase III trial to evaluate the effectiveness of CRT compared with chemotherapy alone after three months of induction with gemcitabine or FOLFIRINOX, R1 resection rate and pathologic complete response rate were significantly superior in CRT than in chemotherapy alone, although there was no difference in OS and PFS for all patients [80].
SALVAGE AND/OR PALLIATIVE
It is generally accepted that progression or recurrence of PDAC after surgical resection and/or systemic therapy, even if localized, is incurable. Although the occurrence of these clinical situations indicates the early stage of systemic dissemination of the tumor in most cases, clinical evidence continues to show that a small proportion of patients showing progression confined to primary or OMD can benefit from the application of active local treatment under the backbone of effective systemic management. Table 3 presents the results of studies evaluating the effectiveness of LAT, including surgery and RT, for PDAC with isolated local recurrence (ILR) or OMD. Although there are significant differences in treatment outcomes, ranging from 12 to 24 months of median OS in ILR [86-93], and 11 to more than 50 months in OMD [24,94-102], depending on various conditions such as tumor extent and status at the time of LAT application, duration of systemic therapy, general condition of the patient, and site of metastasis, it is clear that favorable outcomes can be expected in some well-selected patients. The Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND) trial, which evaluated the efficacy of metastasis-directed therapy (MDT) with systemic therapy compared to systemic therapy only in PDAC with OMD, showed that the combination of MDT was associated with improved PFS compared with systemic therapy alone [100]. Additionally, the nationwide randomized controlled trial on additional treatment for isolated local pancreatic cancer recurrence using stereotactic body radiation therapy (ARCADE) trial, a nationwide Dutch RCT, is ongoing to evaluate the effect of combined SABR on ILR (NCT04881487) [103].
Studies evaluating the efficacy of local therapy in isolated locoregional recurrence and/or oligometastatic pancreatic adenocarcinoma
SUMMARY
With the advancement of tumor biology, imaging modalities, and systemic treatment in PDAC, the need for more effective LAT along with surgery is increasing. Recent research has re-examined the role of RT in treating pancreatic cancer across various clinical scenarios. The recently developed RT technique, along with the backbone of appropriate systemic treatment, can help achieve favorable local control of primary and/or OMD lesions that are difficult to resect surgically. Thus, RT can alleviate symptoms caused by gross tumor lesions, increase PFS, and improve long-term OS. However, to ensure the safety of the highly radiosensitive surrounding normal organs with focused high-dose radiation to the tumor, the proactive application of the recent RT techniques, including IMRT with SIB and/or SIP, IGRT, respiration motion-controlled RT, and ART, etc. should be considered [44,52,104-106]. Ongoing research aims to identify ideal patients for RT and tailor treatment approaches to maximize benefit. Optimizing indications, sequence, timing, and dose requires further research.
Notes
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: JIY.
Acquisition, analysis, or interpretation of data: JIY.
Drafting the work or revising: JIY.
Final approval of the manuscript: JIY.
Acknowledgements
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (NRF-2022R1C1C1005415) and by the Future Medicine 2030 Project of the Samsung Medical Center (SMX1220101).