Adaptive radiotherapy for gastrointestinal malignancies

Abstract

Background

Adaptive radiotherapy (ART) is an advanced form of image-guided radiotherapy that involves the re-contouring and re-planning of a patient’s treatment plan, either while the patient is on the table (online) or in between fractions (offline). ART allows for the adjustment of a treatment plan to respect a patient’s changes in internal anatomy, something that is critical in the treatment of gastrointestinal (GI) malignancies in which the mobile and radiosensitive GI tract plays a key role in driving toxicity. Herein we review the indications for both online and offline ART in GI cancers.

Main text

Online ART plays a critical role in the treatment of pancreatic cancer when using stereotactic body radiotherapy (SBRT). A variety of ART workflows have demonstrated that ART allows for the safe dose-escalated treatment of locally advanced pancreatic cancer. In addition to pancreatic cancer, there are now a bevy of data demonstrating that ART plays a key role in the treatment of liver cancers and abdominal oligometastases when using SBRT and allows for the safe delivery of single-fraction abdominal SBRT. While lower GI cancers are generally not treated with SBRT-like doses, both online and offline ART workflows have been shown to potentially reduce toxicity in patients with anal and rectal cancers. Improved integration of artificial intelligence and direct-to-unit workflows in ART hold promise that the overall process can become more efficient, allowing for more widespread adoption in GI radiation oncology.

Conclusions

ART is an expanding radiotherapy paradigm in which a patient’s treatment plan is adjusted to match observed changes in patient anatomy and has been successfully incorporated into the treatment of a variety of GI cancers. The successful implementation of workflows in pancreatic cancer, liver cancers, and lower GI cancers, amongst others, as well as incorporation into multi-center clinical trials, suggest that ART will continue to play a critical role of GI radiation oncology for years to come. As improvements in efficiency and access allow for increasing use of ART world-wide, we predict that ART will continue to play a critical part in the management of patients with GI malignancies.

Introduction

Adaptive radiotherapy (ART) is an advanced form of image-guided radiotherapy (IGRT) in which high-quality on-board daily imaging is acquired and used for re-contouring and re-planning of a patient’s radiotherapy treatment plan [1]. While this can occur offline, in between treatment fractions, it is commonly used online, meaning all plan changes occur while the patient is on the treatment table ahead of the daily treatment. Such adaption of treatment plans allows for adjustment of the radiation treatment plan in response to observed changes in patient and tumor anatomy. This allows for a patient’s treatment plan to be tailored daily to reflect the patient-specific anatomy-of-the-day, which contrasts with standard IGRT, in which on-board imaging is used purely to align a patient’s initial treatment plan for daily treatments. ART is available on both cone-beam computed tomography (CTgART) and magnetic resonance (MRgART)-guidance platforms and has been incorporated into radiotherapy workflows for patients with a variety of disease-types using a variety of treatment paradigms including stereotactic body radiation therapy (SBRT) and conventionally fractionated radiotherapy [2–6].

Gastrointestinal (GI) malignancies represent a particularly strong use case for ART. The luminal gastrointestinal tract is both mobile and radiosensitive, and it is common for the bowel to re-position itself even within a matter of hours during the course of peristalsis. As a result of this, historically, the delivery of definitive and/or dose-escalated radiotherapy to GI targets, particularly when attempting to deliver SBRT to the upper abdomen, has resulted in unacceptable rates of high-grade toxicity [7, 8]. In addition to this, the abdominal contents are subject to imaging artifacts because of bowel gases and ascites, amongst other issues, leading to inconsistencies in target deformation and alignment. Online ART, which involves high-quality on-board imaging and enables the treating team to amend a patient’s treatment plan based on the position of the patient’s GI tract on the day of delivery, provides a solution for these issues. This has resulted in online ART becoming an increasingly common part of GI radiation oncology, especially for safe, ablative dose delivery [3, 9, 10].

With the rise of online ART, offline ART applications have also become increasingly mainstream, allowing for pre-planned or triggered adjustment of plans in response to durable changes in anatomy and disease response, such as tumor response during the course of treatment. Offline approaches, in addition to online approaches may be well suited to lower GI cancer management, where courses of treatment are often protracted (5–6 weeks in length), offering opportunity for plan adjustment for disease response. Herein, we will review the primary indications for both online and offline ART for patients with GI malignancies including SBRT for pancreatic and liver cancers and conventionally fractionated radiotherapy for lower GI cancers, as well as potential future directions of ART for GI malignancy management.

Pancreatic cancer

Arguably the best-evidenced use of ART for GI malignancies is the use of online ART for the ablative treatment of borderline resectable and inoperable pancreatic cancer. As background, the use of conventionally fractionated chemoradiotherapy (5–6 weeks of 1.8–2.0 Gy per fraction radiation treatment with concurrent chemotherapy) for patients with unresectable pancreatic cancer has been shown to have minimal efficacy for local control and no survival benefit [11]. This approach is largely ineffective and is also toxic, due to inherent radio-resistance of the disease in addition to challenges of adequate dose delivery in the context tumor and organ-at-risk motion management. SBRT, or focal, high dose per fraction treatment, was explored as a solution to this, but initial results were mixed, as toxicity limited dose escalation when target coverage was prioritized over OAR sparing [8, 12, 13]. The pancreas is uniquely challenging in terms of OAR risk; it resides in close contact with the stomach, duodenum, and portions of the small bowel. In addition, both pancreas targets as well as adjacent OARs are mobile during treatment, due to adjacency to the diaphragm (intra-fraction respiratory motion) as well as daily displacement of OARs (inter-fraction OAR motion relative to the tumor). Thus, delivery of high dose SBRT treatments without prioritization of OAR sparing or a means of response to inter-fraction OAR motion exposes these organs to dangerous doses of radiotherapy, likely resulting in the historic observations of frequent high-grade complications such as duodenal ulceration [8]. This led to dose-reduction in SBRT approaches to dose levels that are non-ablative or near-palliative [12]. Although dose-reduced SBRT offers a more convenient and potentially less toxic approach than conventionally fractionated chemoradiotherapy, it has similarly limited benefit for local control and no proven survival benefit [12, 14].

Online ART resolves these inherent limitations of SBRT for pancreas cancer by enabling prioritization of OAR sparing and improved motion management through daily adaptation, in addition to the benefits of modernized respiratory motion management enabled on ART platforms. Figure 1 demonstrates a typical CTgART pancreatic SBRT plan. Early in silico studies of pancreatic SBRT combined with daily online ART demonstrated dosimetric benefits of adaptation [15, 16]. These dosimetric gains of improved OAR sparing with improved or maintained target coverage were confirmed by a Phase I trial of online adaptive SBRT using MRI guidance for upper abdominal disease sites, including pancreas cancer [3]. Subsequent retrospective studies including multi-institutional analysis of online ART for pancreas cancer showed an association between use of online ART with safe dose escalation, and in turn, association between dose escalation and overall survival benefit with reduced toxicity rates for patients with unresectable pancreas cancer [17, 18].

Fig. 1.

CBCT-guided adaptive pancreas SBRT. This figure demonstrates the benefits of ART in pancreatic SBRT. The original plan was based on the CT sim anatomy (A). At the time of treatment (B), his duodenum position had changed and now overlapped with the high dose volume, which was resolved with the adaptive plan (C). D Demonstrates the DVH for both the scheduled (dotted line) and adaptive (solid line) plans

These findings prompted the phase II SMART trial, which provides the best data to date for the use of online ART for pancreatic cancer [10, 19]. This multi-center, prospective study enrolled 136 patients with borderline (43.4%) and locally advanced/inoperable (56.4%) pancreatic cancer all of whom were treated with stereotactic MRgART to an escalated dose of 50 Gy in 5 fractions (fx), which is a biologically effective dose (BED) of 100 Gy. All patients received at least 3 months of chemotherapy prior to MRgART, and 34.6% of patients had surgery after treatment. The study met its initial primary endpoint with a 0% rate of acute GI toxicity definitely related to SBRT, significantly reduced compared to prior studies evaluating similar doses. Local control in this study was 78.2% at two-years and median overall survival was 22.9 months, confirming that the use of dose-escalated radiotherapy can overcome the radio-resistance of the disease for local control benefit, and suggesting potential translation of this approach to improved survival for a patient population in need of improved options.

The success of the SMART trial paved the way for additional exploration into the use of ART for pancreatic cancer. The on-going phase II ARTIA-pancreas trial (NCT05764720) was opened to evaluate the use of CTgART for patients with borderline resectable and locally advanced pancreatic cancers. The primary endpoint of this study is acute and late GI toxicity and it is actively accruing. More recently, the phase III NRG GI-011 LAP-100 study (NCT06958328) was activated, which evaluates the impact of the addition of dose escalated radiotherapy (at least 100 Gy BED₁₀) to chemotherapy for patients with locally advanced pancreatic cancer in a randomized fashion. On this study, MR and CT guided ART is encouraged for centers with these capabilities, although it is not required for study participation.

Primary liver cancers

Similarly to pancreatic cancers, the delivery of dose-escalated radiotherapy and SBRT to liver cancers, including both hepatocellular cancer (HCC) and cholangiocarcinoma, has been improved via the use of ART [20, 21]. Central liver cancers in particular benefit from the use of ART, as these tumors often lie in close proximity to the luminal GI tract. In a study of 99 patients with liver cancers treated with MRgART for SBRT, 53% of patients benefitted dosimetrically from and therefore received ART [22]. The use of ART in this study was largely driven by close proximity of tumors to the duodenum, small bowel, and large bowel. In particular, tumors located within 1 cm of these OARs were most likely to require online plan adaptation. ART in this study was most commonly used for hilar cholangiocarcinomas, likely due to the propensity of the hilar tumor location to also fall in close proximity to OARs. Local control on this study was excellent (91% at 1-year) and in alignment with other studies of ART for liver cancers, all while maintaining low rates of high-grade GI toxicity [21, 23, 24]. Additional evaluations of ART for cholangiocarcinoma include its use to enable dose escalated radiotherapy in pre-transplant conditioning regimens [25]. Figure 2 demonstrates a typical CTgART hilar cholangiocarcinoma SBRT plan.

Fig. 2.

CT-guided adaptive hilar cholangiocarcinoma SBRT. This figure demonstrates the benefits of ART in hilar cholangiocarcinoma SBRT. The original plan was based on the CT sim anatomy (A). At the time of treatment (B), his stomach and duodenum position had changed and now overlapped with the high dose volume, which was resolved with the adaptive plan (C). D Demonstrates the DVH for both the scheduled (dotted line) and adaptive (solid line) plans

HCC can also benefit from online ART, as delineated above. Most often, these are HCCs that are located either near the hilum (such as in the case of HCC with tumor in vein including portal vein involvement) or along the periphery of the liver, where duodenal bulb and bowel proximity may drive adaptation respectively. The pending phase III NRG GI-012 study, which will evaluate the use of SBRT after immunotherapy for patients with hepatocellular carcinoma with macrovascular invasion, such as portal vein involvement, in a randomized fashion, allows for the use of ART (although does not mandate it for study participation) on both MR and CT-guided platforms, highlighting the increasingly mainstream use of ART in primary liver cancer therapy.

Abdominal oligometastases

Across multiple cancer histologies, SBRT has become an essential part of the management of patients with oligometastatic disease. SBRT for oligometastatic disease has demonstrated durable local control and even been proven to improve overall survival in select patients. This includes demonstrated overall survival and progression-free survival benefits specifically for gastrointestinal cancers [26–29]. Furthermore, there is ongoing exploration and interest in combining SBRT with immunotherapy, as SBRT has been demonstrated to have immune-stimulatory effects by stimulating antigen release and presentation, potentially working synergistically with immunotherapy.

However, without use of online ART for careful GI OAR sparing, GI toxicities have been observed, limiting the appeal of SBRT [30]. Therefore, any modality that allows for safe delivery of SBRT is of high clinical value. This includes the use of ART for abdominal SBRT. The earliest example of this was a phase I trial of stereotactic MRgART for abdominal lesions in which there was a 0% acute toxicity rate while treating to a dose of 100 Gy BED₁₀ [3]. The ability to dose escalate SBRT safely for abdominal oligometastases is critical as many GI cancers, such as colorectal metastases, exhibit inherent radiosensitivity benefitting from the delivery of ablative doses of radiation. The ability of MRgART to limit radiotherapy exposure to the bowel when treating with dose escalated SBRT has been demonstrated in several subsequent studies [31, 32]. In addition to MRgART approaches, CT-guided ART planning has been shown to improve the dosimetric therapeutic index of abdominal SBRT including for oligometastases [33].

In the treatment of oligometastases, efficient and timely integration of RT with systemic therapies is critical. In this context, single-fraction SBRT has become increasingly intriguing for patients for oligometastatic disease [34, 35]. This approach involves the delivery of ablative radiotherapy in a single session, allowing for increased patient convenience and more seamless integration with systemic therapy regimens and clinical trials which may require washout from radiotherapy. ART provides an avenue for the safe delivery of single-fraction SBRT in the abdomen, as best exampled with the SMART ONE clinical trial [36]. This was a phase II multi-institution study evaluating single-fraction MRgART for 30 patients with a variety of malignancies including 22 patients with abdominal malignancies. One-year local control on this study was 96.2% and there was only one instance of an acute grade 3 toxicity possibly related to SBRT. ART was utilized in the majority of treatment fractions. These data indicate that use of online ART allows for the safe delivery of abdominal single-fraction SBRT while maintaining excellent local control.

Esophageal cancers

Esophageal cancer represents an intriguing use case for adaptive radiotherapy given the adjacent OARs such as the heart and lung as well as that it’s subject to both intra-fraction motion from the diaphragm and inter-fraction changes in esophageal and stomach filling. Intra-fraction motion management on MRgART systems has be posited as a avenue to reduce PTV volumes [37], and CTgART has been utilized in conventionally fractionated chemoradiation for esophageal cancer to reduce dose to OARs [38, 39]. In one study, CTgART resulted in a reduction of mean heart dose of 3.8% and mean lung V20 reduced by 3.3% [38].

Lower GI cancers

While the use of SBRT-level dosing is not a standard part of the treatment of primary rectal and anal cancers, patients with these cancers still stand to potentially benefit from the use of ART for treatment. This may include both online and offline ART approaches. Online ART approaches in this setting often focus upon margin reduction and plan adjustment for OAR position, whereas offline approaches hinge upon plan changes in response to durable tumor and anatomy change, such as tumor shrinkage and response during treatment.

In anal cancer, one approach under active investigation is the use of online ART to reduce the size of planning target volumes (PTVs). In anal cancer, PTVs are often relatively large, including expansive elective nodal coverage of inguinal, external and internal iliac, mesorectal, and presacral nodal regions. This invariably exposes OARs such as the bowel and bladder to radiation dose, which can lead to significant toxicity. PTVs incorporate added margin of coverage for treatment, including margins for daily variation in patient setup. Through use of daily online ART, PTV expansion size can be reduced, as use of a reoptimized plan that matches the daily setup may eliminate elements of setup uncertainty [40]. As a result, it is possible that use of daily online ART may decrease the target volume size through PTV reduction and consequently reduce bystander OAR radiation exposure. Use of online ART also enables plan optimization to the precise position of OARs on each day of treatment, which may further enable OAR sparing by matching optimization to the anatomy-of-the-day. For definitive treatment of anal cancer, a retrospective in silico study of CTgART demonstrated that the use of ART reduced the volume of bowel receiving at least 45 Gy of radiation by 86.7% [41], and there is an ongoing prospective clinical study evaluating the clinical role of ART for anal cancer (NCT05838391).

In addition to online ART, offline ART is being explored for use in anal cancer. In anal cancer, dose-personalization strategies, including dose de-escalation for early-stage disease [42] and dose intensification for bulky disease [43] are an emerging standard-of-care. In this context, dose personalization based on disease response during treatment is also an active area of investigation. Anal cancer is a uniquely virally-driven GI cancer, and the rate and presence/absence of Human Papilloma Virus (HPV) viral clearance during and after treatment have been associated with disease response [44, 45]. In one currently active multi-center randomized Phase II trial, circulating tumor HPV DNA is being used to tailor radiation treatment. In patients with favorable ctDNA (and thus tumor) mid-treatment response, plans will be adapted for dose-reduction, whereas patients with unfavorable/lack of ctDNA response will be selected for offline adaptation with dose-intensification. Thus, the protracted treatment course style used for anal cancer treatment may lend well to offline ART by disease response, in addition to potential avenues for online ART.

ART has also been explored for use for treatment of primary rectal cancers. Given the reduced daily uncertainty of alignment and positioning with ART, the technique has similarly been explored as a means with which to reduce PTV margins for rectal cancer (5 mm to 3 mm), reducing volume of normal tissue unnecessarily exposed to radiation [46]. ART has also been explored as a means for precise and focal dose-escalation in the context of short-course radiotherapy (a compressed, 5-day RT course for rectal cancer), which may enhance local control outcomes of radiotherapy while improving patient convenience compared to long-course RT (five-to-six-week RT courses using conventional fractionation) [47]. A study evaluating dose-escalated short-course adaptive radiotherapy for rectal cancer is on-going (NCT04677413). Radiomics-driven adaptive radiotherapy may be of utility for rectal cancer in the future, particularly on MRgART platforms [48].

Technical considerations

While we have thus far largely focused on the indications for ART in GI malignancies, it’s also important to acknowledge some of the technical aspects of the workflow and technology, particularly as they apply to the specific ART modalities (MRgART, CTgART). ART is primarily a form of inter-fraction motion management, but intra-fraction motion management must be considered as well, particularly for abdominal SBRT. MRgART platforms typically employ real-time MR-cine gating, which is particularly useful for pancreatic and hepatic SBRT [49]. CTgART platforms primarily use breath-hold technique in combination with optical surface guidance [50, 51], although it’s possible that motion management options on CTgART platforms are expanded on and improved in the future.

The available motion management technique is one of many considerations when a clinic is selecting the best ART platform for their respective institution. Which ART platform is best for each individual clinic is based upon several factors. For example, MRgART platforms offer excellent visualization of pancreatic and hepatic lesions as well as real-time MR-cine gating but require specialty training and shielding that may not be feasible for a single linac clinic. CTgART platforms employ CBCT-based imaging, which does not characterize hepatic tissue as well as MR-based imaging [52], but may be more easily installed in a resource limited clinic. Ultimately, the ideal ART platform is institution specific.

Future directions

The field of GI ART is constantly evolving and there are multiple exciting potential future avenues for this novel treatment paradigm. One opportunity for growth in the ART approach is the integration of artificial intelligence and auto-planning for daily contour generation and plan creation. At present, ART is inherently time consuming and resource intensive; it is a complex process that involves increased time at the machine for a variety of staff members including physicians and physicists and specialty training for the entire team. ART is highly resource intensive, not too dissimilar from a brachytherapy program, and therefore represents one of the major current limitations of ART preventing it from becoming more commonly implemented. The workflow itself for new plan generation can take between 10 and 40 min per session on average, and a pancreas ART session make therefore take 40–90 min per fraction compared to a typical abdominal SBRT session, which may take closer to 30–45 min [2, 4, 16]. With increased artificial intelligence integration into the ART process, outsourcing of physician workload to alternative members of the ART team [53], and improved ART training, future ART workflows will likely be more resource and time efficient to allow for more widespread integration of ART into radiation oncology clinics.

Access to ART has also historically been limited. The earliest iteration of ART was limited to MR-guided technologies, which require specialty shielding and construction, and specialty staffing and training, typically limiting its use to high-volume large academic centers. This therefore represented one of the historic limitations to widespread adoption of ART. However, the emergence and rapid growth of CT-guided ART platforms has altered the ART landscape. With multiple ART platforms commercially available including CTgART platforms that have fewer specialty requirements, ART is likely to increase in use. Globally accessible CT guided platforms may be more easily implemented in community clinics, allowing for increased access to the technique in the rural and global radiotherapy clinic [54]. Ultimately, increasing access to ART platforms and reducing the resource requirement of the workflows will allow for more clinics to install an ART program and for the more frequent inclusion of large-scale ART-inclusive clinical trials, which will increase ART indications and usage.

Direct-to-unit (DTU) radiotherapy workflows (also known as simulation-free RT) have become increasingly popular in recent years. In these workflows, a traditional CT simulation planning session is omitted [55, 56]. In such workflows, a plan may instead be constructed using patients’ diagnostic images. DTU has shown the potential to increase the speed with which patients can access treatment and potentially make the radiotherapy workflow more efficient and patient-centric. Yet, an inherent challenge with DTU approaches is that the diagnostic image is not always reflective of the patient positioning and anatomy on the day of treatment, which initially limited DTU to low-dose palliative treatment intents. However, this limitation can be bypassed using online ART. In modern versions of DTU, a diagnostic image may be used for a pre-plan, but online ART is then used to update the planning image and create the final, adjusted to the anatomy-of-the-day at the time of treatment (Fig. 3). There has already been substantial intrigue in combining DTU with stereotactic ART treatments, as separate in silico studies demonstrated feasibility for this paradigm for abdominal malignancies and celiac plexus ablation, and a multi-center prospective clinical study evaluating DTU celiac plexus ablation is soon to be open [57, 58]. Of note, DTU does have operational limitations in the United States due to the implications of not billing for a CT simulation appointment, which must be taken into account when a clinic is installing a DTU program.

Fig. 3.

Direct-to-unit workflows. Overviews of the traditional CT simulation workflow (A), non-adaptive direct-to-unit workflow (B), and adaptive direct-to-unit workflow (C). Adaptive resolves inherent issues with the direct-to-unit workflow such as differences in anatomy from the diagnostic image to the day of treatment by allowing for the editing of a treatment plan to match the patient’s specific anatomy-of-the-day

Conclusions

Adaptive radiotherapy is a growing radiotherapy paradigm in which a patient’s treatment plan is adjusted to match observed changes in patient tumor and/or OAR anatomy. It can be implemented with success for upper and lower GI cancers, in both offline and online ART formats. There has been rapid growth and incorporation of ART into GI radiation oncology, with the successful implementation of workflows in pancreatic cancer, liver cancers, and lower GI cancers, amongst others, as well as incorporation into multi-center clinical trials including major, mainstream cooperative group studies. As it becomes increasingly efficient and accessible, we predict that ART will be integrated as a critical part of the management of patients with GI malignancies.

Abbreviations

ART

Adaptive radiotherapy

IGRT

Image–guided radiotherapy

CTgART

Cone–beam computed tomography guided adaptive radiotherapy

MRgART

Magnetic resonance guided adaptive radiotherapy

SBRT

Stereotactic body radiotherapy

GI

Gastrointestinal

OAR

Organ at risk

BED

Biologically effective dose

HCC

Hepatocellular carcinoma

PTV

Planning target volume

HPV

Human papilloma virus

DTU

Direct–to–unit

Author contributions

All authors contributed to the writing of this manuscript as well as read and approved the final manuscript.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.