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Quantitative analysis of diffusion weighted imaging in rectal cancer during radiotherapy using a magnetic resonance imaging integrated linear accelerator

Open AccessPublished:June 18, 2022DOI:https://doi.org/10.1016/j.phro.2022.06.003

      Highlights

      • Magnetic resonance imaging integrated platforms (MR-Linac) allows for on-treatment imaging.
      • Diffusion weighted imaging (DWI) taken during treatment can measure biological response.
      • Median apparent diffusion coefficient (ADC) from first fraction to last fraction increases in rectal cancer patients.
      • No change is seen in median ADC value from first fraction to last fraction in normal tissue.
      • DWI demonstrates promise in its ability to determine response to treatment in rectal cancer patients.

      Abstract

      Background and purpose

      Magnetic resonance imaging integrated linear accelerator (MR-Linac) platforms enable acquisition of diffusion weighted imaging (DWI) during treatment providing potential information about treatment response. Obtaining DWI on these platforms is technically different from diagnostic magnetic resonance imaging (MRI) scanners. The aim of this project was to determine feasibility of obtaining DWI and calculating apparent diffusion coefficient (ADC) parameters longitudinally in rectal cancer patients on the MR-Linac.

      Materials and methods

      Nine patients undergoing treatment on MR-Linac had DWI acquired using b-values 0, 30, 150, 500 s/mm2. Gross tumour volume (GTV) and normal tissue was delineated on DWI throughout treatment and median ADC was calculated using an in-house tool (pyOsirix ®).

      Results

      Seven out of nine patients were included in the analysis; all demonstrated downstaging at follow-up. A total of 63 out of 70 DWI were analysed (7 excluded due to poor image quality). An increasing trend of ADC median for GTV (1.15 × 10−3 mm2/s interquartile range (IQ): 1.05–1.17 vs 1.59 × 10−3 mm2/s IQ: 1.37 – 1.64; p = 0.0156), correlating to treatment response. In comparison ADC median for normal tissue remained the same between first and last fraction (1.61 × 10−3 mm2/s IQ: 1.56–1.71 vs 1.67 × 10−3 mm2/s IQ: 1.37–2.00; p = 0.9375).

      Conclusions

      DWI assessment in rectal cancer patients on MR-Linac is feasible. Initial results provide foundations for further studies to determine DWI use for treatment adaptation in rectal cancer.

      Keywords

      1. Introduction

      Management of locally advanced rectal adenocarcinoma includes neo-adjuvant chemoradiotherapy (nCRT) to rectum and pelvic nodes followed by surgery [
      • Glynne-Jones R.
      • Wyrwicz L.
      • Tiret E.
      • Brown G.
      • Rödel C.
      • Cervantes A.
      • et al.
      Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Glynne-Jones R.
      • Wyrwicz L.
      • Tiret E.
      • Brown G.
      • Rödel C.
      • Cervantes A.
      • et al.
      Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. Pathological complete response (pCR) is seen in 15–25% [
      • Habr-Gama A.
      • Perez R.O.
      • Nadalin W.
      • Sabbaga J.
      • Ribeiro U.
      • Sousa S.E.
      • et al.
      Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results.
      ] following nCRT, which improves 5-year overall survival (OS) in these patients to >87% [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rödel C.
      • Kuo L.-J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ] compared to 50–60% in those who do not achieve pCR [
      • Zorcolo L.
      • Rosman A.S.
      • Restivo A.
      • Pisano M.
      • Nigri G.R.
      • Fancellu A.
      • et al.
      Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis.
      ,

      van Gijn W, Marijnen CAM, Nagtegaal ID, Kranenbarg EM-K, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011;12:575–82. https://doi.org/10.1016/S1470-2045(11)70097-3.

      ]. Achieving pCR or tumour regression grade (TRG) 0–2 [
      • Mandard A.-M.
      • Dalibard F.
      • Mandard J.-C.
      • Marnay J.
      • Henry-Amar M.
      • Petiot J.-F.
      • et al.
      Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
      ] in rectal cancer is shown to be an independent prognostic factor for OS, local recurrence, and disease free survival [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • Das P.
      • Rödel C.
      • Kuo L.-J.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Zorcolo L.
      • Rosman A.S.
      • Restivo A.
      • Pisano M.
      • Nigri G.R.
      • Fancellu A.
      • et al.
      Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis.
      ,
      • Vecchio F.M.
      • Valentini V.
      • Minsky B.D.
      • Padula G.D.A.
      • Venkatraman E.S.
      • Balducci M.
      • et al.
      The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
      ,
      • Hall M.D.
      • Schultheiss T.E.
      • Smith D.D.
      • Fakih M.G.
      • Wong J.Y.C.
      • Chen Y.-J.
      Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.
      ,
      • Mohiuddin M.
      • Regine W.F.
      • John W.J.
      • Hagihara P.F.
      • McGrath P.C.
      • Kenady D.E.
      • et al.
      Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response.
      ], and a ‘watch and wait’ policy of delaying surgery until the first signs of recurrence is advocated in these patients [
      • O’Neill B.D.
      • Brown G.
      • Heald R.
      • Cunningham D.
      • Tait D.M.
      Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer.
      ,
      • Bernier L.
      • Balyasnikova S.
      • Tait D.
      • Brown G.
      Watch-and-wait as a therapeutic strategy in rectal cancer.
      ,
      • Wang Q.
      • Zhang R.
      • Xiao W.
      • Zhang S.
      • Wei M.
      • Li Y.
      • et al.
      The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy.
      ] under strict imaging surveillance [
      • Glynne-Jones R.
      • Hughes R.
      Complete response after chemoradiotherapy in rectal cancer (watch-and-wait): have we cracked the code?.
      ].
      To improve pathological response to nCRT dose escalated treatment at >60 Gy to gross tumour volume (GTV) is required [
      • Appelt A.L.
      • Pløen J.
      • Vogelius I.R.
      • Bentzen S.M.
      • Jakobsen A.
      Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
      ]. However, increasing dose to tumour comes with worsening toxicity to normal tissue [
      • Burbach J.P.M.
      • den Harder A.M.
      • Intven M.
      • van Vulpen M.
      • Verkooijen H.M.
      • Reerink O.
      Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: a systematic review and meta-analysis.
      ], and consequently a fine balancing act is required between improving tumour response and limiting long-term morbidity. Image guided radiotherapy (IGRT) and intensity modulated radiotherapy (IMRT) reduces dose delivered to organs at risk (OARs) such as small bowel [
      • Urbano M.T.G.
      • Henrys A.J.
      • Adams E.J.
      • Norman A.R.
      • Bedford J.L.
      • Harrington K.J.
      • et al.
      Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels.
      ,
      • Parekh A.
      • Truong M.T.
      • Pashtan I.
      • Qureshi M.M.
      • Martin N.E.
      • Nawaz O.
      • et al.
      Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer.
      ]. Using magnetic resonance imaging integrated linear accelerator (MR-Linac) platforms online adaptations to treatment can be made based on anatomy of the day further improving dose delivery to tumour whilst sparing normal tissue [
      • Gani C.
      • Boldrini L.
      • Valentini V.
      Online MR guided radiotherapy for rectal cancer. New opportunities.
      ].
      Magnetic resonance imaging (MRI) also provides the added benefit of giving functional information about tumour biology in the form of diffusion weighted imaging (DWI). High intensity signal on DWI corresponds to malignant tissue [
      • Le Bihan D.
      • Iima M.
      Diffusion magnetic resonance imaging: what water tells us about biological tissues.
      ] and reduction of signal relates to disruption of cell membrane integrity thus suggesting regression of tumour caused by treatment [
      • Koh D.M.
      • Collins D.J.
      Diffusion-weighted MRI in the body: applications and challenges in oncology.
      ]. Several studies have been published demonstrating ability to stratify rectal cancer patients into good and poor responders using pre-treatment DWI and apparent diffusion coefficient (ADC) [
      • Hu F.
      • Tang W.
      • Sun Y.
      • Wan D.
      • Cai S.
      • Zhang Z.
      • et al.
      The value of diffusion kurtosis imaging in assessing pathological complete response to neoadjuvant chemoradiation therapy in rectal cancer: a comparison with conventional diffusionweighted imaging.
      ,
      • Bin Z.H.
      • Zhang X.Y.
      • Zhou X.H.
      • Li X.T.
      • Liu Y.L.
      • Wang S.
      • et al.
      Assessment of pathological complete response to preoperative chemoradiotherapy by means of multiple mathematical models of diffusion-weighted MRI in locally advanced rectal cancer: a prospective single-center study.
      ,
      • Intven M.
      • Reerink O.
      • Philippens M.E.P.
      Diffusion-weighted MRI in locally advanced rectal cancer: Pathological response prediction after neo-adjuvant radiochemotherapy.
      ,
      • Chen Y.G.
      • Chen M.Q.
      • Guo Y.Y.
      • Li S.C.
      • Wu J.X.
      • Xu B.H.
      Apparent diffusion coefficient predicts pathology complete response of rectal cancer treated with neoadjuvant chemoradiotherapy.
      ,
      • Kim S.H.
      • Lee J.Y.
      • Lee J.M.
      • Han J.K.
      • Choi B.I.
      Apparent diffusion coefficient for evaluating tumour response to neoadjuvant chemoradiation therapy for locally advanced rectal cancer.
      ], with good responders exhibiting an earlier response to treatment compared to the poor responders [
      • Sun Y.S.
      • Zhang X.P.
      • Tang L.
      • Ji J.F.
      • Gu J.
      • Cai Y.
      • et al.
      Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging.
      ]. Recognising poor responders early in treatment could potentially allow for treatment adaptation with dose escalation in order to achieve pCR [
      • Chan A.K.P.
      • Wong A.O.
      • Langevin J.
      • Jenken D.
      • Heine J.
      • Buie D.
      • et al.
      Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study.
      ].
      However, these finding are not successfully reproduced in the majority of studies and DWI is yet to be validated as an imaging biomarker in this setting [
      • Xie H.
      • Sun T.
      • Chen M.
      • Wang H.
      • Zhou X.
      • Zhang Y.
      • et al.
      Effectiveness of the apparent diffusion coefficient for predicting the response to chemoradiation therapy in locally advanced rectal cancer: a systematic review and meta-analysis.
      ]. Furthermore, reproducing the methodology of DWI across studies is difficult due to use of different diagnostic MRI scanners and varying sequencing protocols [
      • Pham T.T.
      • Liney G.P.
      • Wong K.
      • Barton M.B.
      Functional MRI for quantitative treatment response prediction in locally advanced rectal cancer.
      ]. Acquiring multiple MRI scans during treatment is also not feasible in a busy clinical department [
      • Koh D.M.
      • Collins D.J.
      Diffusion-weighted MRI in the body: applications and challenges in oncology.
      ], therefore simultaneously scanning and treating the patient on an MR-Linac overcomes this hurdle [
      • Raaymakers B.W.
      • Lagendijk J.J.W.
      • Overweg J.
      • Kok J.G.M.
      • Raaijmakers A.J.E.
      • Kerkhof E.M.
      • et al.
      Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept.
      ] providing a means of investigating real time biological changes in tumour [
      • Kooreman E.S.
      • van Houdt P.J.
      • Nowee M.E.
      • van Pelt V.W.J.
      • Tijssen R.H.N.
      • Paulson E.S.
      • et al.
      Feasibility and accuracy of quantitative imaging on a 1.5 T MR-linear accelerator.
      ].
      The design of one such MR-Linac differs from diagnostic MRI scanners [
      • Raaymakers B.W.
      • Lagendijk J.J.W.
      • Overweg J.
      • Kok J.G.M.
      • Raaijmakers A.J.E.
      • Kerkhof E.M.
      • et al.
      Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept.
      ] and causes technical difficulties in obtaining DWI at higher b-values [
      • Kooreman E.S.
      • van Houdt P.J.
      • Keesman R.
      • Pos F.J.
      • van Pelt V.W.J.
      • Nowee M.E.
      • et al.
      ADC measurements on the unity MR-linac – a recommendation on behalf of the elekta unity MR-linac consortium.
      ]. As such, the quality of images obtained on this MR-Linac in rectal cancer longitudinally throughout treatment is not known and requires assessment. The aim of this study was to demonstrate feasibility and clinical relevance of DWI obtained in rectal cancer patients treated on an MR-Linac.

      2. Material and methods

      2.1 Patients and treatment

      Patients with a locally advanced rectal cancer (stage ≥T3, nodal involvement, circumferential margin (CRM) involvement, presence of extramural vascular invasion (EMVI) or threatened levators) [
      • Glynne-Jones R.
      • Wyrwicz L.
      • Tiret E.
      • Brown G.
      • Rödel C.
      • Cervantes A.
      • et al.
      Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ], tumour size <12 cm, suitable for nCRT and with no contraindications to MRI and suitable for MR-Linac treatment or imaging were recruited to research and ethics commitee approved institutional based studies for treatment and imaging (PERMIT trial (NCT03727698) and PRIMER trial (NCT02973828)). Staging investigations such as CT and MRI, colonoscopy and biopsy were undertaken in local hospitals prior to referral to our unit. All patients’ treatment pathways were discussed in central multidisciplinary meeting. Patients were treated with nCRT with concurrent Capecitabine 825 mg/m2 BD or Raltitrexed 3 mg/m2 day 1 every 21 days if Capecitabine was contraindicated. A two-phase radiotherapy protocol was delivered; Phase 1 boost to gross tumour volume (GTV) and nodes delivering 9 Gy/5# on MR-Linac (delivered first due to longer duration of daily treatment on MR-Linac which symptomatic patients may not tolerate in last week of radiotherapy) followed by Phase 2 treatment to pelvis via C-arm Linac delivering 45 Gy/25# to GTV plus mesorectum and pelvic nodes. Response to treatment was assessed 8–12 weeks post-treatment with follow-up diagnostic MRI and/or histopathology following surgery using TRG response [
      • Mandard A.-M.
      • Dalibard F.
      • Mandard J.-C.
      • Marnay J.
      • Henry-Amar M.
      • Petiot J.-F.
      • et al.
      Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
      ].

      2.2 Pre-treatment planning

      Patients treated on MR-Linac underwent a planning CT scan (Philips, Big Bore CT) and MR simulation scan either on diagnostic MRI (Siemens, Aera 1.5T) or MR-Linac (Elekta Unity, 1.5 T). Bladder filling protocol on MR simulation required patients to empty bladder and drink 700 mls of water 1 h prior to scanning. Scanning was performed in treatment position, ideally with an empty rectum. If rectum ≥5 cm on initial planning scan patients were re-scanned following bowel preparation. Radiotherapy planning was performed on Monaco® v5.40.01 (Elekta AB, Stockholm, Sweden) for Phase 1 and Raystation® v10.0.1.52 (RaySearch Laboratories AB, Stockholm, Sweden) for Phase 2.

      2.3 Imaging acquisition on MR-Linac

      Imaging on MR-linac included T2 weighted 2 min scans utilised for online adaptation as described previously [
      • Winkel D.
      • Bol G.H.
      • Kroon P.S.
      • van Asselen B.
      • Hackett S.S.
      • Werensteijn-Honingh A.M.
      • et al.
      Adaptive radiotherapy: the Elekta Unity MR-linac concept.
      ,

      Intven MPW, de Mol van Otterloo SR, Mook S, Doornaert PAH, de Groot-van Breugel EN, Sikkes GG, et al. Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience. Radiother Oncol 2021;154:172–8. https://doi.org/10.1016/j.radonc.2020.09.024.

      ], followed by research imaging including DWI sequences. DWI acquisition was in keeping with consensus guidelines [
      • Kooreman E.S.
      • van Houdt P.J.
      • Keesman R.
      • Pos F.J.
      • van Pelt V.W.J.
      • Nowee M.E.
      • et al.
      ADC measurements on the unity MR-linac – a recommendation on behalf of the elekta unity MR-linac consortium.
      ] and included diffusion weightings b = 0, 30, 150, 500 s/mm2 combined to make 4D DWI (Fig. 1). Table 1 demonstrates sequencing parameters for acquisition of rectal DWI on MR-Linac. DWI was acquired daily during phase 1 and weekly during phase 2.
      Figure thumbnail gr1
      Fig. 1Diffusion weighted images b = 0, 30, 150 and 500 s/mm2 and T2 weighted image at first fraction of a patient with an upper rectal cancer tumour with GTV contour (purple).
      Table 1MRI sequencing parameters for DWI acquisition on Elekta Unity MR-Linac.
      ParametersRectal DWI sequencing
      Field of view (mm)AP = 420
      RL = 420
      FH = 120
      Recon. Voxel (mm)
      AP1.75
      RL1.75
      TR (ms)4483
      TE (ms)81
      DELTA/delta (ms)40.7/20.3
      Fat SuppressionSTIR
      EPI factor55
      Parallel imaging factor2.2
      Section thickness (mm)4
      Direction of motion probing gradientsIsotropic
      b-factors (s/mm2)0, 30, 150, 500
      b-factor averages
      b = 08
      b = 308
      b = 1508
      b = 50016

      2.4 Quantitative analysis

      Between Jan 2018 and Dec 2020, nine patients were consecutively recruited for nCRT on MR-Linac. DWI was not obtained in the first two patients therefore these patients were excluded from the analysis. Demographics of the remaining seven are shown in Table 2. All patients demonstrated a TRG 1–3 response following treatment as assessed by MRI or histopathology following surgery.
      Table 2Patient and tumour characteristics.
      N = 7
      GenderMale6 (86%)
      Female1 (14%)
      Age61.3 yrs (Range 37–74)
      T stageT3a1 (14%)
      T3b1 (14%)
      T3c3 (43%)
      T42 (29%)
      N StageN15 (71%)
      N22 (29%)
      M StageM07 (100%)
      CRM involvedYes5 (71%)
      No2 (29%)
      EMVI presentYes7 (100%)
      Mandard response post treatmentTRG 13 (43%)
      TRG 22 (29%)
      TRG 32 (29%)
      For each patient, ten DWI were acquired during treatment. 7/70 DWI were excluded from analysis as either DWI was not performed or not centred on tumour; thus 63 DWI were analysed in total.
      DICOM images were imported into an open-source medical image viewer (Horos, GNU Lesser General Public License, Version 3 (LGPL-3.0)) where DWI were evaluated and GTV delineation on DWI was performed by a single experienced observer to minimise intra-observer delineation variability.
      Utilising an in-house plug in tool (pyOsirix® [
      • Blackledge M.D.
      • Tunariu N.
      • Zugni F.
      • Holbrey R.
      • Orton M.R.
      • Ribeiro A.
      • et al.
      Noise-corrected, exponentially weighted, diffusion-weighted MRI (niceDWI) improves image signal uniformity in whole-body imaging of metastatic prostate cancer.
      ,
      • Blackledge M.D.
      • Collins D.J.
      • Koh D.M.
      • Leach M.O.
      Rapid development of image analysis research tools: bridging the gap between researcher and clinician with pyOsiriX.
      ]) ADC maps were created from b-values 150 and 500 s/mm2. Contours for GTV and normal tissue (ovary for female, seminal vesicles for male), delineated on b = 500 s/mm2 image, were transposed from DWI onto ADC map. Ovary and seminal vesicles chosen as normal tissue example as these organs were within planning tumour volume (PTV) and received same dose as GTV. ADC median for region of interest (ROI) at each fraction was calculated using in house-tool. Statistical analyses and graph modelling was performed using GraphPad Prism v9.1.2.

      3. Results

      An area of low ADC value was present on ADC maps corresponding to region of signal on b = 500 s/mm2, which can be considered to demonstrate presence of tumour (Fig. 2a). All patients demonstrated a trend of increasing ADC median from fraction 1 (1.15 × 10−3 mm2/s interquartile range (IQ): 1.05–1.17) to fraction 30 (1.60 × 10−3 mm2/s IQ: 1.37–1.64) (Fig. 2b). Using Wilcoxon t-test the difference in ADC median between fraction 1 and 30 was found to be statistically significant (p = 0.0156). In comparison ADC median calculated in normal tissue showed no difference between first and last fraction (1.61 × 10−3 mm2/s IQ: 1.56–1.71 vs 1.67 × 10−3 mm2/s IQ: 1.37–2.00; p = 0.9375) (Fig. 2c). %ΔADC median calculated at weekly intervals demonstrates 3 patients (patients 4, 5 and 6) experiencing a >50% ΔADC from baseline by week 3, whilst 2 patients (patients 2 and 7) remain < 50%ΔADC from baseline throughout treatment (Fig. 3). There was no histopathological correlation to these trends.
      Figure thumbnail gr2
      Fig. 2a. Example of b = 500 s/mm2 images and corresponding ADC maps from week 1, 3 and 6 of patient with an upper rectal tumour (orange contour) and ovary (pink contour). An area of low ADC value is seen in week 1 corresponding to area of high signal seen on DWI in GTV. b. Median ADC of tumour between first and last fraction, with an increasing trend seen. c. Median ADC of normal tissue between first and last fraction, with no change seen.
      Figure thumbnail gr3
      Fig. 3Graph indicating relative ΔADC median (%) from baseline at weekly intervals.

      4. Discussion

      The findings from this study hold promise for utilisation of DWI signal and ADC metrics for adaptation of treatment according to treatment response on MR-Linac. Preliminary work on the longitudinal analysis of DWI and ADC median in rectal cancer on the MR-Linac demonstrated that an increase in ADC median in GTV is seen in all patients, whereas ADC median in normal tissue remains at similar value. ADC median of GTV also increases to a value comparable to normal tissue. Given that all patients demonstrated a pathological response TRG 1–3 to treatment, we suggest that Median ADC measured on MR-Linac appears to correlate to treatment response, which is in keeping with published literature [
      • Intven M.
      • Reerink O.
      • Philippens M.E.P.
      Diffusion-weighted MRI in locally advanced rectal cancer: Pathological response prediction after neo-adjuvant radiochemotherapy.
      ,
      • Fu Z.Z.
      • Peng Y.
      • Cao L.Y.
      • Chen Y.S.
      • Li K.
      • Fu B.H.
      Value of apparent diffusion coefficient (ADC) in assessing radiotherapy and chemotherapy success in cervical cancer.
      ]. These results are similar to a study performed on 0.35 T MR integrated platform looking at DWI in 3 patients [
      • Shaverdian N.
      • Yang Y.
      • Hu P.
      • Hart S.
      • Sheng K.
      • Lamb J.
      • et al.
      Feasibility evaluation of diffusion-weighted imaging using an integrated MRI-radiotherapy system for response assessment to neoadjuvant therapy in rectal cancer.
      ].
      Based on published evidence in rectal cancer, the principal parameter that predicts treatment response is %ΔADC (which compares post-treatment ADC metrics to pre-treatment ADC metrics calculated 6–8 weeks after completion of treatment) where patients with pCR demonstrate a >50% ΔADC compared to patients who do not achieve pCR [
      • Chen Y.G.
      • Chen M.Q.
      • Guo Y.Y.
      • Li S.C.
      • Wu J.X.
      • Xu B.H.
      Apparent diffusion coefficient predicts pathology complete response of rectal cancer treated with neoadjuvant chemoradiotherapy.
      ,
      • Kim S.H.
      • Lee J.Y.
      • Lee J.M.
      • Han J.K.
      • Choi B.I.
      Apparent diffusion coefficient for evaluating tumour response to neoadjuvant chemoradiation therapy for locally advanced rectal cancer.
      ,
      • Intven M.
      • Reerink O.
      • Philippens M.E.P.
      Repeatability of diffusion-weighted imaging in rectal cancer.
      ,

      Blazic I, Lilic G, Gajic M. Gastrointestinal imaging: quantitative assessment of rectal cancer response to neoadjuvant CRT Blazic et al. Radiology 2017;282:418–28.

      ]. However, we have observed that in five out of seven patients %ΔADC is <50% by the last fraction. One explanation is that the final DWI that we analyzed was obtained during the final week of RT as opposed to 6–8 weeks post-treatment as stated in the published studies. It is well known that tumour regression can continue following completion of CRT [
      • Petrelli F.
      • Sgroi G.
      • Sarti E.
      • Barni S.
      Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer: A Meta-analysis of Published Studies.
      ]. In addition, the signal intensity in the tumour is reduced by the end of treatment, leading to smaller volume of ROI for ADC calculations which can result in inaccuracies in ADC measurements [

      Blazic I, Lilic G, Gajic M. Gastrointestinal imaging: quantitative assessment of rectal cancer response to neoadjuvant CRT Blazic et al. Radiology 2017;282:418–28.

      ].
      Sun et al demonstrated a significant increase in ADC metrics and %ΔADC during treatment where down-staged patients (TRG 1–3) had an earlier increase in ADC metrics by end of week 1 (1.07 × 10−3 mm/s2 ± SD 0.13 pre-treatment to 1.32 × 10−3 mm/s2 ± SD 0.16; p < 0.001) at end of week 1 and larger change in %ΔADC by end of week 2 (28.2% vs 9.8%; p < 0.01) compared to non-downstaged patients (TRG 4–5) [
      • Sun Y.S.
      • Zhang X.P.
      • Tang L.
      • Ji J.F.
      • Gu J.
      • Cai Y.
      • et al.
      Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging.
      ]. Our results demonstrated three out of seven patients exhibit similar early rises in Median ADC and large %ΔADC by week 3 (fig, 2c and 3). However on further analysis based on TRG stratification, it was difficult to demonstrate a difference in trend between good (TRG 1–2) and poor responders (TRG 3–5).
      Our study is limited by small patient numbers; therefore, further studies with larger patient numbers are required to demonstrate correlation between DWI measurements and pathological outcome in order to establish DWI as an imaging biomarker in clinical practice. We also recognise that combining ovary and seminal vesicles within normal tissue ROI may not give true representation of median ADC within normal tissue; however as these organs are included in the PTV and receive same dose as GTV it was deemed that this comparison was the most similar. Furthermore, assessing repeatability is also required if utilising DWI for patient stratification in order to ensure that ADC metric changes are due to treatment related changes in tumour biology, and not machine or other patient related factors [
      • Kooreman E.S.
      • van Houdt P.J.
      • Nowee M.E.
      • van Pelt V.W.J.
      • Tijssen R.H.N.
      • Paulson E.S.
      • et al.
      Feasibility and accuracy of quantitative imaging on a 1.5 T MR-linear accelerator.
      ].
      Previous analysis of our data included b-values <100 s/mm2 in ADC calculations where we demonstrated one patient with a decreasing trend of ADC metrics [
      • Ingle M.
      • Blackledge M.D.
      • White I.M.
      • Lalondrelle S.
      • Hafeez S.
      • Bhide S.
      OC - 0397 Quantitative Analysis of diffusion weighted imaging in rectal cancer during MR-Linac radiotherapy.
      ]. Excluding b-values <100 s/mm2 reversed this trend, indicating that lower b-values make ADC a more sensitive biomarker, especially to perfusion [
      • Kooreman E.S.
      • van Houdt P.J.
      • Keesman R.
      • Pos F.J.
      • van Pelt V.W.J.
      • Nowee M.E.
      • et al.
      ADC measurements on the unity MR-linac – a recommendation on behalf of the elekta unity MR-linac consortium.
      ]. Intra-voxel incoherent motion (IVIM) analysis may provide more accurate assessment of tumour response to treatment by separating perfusion and diffusion factors [
      • Yang L.
      • Xia C.
      • Zhao J.
      • Zhou X.
      • Wu B.
      The value of intravoxel incoherent motion and diffusion kurtosis imaging in the assessment of tumor regression grade and T stages after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.
      ], giving a more robust picture of tumour microcellularity during treatment.
      In conclusion, DWI signal change and ADC metrics can be measured on MR-Linac in rectal cancer, demonstrating promise in its ability to determine response to treatment. Integration of DWI in adaptive radiotherapy planning may increase confidence in delivering dose escalated radiotherapy to GTV with the aim of improving treatment related outcomes in rectal cancer patients.

      Declaration of Competing Interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SL reports travel and educational grants from Elekta (Elekta AB, Stockholm, Sweden). SH reports non-financial support from Elekta (Elekta AB, Stockholm, Sweden), non-financial support from Merck Sharp & Dohme (MSD), personal fees and non-financial support from Roche outside the submitted work. SB reports travel and educational grants from Elekta (Elekta AB, Stockholm, Sweden)..

      Acknowledgements

      This study represents independent research supported by the National Institute for Health Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This work was supported by The Institute of Cancer Research and Cancer Research UK (CRUK) grant number C33589/A28284 and the Royal Marsden Cancer Charity.

      References

        • Glynne-Jones R.
        • Wyrwicz L.
        • Tiret E.
        • Brown G.
        • Rödel C.
        • Cervantes A.
        • et al.
        Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2017; 28 (iv22–40)https://doi.org/10.1093/annonc/mdx224
        • Glynne-Jones R.
        • Wyrwicz L.
        • Tiret E.
        • Brown G.
        • Rödel C.
        • Cervantes A.
        • et al.
        Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2017; 28 (iv22–40)https://doi.org/10.1093/annonc/mdx224
        • Habr-Gama A.
        • Perez R.O.
        • Nadalin W.
        • Sabbaga J.
        • Ribeiro U.
        • Sousa S.E.
        • et al.
        Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results.
        Ann Surg. 2004; https://doi.org/10.1097/01.sla.0000141194.27992.32
        • Maas M.
        • Nelemans P.J.
        • Valentini V.
        • Das P.
        • Rödel C.
        • Kuo L.-J.
        • et al.
        Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
        Lancet Oncol. 2010; 11: 835-844https://doi.org/10.1016/S1470-2045(10)70172-8
        • Zorcolo L.
        • Rosman A.S.
        • Restivo A.
        • Pisano M.
        • Nigri G.R.
        • Fancellu A.
        • et al.
        Complete pathologic response after combined modality treatment for rectal cancer and long-term survival: a meta-analysis.
        Ann Surg Oncol. 2012; 19: 2822-2832https://doi.org/10.1245/s10434-011-2209-y
      1. van Gijn W, Marijnen CAM, Nagtegaal ID, Kranenbarg EM-K, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 2011;12:575–82. https://doi.org/10.1016/S1470-2045(11)70097-3.

        • Mandard A.-M.
        • Dalibard F.
        • Mandard J.-C.
        • Marnay J.
        • Henry-Amar M.
        • Petiot J.-F.
        • et al.
        Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations.
        Cancer. 1994; 73: 2680-2686https://doi.org/10.1002/1097-0142(19940601)73:11<2680::AID-CNCR2820731105>3.0.CO;2-C
        • Vecchio F.M.
        • Valentini V.
        • Minsky B.D.
        • Padula G.D.A.
        • Venkatraman E.S.
        • Balducci M.
        • et al.
        The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
        Int J Radiat Oncol. 2005; 62: 752-760https://doi.org/10.1016/j.ijrobp.2004.11.017
        • Hall M.D.
        • Schultheiss T.E.
        • Smith D.D.
        • Fakih M.G.
        • Wong J.Y.C.
        • Chen Y.-J.
        Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.
        Acta Oncol (Madr). 2016; 55: 1392-1399https://doi.org/10.1080/0284186X.2016.1235797
        • Mohiuddin M.
        • Regine W.F.
        • John W.J.
        • Hagihara P.F.
        • McGrath P.C.
        • Kenady D.E.
        • et al.
        Preoperative chemoradiation in fixed distal rectal cancer: dose time factors for pathological complete response.
        Int J Radiat Oncol. 2000; 46: 883-888https://doi.org/10.1016/S0360-3016(99)00486-1
        • O’Neill B.D.
        • Brown G.
        • Heald R.
        • Cunningham D.
        • Tait D.M.
        Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer.
        Lancet Oncol. 2007; https://doi.org/10.1016/S1470-2045(07)70202-4
        • Bernier L.
        • Balyasnikova S.
        • Tait D.
        • Brown G.
        Watch-and-wait as a therapeutic strategy in rectal cancer.
        Curr Colorectal Cancer Rep. 2018; https://doi.org/10.1007/s11888-018-0398-5
        • Wang Q.
        • Zhang R.
        • Xiao W.
        • Zhang S.
        • Wei M.
        • Li Y.
        • et al.
        The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy.
        Radiat Oncol. 2021; 16: 16https://doi.org/10.1186/s13014-021-01746-0
        • Glynne-Jones R.
        • Hughes R.
        Complete response after chemoradiotherapy in rectal cancer (watch-and-wait): have we cracked the code?.
        Clin Oncol. 2016; 28: 152-160https://doi.org/10.1016/j.clon.2015.10.011
        • Appelt A.L.
        • Pløen J.
        • Vogelius I.R.
        • Bentzen S.M.
        • Jakobsen A.
        Radiation dose-response model for locally advanced rectal cancer after preoperative chemoradiation therapy.
        Int J Radiat Oncol. 2013; 85: 74-80https://doi.org/10.1016/j.ijrobp.2012.05.017
        • Burbach J.P.M.
        • den Harder A.M.
        • Intven M.
        • van Vulpen M.
        • Verkooijen H.M.
        • Reerink O.
        Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: a systematic review and meta-analysis.
        Radiother Oncol. 2014; 113: 1-9https://doi.org/10.1016/j.radonc.2014.08.035
        • Urbano M.T.G.
        • Henrys A.J.
        • Adams E.J.
        • Norman A.R.
        • Bedford J.L.
        • Harrington K.J.
        • et al.
        Intensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels.
        Int J Radiat Oncol. 2006; 65: 907-916https://doi.org/10.1016/j.ijrobp.2005.12.056
        • Parekh A.
        • Truong M.T.
        • Pashtan I.
        • Qureshi M.M.
        • Martin N.E.
        • Nawaz O.
        • et al.
        Acute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer.
        Gastrointest Cancer Res. 2013; 6: 137-143
        • Gani C.
        • Boldrini L.
        • Valentini V.
        Online MR guided radiotherapy for rectal cancer. New opportunities.
        Clin Transl Radiat Oncol. 2019; 18: 66-67https://doi.org/10.1016/j.ctro.2019.04.005
        • Le Bihan D.
        • Iima M.
        Diffusion magnetic resonance imaging: what water tells us about biological tissues.
        PLoS Biol. 2015; 13: 1-13https://doi.org/10.1371/journal.pbio.1002203
        • Koh D.M.
        • Collins D.J.
        Diffusion-weighted MRI in the body: applications and challenges in oncology.
        Am J Roentgenol. 2007; 188: 1622-1635https://doi.org/10.2214/AJR.06.1403
        • Hu F.
        • Tang W.
        • Sun Y.
        • Wan D.
        • Cai S.
        • Zhang Z.
        • et al.
        The value of diffusion kurtosis imaging in assessing pathological complete response to neoadjuvant chemoradiation therapy in rectal cancer: a comparison with conventional diffusionweighted imaging.
        Oncotarget. 2017; 8: 75597-75606https://doi.org/10.18632/oncotarget.17491
        • Bin Z.H.
        • Zhang X.Y.
        • Zhou X.H.
        • Li X.T.
        • Liu Y.L.
        • Wang S.
        • et al.
        Assessment of pathological complete response to preoperative chemoradiotherapy by means of multiple mathematical models of diffusion-weighted MRI in locally advanced rectal cancer: a prospective single-center study.
        J Magn Reson Imaging. 2017; 46: 175-183https://doi.org/10.1002/jmri.25567
        • Intven M.
        • Reerink O.
        • Philippens M.E.P.
        Diffusion-weighted MRI in locally advanced rectal cancer: Pathological response prediction after neo-adjuvant radiochemotherapy.
        Strahlentherapie Und Onkol. 2013; 189: 117-122https://doi.org/10.1007/s00066-012-0270-5
        • Chen Y.G.
        • Chen M.Q.
        • Guo Y.Y.
        • Li S.C.
        • Wu J.X.
        • Xu B.H.
        Apparent diffusion coefficient predicts pathology complete response of rectal cancer treated with neoadjuvant chemoradiotherapy.
        PLoS ONE. 2016; 11: 1-12https://doi.org/10.1371/journal.pone.0153944
        • Kim S.H.
        • Lee J.Y.
        • Lee J.M.
        • Han J.K.
        • Choi B.I.
        Apparent diffusion coefficient for evaluating tumour response to neoadjuvant chemoradiation therapy for locally advanced rectal cancer.
        Eur Radiol. 2011; 21: 987-995https://doi.org/10.1007/s00330-010-1989-y
        • Sun Y.S.
        • Zhang X.P.
        • Tang L.
        • Ji J.F.
        • Gu J.
        • Cai Y.
        • et al.
        Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging.
        Radiology. 2010; 254: 170-178https://doi.org/10.1148/radiol.2541082230
        • Chan A.K.P.
        • Wong A.O.
        • Langevin J.
        • Jenken D.
        • Heine J.
        • Buie D.
        • et al.
        Preoperative chemotherapy and pelvic radiation for tethered or fixed rectal cancer: a phase II dose escalation study.
        Int J Radiat Oncol. 2000; 48: 843-856https://doi.org/10.1016/S0360-3016(00)00692-1
        • Xie H.
        • Sun T.
        • Chen M.
        • Wang H.
        • Zhou X.
        • Zhang Y.
        • et al.
        Effectiveness of the apparent diffusion coefficient for predicting the response to chemoradiation therapy in locally advanced rectal cancer: a systematic review and meta-analysis.
        Medicine (Baltimore). 2015; 94: e517
        • Pham T.T.
        • Liney G.P.
        • Wong K.
        • Barton M.B.
        Functional MRI for quantitative treatment response prediction in locally advanced rectal cancer.
        Br J Radiol. 2017; 90https://doi.org/10.1259/bjr.20151078
        • Raaymakers B.W.
        • Lagendijk J.J.W.
        • Overweg J.
        • Kok J.G.M.
        • Raaijmakers A.J.E.
        • Kerkhof E.M.
        • et al.
        Integrating a 1.5 T MRI scanner with a 6 MV accelerator: proof of concept.
        Phys Med Biol. 2009; 54: N229-N237https://doi.org/10.1088/0031-9155/54/12/n01
        • Kooreman E.S.
        • van Houdt P.J.
        • Nowee M.E.
        • van Pelt V.W.J.
        • Tijssen R.H.N.
        • Paulson E.S.
        • et al.
        Feasibility and accuracy of quantitative imaging on a 1.5 T MR-linear accelerator.
        Radiother Oncol. 2019; 133: 156-162https://doi.org/10.1016/j.radonc.2019.01.011
        • Kooreman E.S.
        • van Houdt P.J.
        • Keesman R.
        • Pos F.J.
        • van Pelt V.W.J.
        • Nowee M.E.
        • et al.
        ADC measurements on the unity MR-linac – a recommendation on behalf of the elekta unity MR-linac consortium.
        Radiother Oncol. 2020; https://doi.org/10.1016/j.radonc.2020.09.046
        • Winkel D.
        • Bol G.H.
        • Kroon P.S.
        • van Asselen B.
        • Hackett S.S.
        • Werensteijn-Honingh A.M.
        • et al.
        Adaptive radiotherapy: the Elekta Unity MR-linac concept.
        Clin Transl Radiat Oncol. 2019; 18: 54-59https://doi.org/10.1016/j.ctro.2019.04.001
      2. Intven MPW, de Mol van Otterloo SR, Mook S, Doornaert PAH, de Groot-van Breugel EN, Sikkes GG, et al. Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience. Radiother Oncol 2021;154:172–8. https://doi.org/10.1016/j.radonc.2020.09.024.

        • Blackledge M.D.
        • Tunariu N.
        • Zugni F.
        • Holbrey R.
        • Orton M.R.
        • Ribeiro A.
        • et al.
        Noise-corrected, exponentially weighted, diffusion-weighted MRI (niceDWI) improves image signal uniformity in whole-body imaging of metastatic prostate cancer.
        Front Oncol. 2020; 10: 1-12https://doi.org/10.3389/fonc.2020.00704
        • Blackledge M.D.
        • Collins D.J.
        • Koh D.M.
        • Leach M.O.
        Rapid development of image analysis research tools: bridging the gap between researcher and clinician with pyOsiriX.
        Comput Biol Med. 2016; 69: 203-212https://doi.org/10.1016/j.compbiomed.2015.12.002
        • Fu Z.Z.
        • Peng Y.
        • Cao L.Y.
        • Chen Y.S.
        • Li K.
        • Fu B.H.
        Value of apparent diffusion coefficient (ADC) in assessing radiotherapy and chemotherapy success in cervical cancer.
        Magn Reson Imaging. 2015; 33: 516-524https://doi.org/10.1016/j.mri.2015.02.002
        • Shaverdian N.
        • Yang Y.
        • Hu P.
        • Hart S.
        • Sheng K.
        • Lamb J.
        • et al.
        Feasibility evaluation of diffusion-weighted imaging using an integrated MRI-radiotherapy system for response assessment to neoadjuvant therapy in rectal cancer.
        Br J Radiol. 2017; 90: 20160739https://doi.org/10.1259/bjr.20160739
        • Intven M.
        • Reerink O.
        • Philippens M.E.P.
        Repeatability of diffusion-weighted imaging in rectal cancer.
        J Magn Reson Imaging. 2014; 40: 146-150https://doi.org/10.1002/jmri.24337
      3. Blazic I, Lilic G, Gajic M. Gastrointestinal imaging: quantitative assessment of rectal cancer response to neoadjuvant CRT Blazic et al. Radiology 2017;282:418–28.

        • Petrelli F.
        • Sgroi G.
        • Sarti E.
        • Barni S.
        Increasing the Interval Between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer: A Meta-analysis of Published Studies.
        Ann Surg. 2016; 263: 458-464
        • Ingle M.
        • Blackledge M.D.
        • White I.M.
        • Lalondrelle S.
        • Hafeez S.
        • Bhide S.
        OC - 0397 Quantitative Analysis of diffusion weighted imaging in rectal cancer during MR-Linac radiotherapy.
        Radiat Oncol. 2021; 161 (S293–4)
        • Yang L.
        • Xia C.
        • Zhao J.
        • Zhou X.
        • Wu B.
        The value of intravoxel incoherent motion and diffusion kurtosis imaging in the assessment of tumor regression grade and T stages after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer.
        Eur J Radiol. 2021; 136109504https://doi.org/10.1016/j.ejrad.2020.109504