Locally advanced pancreatic cancer (LAPC) is characterized by poor prognosis and low response durability with standard-of-care chemotherapy or chemoradiotherapy treatment. Stereotactic body radiation therapy (SBRT), which has a shorter treatment course than conventionally fractionated radiotherapy and allows for better integration with systemic therapy, may confer a survival benefit but is limited by gastrointestinal toxicity. Stereotactic MRI-guided adaptive radiation therapy (SMART) has recently gained attention for its potential to increase treatment precision and thus minimize this toxicity through continuous real-time soft-tissue imaging during radiotherapy. The case presented here illustrates the promising outcome of a 69-year-old male patient with LAPC treated with SMART with daily adaptive planning and respiratory-gated technique

Cao, Minsong

Lamb, James

Lee, Percy

Low, Daniel A

Luterstein, Elaine

Raldow, Ann C

Steinberg, Michael L

Cureus

English

Elaine Luterstein

Minsong Cao

James Lamb

Ann C Raldow

Daniel A Low

Michael L. Steinberg

Percy Lee

Crossref

Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer: A Promising Approach

eScholarship - University of California

UCLAUCLA Previously Published WorksTitleStereotactic MRI-guided Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer: A Promising ApproachPermalinkhttps://escholarship.org/uc/item/35s9r97gJournalCureus, 10(3)ISSN2168-8184AuthorsLuterstein, ElaineCao, MinsongLamb, Jameset al.Publication Date2018-03-14DOI10.7759/cureus.2324 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaReceived 02/05/2018 Review began  02/07/2018 Review ended  03/07/2018 Published 03/14/2018© Copyright 2018Luterstein et al. This is an openaccess article distributed under theterms of the Creative CommonsAttribution License CC-BY 3.0.,which permits unrestricted use,distribution, and reproduction in anymedium, provided the originalauthor and source are credited.Stereotactic MRI-guided AdaptiveRadiation Therapy (SMART) for LocallyAdvanced Pancreatic Cancer: A PromisingApproachElaine Luterstein  , Minsong Cao  , James Lamb  , Ann C. Raldow  , Daniel A. Low  , MichaelL. Steinberg  , Percy Lee 1. Department of Radiation Oncology, University of California, Los Angeles Corresponding author: Elaine Luterstein, eluterstein@mednet.ucla.edu Disclosures can be found in Additional Information at the end of the articleAbstractLocally advanced pancreatic cancer (LAPC) is characterized by poor prognosis and low responsedurability with standard-of-care chemotherapy or chemoradiotherapy treatment. Stereotacticbody radiation therapy (SBRT), which has a shorter treatment course than conventionallyfractionated radiotherapy and allows for better integration with systemic therapy, may confer asurvival benefit but is limited by gastrointestinal toxicity. Stereotactic MRI-guided adaptiveradiation therapy (SMART) has recently gained attention for its potential to increase treatmentprecision and thus minimize this toxicity through continuous real-time soft-tissue imagingduring radiotherapy. The case presented here illustrates the promising outcome of a 69-year-old male patient with LAPC treated with SMART with daily adaptive planning and respiratory-gated technique.Categories: Radiation OncologyKeywords: locally advanced pancreatic cancer, sbrt, mri-guided adaptive radiotherapy, smartIntroductionLocally advanced pancreatic cancer (LAPC) has traditionally been treated with first-line single-agent chemotherapy or conventionally fractionated chemoradiotherapy over a period of five tosix weeks, with characteristically poor prognosis due to unresectability of a disease in whichlong-term survival is achieved almost exclusively through curative resection. While newertherapeutic agents such as nab-paclitaxel and FOLFIRINOX have improved the efficacy of thesestandard-of-care treatments [1], survival outcomes remain poor, and studies are ongoing toevaluate the benefit of various radiotherapy treatment modalities in combination withemergent systemic therapies.The LAP07 trial determined that conventionally fractionated chemoradiotherapy is able toachieve survival outcomes similar to those of chemotherapy alone but introduces additionaltreatment toxicities [2]. The predominant benefit of chemoradiotherapy was improved localcontrol, which suggested a sustained role for radiotherapy through an intensified radiotherapyregime that would increase dose and reduce toxicity.Stereotactic body radiation therapy (SBRT) is an innovative treatment modality notable for itsshorter treatment course (one to two weeks), which is beneficial for systemic therapyintegration and allows for minimal interruption of chemotherapy. A review of locally advanced1 1 1 1 11 1 Open Access CaseReport  DOI: 10.7759/cureus.2324How to cite this articleLuterstein E, Cao M, Lamb J, et al. (March 14, 2018) Stereotactic MRI-guided Adaptive Radiation Therapy(SMART) for Locally Advanced Pancreatic Cancer: A Promising Approach. Cureus 10(3): e2324. DOI10.7759/cureus.2324pancreatic cancer patients in the National Cancer Database juxtaposed SBRT withconventionally fractionated radiotherapy (CFRT) and found that SBRT was a viable radiotherapymodality that conferred a significant overall survival (OS) benefit (13.9 months vs 11.6 monthsfor CFRT) [3]. A related study, in which patients without metastases after two cycles ofgemcitabine were treated with SBRT, demonstrated a median OS of 20 months and a localcontrol rate of 85% at median follow-up time (21 months) [4]. The study targeted patients mostlikely to benefit from local therapy and addressed previous trials that found chemoradiation tohave no apparent survival advantage, with initial chemotherapy response used to excludepatients with rapid metastatic development after induction therapy.SBRT, however, presents several challenges, whereby toxicity remains an issue at higher dosesand treatment efficacy is compromised by lower doses. A phase II multi-institutional trialsought to characterize the gastrointestinal toxicity of SBRT, delivered in five fractions topatients without metastases after up to three cycles of gemcitabine, and reported acute andlate grade ≥2 gastrointestinal toxicity rates of 2% and 11%, respectively, for a patient cohortwith a median OS of 13.9 months and a one-year local control of 78% [5]. In a large single-institution series of LAPC and borderline resectable pancreatic cancer patients, a similar one-year local rate of 78% was reported for unresected patients, with a median OS of 15 months forLAPC patients, and the rate of grade ≥3 toxicity was 7% [6].MRI-guided radiation therapy (MRgRT) optimizes the delivery of hypofractionatedradiotherapy, allowing SBRT to achieve higher doses while avoiding damage to criticalstructures. Endoscopic ultrasound-guided placement of fiducial markers in linac-based SBRTallows for target position verification and location tracking during treatment, but this approachfails to account for inter-fractional changes of surrounding radiosensitive tissue. MRgRT can beutilized to spare radiosensitive normal tissue adjacent to the treatment target: MRgRT countersthe limitations of poor soft-tissue resolution of available cone-beam computed tomography(CT) daily imaging with superior soft-tissue visualization and addresses stochastic inter-fractional changes with on-board adaptive planning.The following LAPC case is illustrative of the unique capabilities of stereotactic MRI-guidedadaptive radiation therapy (SMART), whereby treatment was delivered with respiratory-gatingand adaptive plans were implemented for each of the radiotherapy fractions.Case PresentationThe patient is a 69-year-old man with no family history of cancer and a prior medical historysignificant only for hypertension and irritable bowel syndrome. He presented with threemonths of abdominal pain radiating to his back and a weight loss of 12 pounds; CT imagingdemonstrated a 4.7 x 3.1 cm mass within the pancreatic body, with circumferential encasementof the proximal hepatic artery, superior mesenteric artery, and left gastric artery, and occlusionof the superior mesenteric vein (Figure 1). He was diagnosed with clinical stage III (T4N1M0)locally advanced pancreatic adenocarcinoma with mucinous features on April 28, 2016. At thetime of diagnosis, his CA 19-9 tumor marker level was 5645, and he was started onFOLFIRINOX systemic therapy. On August 15, 2016 the patient was seen in consultation at anoutside institution, where he was offered surgical management with distal or totalpancreatectomy and arterial and venous reconstruction (modified Appleby procedure), but hesought a second opinion. After eight cycles of chemotherapy, he presented for evaluation forradiotherapy on September 8, 2016. His primary pancreatic body lesion had decreased to 3.8 x3.3 cm, his CA 19-9 had dropped to 112, and his Karnofsky performance status was 100.2018 Luterstein et al. Cureus 10(3): e2324. DOI 10.7759/cureus.2324 2 of 6FIGURE 1: Diagnostic computed tomography with visiblepancreatic body lesion.SMART was recommended at a dose of 40 Gy in five fractions (alpha/beta ratio of 10biologically effective dose [BED] = 72), and the patient received definitive SBRT to thepancreatic body over a period of 13 days (9/20/16 – 10/3/16). The gross tumor volume (GTV)was expanded by 3 mm to obtain the planning target volume (PTV), and respiratory gating wasperformed with a 3 mm margin with deep inspiratory breath-hold. Normal tissue constraintswere defined as follows: duodenal loop and stomach V35 Gy < 0.5 cc; spinal cord and left andright kidneys maximum 12.5 Gy; skin maximum 39.5 Gy, V36.5 < 10 cc; liver ≥ 1000 cc < 15 Gy.The prescribed dose constraints were more stringent than reported objectives in similar studiesand represent the ideal target and normal tissue dosimetry, while adaptive plan constraintswere V35 Gy < 1 cc in the duodenum and stomach and a maximum of 20 Gy for the spinal cord.Prior to each treatment, the initial planned treatment dose was predicted onto the patient’scurrent anatomy to ascertain whether the treatment plan was optimal for that day’s specificanatomy (Figure 2, Table 1). The planned doses prioritized normal tissue over PTV coverage,with adaptive planning deemed necessary if the predicted target coverage fell below that of theplan. Adaptive planning constraints were not as conservative as the prescribed objectives, andthe delivered doses were well within the delineated adaptive constraints.FIGURE 2: A) Dose-volume histogram comparing the treatmentplan dosimetry with predicted doses based on fraction 4’sanatomy. The predicted plan significantly violates theprescribed dose constraints for the duodenal loop andstomach and inadequately covers the treatment target. B)2018 Luterstein et al. Cureus 10(3): e2324. DOI 10.7759/cureus.2324 3 of 6Dose-volume histogram illustrating the adapted (delivered)treatment plan. The radiation dose to the organs at risk hasbeen greatly reduced, while PTV coverage has been increased.(GTV - Gross tumor volume; PTV - Planning target volume)Structure Prescribed Planned Predicted DeliveredPTV: Pancreas ≥ 95% at 8 Gy 91.99 87.54 89.62OAR: Duodenal Loop ≤ .5 cc at 7 Gy 0.28 5.96 0.96OAR: Stomach ≤ .5 cc at 7 Gy 0.55 1.13 0.13OAR: Spinal Cord Max 2.5 Gy 2.37 2.11 2.52OAR: Right Kidney Max 2.5 Gy 2.34 2.11 1.88OAR: Left Kidney Max 2.5 Gy 2.71 2.31 2.52OAR: Liver ≥ 1000 cc < 3 Gy 2265.55 2202.82 2240.30OAR: Skin ≤ 10 cc at 7.3 Gy 0.00 0.00 0.00OAR: Skin Max 7.9 Gy 7.30 7.30 7.30TABLE 1: Comparison of the planned, predicted, and delivered (adaptive) doses forfraction 4 in relation to the prescribed dose constraints. (Doses reported perfraction.)(PTV - Planning target volume; OAR - Organ at risk)Adaptive planning was deemed necessary for each of the five fractions due to clinicallysignificant changes in the anatomical relationships between the tumor and normal tissue(Figure 3), which resulted in suboptimal treatment target coverage and excessive radiation ofadjacent normal tissue of the stomach and duodenum.FIGURE 3: Daily positional changes and deformations of the2018 Luterstein et al. Cureus 10(3): e2324. DOI 10.7759/cureus.2324 4 of 6duodenum (purple contour) and stomach (green contour).The patient experienced bilateral shoulder discomfort with the length of treatment during thefirst fraction but did not suffer any adverse events during or following radiation. At thecompletion of treatment, his CA 19-9 level had further diminished to 55. His systemic therapy(FOLFIRINOX) was resumed after radiotherapy to achieve a total of 12 cycles, concluding onDecember 27, 2016. Although there is a trend towards improved survival in resected LAPCpatients [6], and resection remains the only curative intent option, the patient was notinterested in surgical management.The patient continues to undergo follow-up scans every three months and continues to exhibitsustained stability of the radiated pancreatic lesion. Follow-up CT scans on June 27, 2017demonstrated lung nodules that were suspicious for metastasis but were found to have noavidity on positron emission tomography (PET). PET/CT on November 29, 2017 revealed mildlyavid, slowly progressing lung nodules, and the patient opted for surveillance. The patientremains asymptomatic and was most recently evaluated at his 14-month follow-up.DiscussionThe value of MRgRT is demonstrated by the reported patient, who received a BED of 72delivered through SMART with no significant toxicities and minimal treatment discomfort withthe length of treatment. With continued local control at 16 months post radiotherapy and 21months since diagnosis, the patient is an excellent example of the benefit conferred by on-board imaging and adaptive planning. The patient’s response to treatment points to a favorableoutcome in the context of LAPC treatment and emphasizes the value of MRgRT in abdominalsoft-tissue radiation.The total treatment length was clinically feasible and well-tolerated by the patient, with theminimal shoulder discomfort during the first fraction in large part attributable to difficulty withinspiratory breath-hold, which diminished with each subsequent fraction. The adaptiveplanning process, which includes MRI imaging, contouring, re-optimization, and planevaluation and quality assurance, took between 15 and 20 minutes, while the treatmentdelivery time ranged from 21 to 35 minutes, depending on the patient’s breath hold duty cycle.Contouring was performed by the physician the day of treatment, and the contouringinconsistencies between fractions (seen in Figure 3) highlight a limitation of adaptive planningdue to time constraints. However, while there are discrepancies in contouring betweenfractions, the stomach and duodenum had identical dose constraints, and gastrointestinal tractprotection was the main goal. This did not significantly affect dosimetry decisions regarding thenecessity of plan adaptation, and the dosimetry constraints were based on absolute volumesrather than percentages, which additionally minimized the effects of the contouring changes.There remains a trade-off between contouring precision and administering treatment on aclinically deliverable timeline, but development of MR-Linac and auto-segmentation of normalstructures are expected to reduce adaptive planning time and treatment length as the processundergoes further optimization.The success of MRgRT adaptive planning in sparing normal tissue, demonstrated here, mayhave important implications in treatment dose escalations, which have been shown to improvesurvival outcomes. A multi-institutional study presented at the American Society for RadiationOncology (ASTRO) in 2017 determined that patients treated with BED > 70 achieved a higherrate of overall survival than patients with a BED < 70, with 66% of the former cohort treatedwith adaptive portions that allowed for the safe administration of the higher doses [7]. MRgRTallows for delivery of higher BEDs without impacting surrounding tissue, and a prospective,2018 Luterstein et al. Cureus 10(3): e2324. DOI 10.7759/cureus.2324 5 of 6multi‐institutional phase II study of SMART for LAPC is already planned to validate successfulearly retrospective results of safe and effective dose escalation with MRgRT in pancreaticcancer treatment.ConclusionsMRgRT stands at the forefront of efforts to deliver higher doses of radiation more accuratelythrough the use of soft-tissue imaging before and during treatment. Radiation of LAPC ishindered by severe accompanying gastrointestinal toxicity, and SMART may play an importantrole in achieving local control with minimal toxicity. Currently, there are plans to escalate dosefurther to 50 Gy in five fractions in a prospective multi-institutional study, and trials areseeking to validate that dose escalation and more robust planning will further aid the efficacy oflocal therapies as systemic therapies continue to improve in combating metastatic spread.Further investigation is necessary, but early results such as this case have demonstrated thepotential of SMART in advancing treatment precision and safety.Additional InformationDisclosuresHuman subjects: Consent was obtained by all participants in this study. UCLA IRB issuedapproval 17-001550. The UCLA Institutional Review Board (UCLA IRB) approved IRB#17-001550. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, allauthors declare the following: Payment/services info: All authors have declared that nofinancial support was received from any organization for the submitted work. Financialrelationships: Minsong Cao, James Lamb, Daniel A. Low, Michael L. Steinberg, and Percy Leedeclare(s) personal fees from ViewRay. ViewRay Speaking Honorarium. Other relationships:All authors have declared that there are no other relationships or activities that could appear tohave influenced the submitted work.References1. Suker M, Beumer BR, Sadot E, et al.: FOLFIRINOX for locally advanced pancreatic cancer: asystematic review and patient-level meta-analysis. Lancet Oncol. 2016, 17:801-810.10.1016/S1470-2045(16)00172-82. Hammel P, Huguet F, van Laethem JL, et al.: Effect of chemoradiotherapy vs chemotherapy onsurvival in patients with locally advanced pancreatic cancer controlled after 4 months ofgemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA. 2016,315:1844-1853. 10.1001/jama.2016.43243. Zhong J, Patel K, Switchenko J, et al.: Outcomes for patients with locally advanced pancreaticadenocarcinoma treated with stereotactic body radiation therapy versus conventionallyfractionated radiation. Cancer. 2017, 123:3486-3493. 10.1002/cncr.307064. Mahadevan A, Miksad R, Goldstein M, et al.: Induction gemcitabine and stereotactic bodyradiotherapy for locally advanced nonmetastatic pancreas cancer. Int J Radiat Oncol Biol Phys.2011, 81:E615-E622. 10.1016/j.ijrobp.2011.04.0455. Herman JM, Chang DT, Goodman KA, et al.: Phase 2 multi-institutional trial evaluatinggemcitabine and stereotactic body radiotherapy for patients with locally advancedunresectable pancreatic adenocarcinoma. Cancer. 2015, 121:1128-1137. 10.1002/cncr.291616. Mellon EA, Hoffe SE, Springett GM, et al.: Long-term outcomes of induction chemotherapyand neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advancedpancreatic adenocarcinoma. Acta Oncol. 2015, 54:979-985. 10.3109/0284186X.2015.10043677. Rudra S, Jiang N, Rosenberg SA, et al.: High dose adaptive MRI guided radiation therapyimproves overall survival of inoperable pancreatic cancer. Int J Radiat Oncol Biol Phys. 2017,99:E184. 10.1016/j.ijrobp.2017.06.10422018 Luterstein et al. Cureus 10(3): e2324. DOI 10.7759/cureus.2324 6 of 6

https://escholarship.org/content/qt35s9r97g/qt35s9r97g.pdf?t=qaf51b

Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer: A Promising Approach.

Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer: A Promising Approach.

Abstract

Similar works

Full text

Available Versions

Crossref

eScholarship - University of California