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The role of diffusion-weighted MRI and 18F-FDG PET/CT in the prediction of pathologic complete response after radiochemotherapy for rectal cancer: A systematic review

      Abstract

      After neoadjuvant radiochemotherapy (RCT) for locally advanced rectal cancer, 15–27% of the patients experience a pathological complete response (pCR). This observation raises the question as to whether invasive surgery could be avoided in a selected cohort of patients who obtain a clinical complete response after preoperative RCT. In this respect, there has been growing interest in functional imaging techniques to improve clinical response assessment. This systematic review focuses on the role of diffusion-weighted imaging (DWI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the prediction of pCR after RCT for rectal cancer.
      A total of 14 publications on DWI and 25 on 18F-FDG PET/CT were retrieved. Pooled analysis of individual patient data shows both imaging modalities have a low positive predictive value in the prediction of pCR (mean PPV of 54% and 39% for DWI- and 18F-FDG PET/CT-based parameters respectively). Especially pre-RCT imaging is unable to predict pCR with overall accuracies of 68–72% for DWI and 44% for 18F-FDG PET/CT. Qualitative DWI assessment 5–10 weeks after the end of RCT may outperform apparent diffusion coefficient (ADC)-based DWI-parameters (overall accuracy of 87% vs. 74–78%). Although few data are available, early changes in FDG-uptake seem promising in the prediction of pCR and the role of 18F-FDG PET/CT during RCT should be further investigated. Quantitative and qualitative 18F-FDG PET/CT measurements are equally effective in the assessment of pCR after RCT.
      The major strength of DWI and 18F-FDG PET/CT lies in the identification of non-responders who are not candidates for organ preservation. Up to now, DWI and 18F-FDG PET/CT are not accurate enough to safely select patients for organ-sparing strategies. Future research must focus on the integration of functional imaging with clinical data and molecular biomarkers.

      Keywords

      Neoadjuvant radiochemotherapy (RCT) followed by total mesorectal excision (TME) surgery is currently the standard treatment for locally advanced rectal carcinoma [
      • Sauer R.
      • Becker H.
      • Hohenberger W.
      • et al.
      Preoperative versus postoperative chemoradiotherapy for rectal cancer.
      ,
      • Bosset J.F.
      • Collette L.
      • Calais G.
      • et al.
      Chemotherapy with preoperative radiotherapy in rectal cancer.
      ,
      • MacFarlane J.K.
      • Ryall R.D.
      • Heald R.J.
      Mesorectal excision for rectal cancer.
      ]. The tumoral response to this preoperative treatment is very heterogeneous: while 15–27% of the patients achieve a pathological complete response (pCR), a partial response is seen in 54–75% and others show no response at all [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ]. Patients who achieve a pCR have a favorable long-term outcome with excellent local control and disease-free survival regardless of their initial T- and N-stages [
      • Maas M.
      • Nelemans P.J.
      • Valentini V.
      • et al.
      Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data.
      ,
      • Valentini V.
      • Coco C.
      • Picciocchi A.
      • et al.
      Does downstaging predict improved outcome after preoperative chemoradiation for extraperitoneal locally advanced rectal cancer? A long-term analysis of 165 patients.
      ,
      • Vecchio F.M.
      • Valentini V.
      • Minsky B.D.
      • et al.
      The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.
      ]. Retrospective studies from Brazil have highlighted the ‘wait-and-see’ policy in such patients [
      • Habr-Gama A
      • Perez
      • Nadalin W
      Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results.
      ]. More recent series support the feasibility of this approach [
      • Maas M.
      • Beets-Tan R.G.
      • Lambregts D.M.
      • et al.
      Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer.
      ,
      • Dalton R.S.
      • Velineni R.
      • Osborne M.E.
      • et al.
      A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management?.
      ]. Adopting a non-operative strategy for clinical complete responders will avoid the risks of surgical morbidity and mortality, and will spare them the need for a stoma [
      • Peeters K.C.
      • van de Velde C.J.
      • Leer J.W.
      • et al.
      Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients–a Dutch colorectal cancer group study.
      ,
      • Remzi F.H.
      • Fazio V.W.
      • Gorgun E.
      • et al.
      Quality of life, functional outcome, and complications of coloplasty pouch after low anterior resection.
      ,
      • Sartori C.A.
      • Sartori A.
      • Vigna S.
      • Occhipinti R.
      • Baiocchi G.L.
      Urinary and sexual disorders after laparoscopic TME for rectal cancer in males.
      ]. However, before a ‘wait-and-see’ policy could be safely implemented, a precise selection of the eligible patients is mandatory.
      The gold standard for assessing the tumoral response to preoperative RCT is conventional histopathological analysis. This method, however, is only applicable in the postoperative setting and consequently cannot be used for the preoperative selection for an individualized treatment. Computed tomography (CT), endorectal ultrasound (EUS) and conventional magnetic resonance imaging (MRI) have shown to lack accuracy for restaging after RCT [
      • Zhao R.S.
      • Wang H.
      • Zhou Z.Y.
      • Zhou Q.
      • Mulholland M.W.
      Restaging of locally advanced rectal cancer with magnetic resonance imaging and endoluminal ultrasound after preoperative chemoradiotherapy: a systemic review and meta-analysis.
      ,
      • Hanly A.M.
      • Ryan E.M.
      • Rogers A.C.
      • et al.
      Multicenter Evaluation of Rectal cancer ReImaging pOst Neoadjuvant (MERRION) Therapy.
      ,
      • Huh J.W.
      • Park Y.A.
      • Jung E.J.
      • Lee K.Y.
      • Sohn S.K.
      Accuracy of endorectal ultrasonography and computed tomography for restaging rectal cancer after preoperative chemoradiation.
      ,
      • Lee J.H.
      • Jang H.S.
      • Kim J.G.
      Prediction of pathologic staging with magnetic resonance imaging after preoperative chemoradiotherapy in rectal cancer: pooled analysis of KROG 10-01 and 11-02.
      ]. In recent years, there has been growing interest in functional imaging techniques to improve clinical response assessment. These imaging modalities depict the microstructural and metabolic characteristics of the tumor, allowing assessment of treatment-induced changes before morphological changes become apparent. In this respect, diffusion-weighted imaging (DWI) and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) have emerged as powerful tools in the response prediction before, during and after neoadjuvant RCT for rectal cancer.
      DWI is a non-invasive imaging modality, providing functional information on the microstructure of tissues through the assessment of differences in water proton mobility [
      • Patterson D.M.
      • Padhani A.R.
      • Collins D.J.
      Technology insight: water diffusion MRI – a potential new biomarker of response to cancer therapy.
      ]. Water diffusion characteristics depend on several factors such as cell density, vascularity, viscosity of the extracellular fluid and cell membrane integrity. By quantifying these properties as the apparent diffusion coefficient (ADC), DWI can be used as an imaging biomarker to monitor and predict tumoral response to RCT [
      • Koh D.M.
      • Collins D.J.
      Diffusion-weighted MRI in the body: applications and challenges in oncology.
      ,
      • Seierstad T.
      • Røe K.
      • Olsen D.R.
      Noninvasive monitoring of radiation-induced treatment response using proton magnetic resonance spectroscopy and diffusion-weighted magnetic resonance imaging in a colorectal tumor model.
      ].
      18F-FDG PET semi-quantitatively assesses tumor glucose metabolic activity through changes in FDG-uptake. A decrease in FDG-uptake after radiotherapy and/or chemotherapy has been correlated with pathological response in several tumor types [
      • Schelling M.
      • Avril N.
      • Nährig J.
      • et al.
      Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer.
      ,
      • Wieder H.A.
      • Brücher B.L.
      • Zimmermann F.
      • et al.
      Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment.
      ,
      • Bokemeyer C.
      • Kollmannsberger C.
      • Oechsle K.
      • et al.
      Early prediction of treatment response to high-dose salvage chemotherapy in patients with relapsed germ cell cancer using [(18)F]FDG PET.
      ].
      In this systematic review, we collect the current evidence of the role of DWI and 18F-FDG PET/CT in the prediction of pCR after preoperative RCT for locally advanced rectal cancer.

      Materials and methods

      Search strategy and selection criteria

      The MEDLINE and Embase databases were searched for the terms (“rectal cancer” AND “diffusion magnetic resonance imaging” AND “response”) and for (“rectal cancer” AND “positron emission tomography” AND “response”) (29 September 2014) [
      • Macbeth F.
      • Overgaard J.
      Expert reviews, systematic reviews and meta-analyses.
      ]. These initial searches yielded 155 and 222 publications respectively. Only papers published in English, German, and French were included, resulting in 153 and 216 articles. All titles and abstracts were screened and only studies reporting on the role of DWI or 18F-FDG PET in the assessment of pCR after RCT for locally advanced rectal cancer were retained. Reviews, general overview articles and congress abstracts were excluded. To identify additional relevant studies, the reference lists of the retrieved studies were checked manually. A total of 14 relevant DWI and 25 18F-FDG PET/CT papers were identified. Selected studies were evaluated for methodological quality using the quality assessment of diagnostic accuracy studies (QUADAS) criteria [
      • Whiting P.
      • Rutjes A.W.
      • Reitsma J.B.
      • Bossuyt P.M.
      • Kleijnen J.
      The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews.
      ]. Literature selection results are depicted in Fig. 1. A meta-analysis was not performed due to the wide heterogeneity between the included studies.

      Data extraction

      We extracted all available data on the performance of following quantitative DWI parameters: pretreatment ADC (ADCpre), ADC during RCT (ADCduring), posttreatment ADC (ADCpost), change in ADC during RCT (ΔADCduring) and change in ADC after RCT (ΔADCpost). Additionally, volumetric data and data on qualitative DWI assessment were collected. Following 18F-FDG PET/CT parameters were retained: the mean and maximum standardized uptake value (SUV) measured before (SUVmeanpre, SUVmaxpre), during (SUVmeanduring, SUVmaxduring) and after RCT (SUVmeanpost, SUVmaxpost). The absolute change in SUVmax (ΔSUVmax) and the response indices were also extracted (RI SUVmean, RI SUVmax), as was the total lesion glycolysis (TLG) and the metabolic tumor volume (MTV). The visual response score (VRS) was retained as a qualitative parameter.
      Some papers used receiver operating characteristic (ROC) analysis to calculate cutoff values for the individual response parameters. A ROC curve plots the true positive rate against the false positive rate at various threshold settings, thereby allowing to calculate optimal cutoff values. If cutoff values were provided, 2 × 2 contingency tables were constructed and the sensitivity, specificity, positive and negative predictive values of DWI and 18F-FDG PET/CT in the prediction of pCR were calculated (Suppl Fig. 1). We defined the sensitivity for pCR prediction as the fraction of patients with pCR that is correctly identified as such by imaging. The specificity is the fraction of patients without pCR correctly identified as such by DWI or 18F-FDG PET/CT. The positive predictive value (PPV) reflects the probability that a complete response on imaging is confirmed by pathological examination. Conversely, the negative predictive value (NPV) reflects the probability that an incomplete response on imaging is confirmed by pathology. Finally, when available, individual patient data (i.e. true positives, false positives, true negatives and false negatives) were extracted to calculate a pooled accuracy of the retained DWI and 18F-FDG PET/CT parameters.

      Results

      Nine papers reported on the role of ADCpre in the prediction of pCR (Table 1). Three articles found that a low pretreatment ADC significantly correlated with pCR [
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      ,
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      ,
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      ]. Our group demonstrated that a pretreatment ADC lower than 1.06 × 10−3 mm2/s predicted pCR with a sensitivity of 100%, specificity of 86% and overall accuracy of 90% [
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      ]. In a larger patient group, Intven et al. found that a pretreatment ADC lower than 0.97 × 10−3 correctly predicted pCR with an overall accuracy of 81%, but with a sensitivity of only 56% [
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      ]. Pooled data show ADCpre predicts pCR with a NPV of 90% and a specificity of 68%, but with a PPV of only 35%. In a study of 20 patients it was demonstrated that the change in ADC after 10–15 fractions of radiation therapy (ΔADCduring) was significantly correlated with pCR [
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      ]. ROC analysis showed an area under the curve (AUC) of 100% at a cutoff point of 50%. Volumetric assessment of DWI prior to RCT has no value in the prediction of pCR, as shown by three papers [
      • Curvo-Semedo L.
      • Lambregts D.M.
      • Maas M.
      • et al.
      Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging.
      ,
      • Ha H.I.
      • Kim A.Y.
      • Yu C.S.
      • Park S.H.
      • Ha H.K.
      Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy.
      ,
      • Lambregts DM
      • Rao SX
      • Sassen S
      MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: a bi-institutional validation study.
      ].
      Table 1Early pCR prediction with DWI.
      StudyNpCR (%)b-Values (s/mm2), field strengthDWI parameterCorrelation with pCRp-ValueCutoff
      Cutoff values of ADC are in mm2/s, cutoff values of volumes are in cm3.
      Sens

      (%)
      Spec

      (%)
      PPV

      (%)
      NPV

      (%)
      Acc

      (%)
      Lambrecht
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      2030b0-50-100-500-750-1000, 1.5 TADCpreNegative0.0031.06 × 10−3100867510090
      Lambrecht
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      2227b0-50-100-500-750-1000, 1.5TADCpreNegative0.0021.06 × 10−3100887510091
      Intven
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      5915b0-200-800, 3TADCpreNegative0.010.97 × 10−35686429281
      Kim
      • 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.
      7614b0-600-1000, 1.5TADCpreNegative0.40940.91 × 10−38239189345
      Curvo-Semedo
      • Curvo-Semedo L.
      • Lambregts D.M.
      • Maas M.
      • et al.
      Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging.
      49
      In one patient, ADC measurements were not obtained because the tumor had an entirely mucinous aspect.
      27b0-500-1000, 1.5TADCpreNegative0.610.97 × 10−33981427869
      5028VDWIpreNegative0.1612.55778505272
      Engin
      • Engin G.
      • Sharifov R.
      • Güral Z.
      • et al.
      Can diffusion-weighted MRI determine complete responders after neoadjuvant chemoradiation for locally advanced rectal cancer?.
      3030b50-400-800, 1.5TADCprePositive0.066
      Lee
      • Lee E.M.
      • Hong Y.S.
      • Kim K.P.
      • et al.
      Phase II study of preoperative chemoradiation with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.
      3824b0-1000ADCpreNone0.972
      Genovesi
      • Genovesi D
      • Filippone A
      • Ausili Cèfare G
      Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results of a monoinstitutional prospective study.
      2836b0-400-500-600-800-1000, 3TADCpreNegative0.33
      Ha
      • Ha H.I.
      • Kim A.Y.
      • Yu C.S.
      • Park S.H.
      • Ha H.K.
      Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy.
      10035b0-150-1000, 1.5TADCprePositive0.484
      VDWIprePositive0.742
      Lambregts
      • Lambregts DM
      • Rao SX
      • Sassen S
      MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: a bi-institutional validation study.
      11218b0-25-50-100-300-500-1000-1100, 1.5TVDWIpre R1NegativeNA12.55571298868
      VDWIpre R2NegativeNA12.57078419277
      Pooled data22620ADCpre6968359068
      274
      To obtain pooled data, N was multiplied by the number of participating radiologists.
      20VDWIpre6175388972
      Acc = accuracy; ADC = apparent diffusion coefficient; DWI = diffusion weighted imaging; N = number of patients; NA = not available; NPV = negative predictive value; pCR = pathologic complete response; PPV = positive predictive value; R = radiologist; Sens = sensitivity; Spec = specificity; T = Tesla; V = volume.
      low asterisk Cutoff values of ADC are in mm2/s, cutoff values of volumes are in cm3.
      In one patient, ADC measurements were not obtained because the tumor had an entirely mucinous aspect.
      To obtain pooled data, N was multiplied by the number of participating radiologists.
      Seven papers demonstrated that a high ADCpost value significantly correlated with pCR (Table 2). In a retrospective analysis of 40 patients, Kim et al. found that a mean ADCpost > 1.20 × 10−3 mm2/s predicted pCR with a sensitivity and overall accuracy of 100% and 85% respectively [
      • Kim S.H.
      • Lee J.M.
      • Hong S.H.
      • et al.
      Locally advanced rectal cancer: added value of diffusion-weighted MR imaging in the evaluation of tumor response to neoadjuvant chemo- and radiation therapy.
      ]. The same authors confirmed this in a larger retrospective study of 76 patients, although the optimal cutoff increased to 1.30 × 10−3 mm2/s [
      • 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.
      ]. Conversely, Curvo-Semedo et al. reported a lower ADCpost in patients who achieved pCR, although this was not significant [
      • Curvo-Semedo L.
      • Lambregts D.M.
      • Maas M.
      • et al.
      Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging.
      ]. Four papers found that an ADC increase of 41–48% was predictive for pCR [
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      ,
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      ,
      • 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.
      ,
      • Lee E.M.
      • Hong Y.S.
      • Kim K.P.
      • et al.
      Phase II study of preoperative chemoradiation with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.
      ]. Pooled analysis shows a moderate performance of late quantitative DWI assessment with overall accuracies of 74% and 78% for ADCpost and ΔADCpost respectively. In contrast to pre-RCT DWI, volumetric assessment after RCT might be a valuable tool for pCR prediction [
      • Curvo-Semedo L.
      • Lambregts D.M.
      • Maas M.
      • et al.
      Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging.
      ,
      • Ha H.I.
      • Kim A.Y.
      • Yu C.S.
      • Park S.H.
      • Ha H.K.
      Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy.
      ,
      • Lambregts DM
      • Rao SX
      • Sassen S
      MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: a bi-institutional validation study.
      ]. Pooled analysis demonstrates that volumetric DWI measurements after RCT can predict pCR with a sensitivity and an overall accuracy of 65% and 90%. Relative changes in tumor volume on DWI can predict pCR with a sensitivity and accuracy of 83% and 85% respectively.
      Table 2Late pCR assessment with DWI.
      StudyNpCR (%)b-values (s/mm2), field strengthDWI parameterInterval RCT-DWI (weeks)Correlation with pCRp-valueCutoff
      Cutoff values of ADC are in mm2/s, cutoff values of volumes are in cm3.
      Sens

      (%)
      Spec

      (%)
      PPV

      (%)
      NPV

      (%)
      Acc

      (%)
      Quantitative analysis
      Lambrecht
      • Lambrecht M.
      • Vandecaveye V.
      • De Keyzer F.
      • et al.
      Value of diffusion-weighted magnetic resonance imaging for prediction and early assessment of response to neoadjuvant radiochemotherapy in rectal cancer: preliminary results.
      2030b0-50-100-500-750-1000, 1.5TΔADCpost (%)5–7Positive0.001148%100938610095
      Intven
      • Intven M.
      • Reerink O.
      • Philippens M.E.
      Diffusion-weighted MRI in locally advanced rectal cancer: pathological response prediction after neo-adjuvant radiochemotherapy.
      5915b0-200-800, 3TADCpost4–8Positive0.047
      ΔADCpost (%)Positive<0.00141%7892649690
      Kim
      • 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.
      7614b0-600-1000, 1.5TADCpost4–6Positive<0.00011.30 × 10−3100855210087
      ΔADCpost (%)Positive<0.000142%100713710075
      Curvo-Semedo
      • Curvo-Semedo L.
      • Lambregts D.M.
      • Maas M.
      • et al.
      Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy–conventional MR volumetry versus diffusion-weighted MR imaging.
      49
      In one patient, ADC measurements were not obtained because the tumor had an entirely mucinous aspect.
      27b0-500-1000, 1.5TADCpost6–8Negative0.481.41 × 10−34656277453
      ΔADCpost (%)Negative0.9625.3%5464357961
      5028VDWIpostNegative<0.0010.15791001009294
      ΔVpost (%)positive<0.00197.5%8689759488
      Engin
      • Engin G.
      • Sharifov R.
      • Güral Z.
      • et al.
      Can diffusion-weighted MRI determine complete responders after neoadjuvant chemoradiation for locally advanced rectal cancer?.
      3030b50-400-800, 1.5TADCpost6Positive0.071
      Lee
      • Lee E.M.
      • Hong Y.S.
      • Kim K.P.
      • et al.
      Phase II study of preoperative chemoradiation with S-1 plus oxaliplatin in patients with locally advanced rectal cancer.
      3824b0-1000ADCpost6Positive0.037
      ΔADCpost (%)Positive0.026
      Genovesi
      • Genovesi D
      • Filippone A
      • Ausili Cèfare G
      Diffusion-weighted magnetic resonance for prediction of response after neoadjuvant chemoradiation therapy for locally advanced rectal cancer: preliminary results of a monoinstitutional prospective study.
      2836b0-400-500-600-800-1000, 3TADCpost8Positive0.003
      Ha
      • Ha H.I.
      • Kim A.Y.
      • Yu C.S.
      • Park S.H.
      • Ha H.K.
      Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy.
      10035b0-150-1000, 1.5TADCpostNAPositive<0.0011.20 × 10−37165528167
      VDWIpostNegative<0.001
      ΔVpost (%)Positive<0.00186.8%9180719584
      Lambregts
      • Lambregts DM
      • Rao SX
      • Sassen S
      MRI and diffusion-weighted MRI volumetry for identification of complete tumor responders after preoperative chemoradiotherapy in patients with rectal cancer: a bi-institutional validation study.
      11218b0-25-50-100-300-500-1000-1100, 1.5TVDWIpost R1NANegativeNA0.156098869291
      VDWIpost R2NegativeNA0.156092639187
      ΔVpost (%) R1PositiveNA97.5%8093739691
      ΔVpost (%) R2PositiveNA97.5%7082459379
      Kim
      • Kim S.H.
      • Lee J.M.
      • Hong S.H.
      • et al.
      Locally advanced rectal cancer: added value of diffusion-weighted MR imaging in the evaluation of tumor response to neoadjuvant chemo- and radiation therapy.
      4028b0-1000, 1.5TADCpost4–6 Positive<0.00011.20 × 10−3100796510085
      Song
      • Song I.
      • Kim S.H.
      • Lee S.J.
      • Choi J.Y.
      • Kim M.J.
      • Rhim H.
      Value of diffusion-weighted imaging in the detection of viable tumour after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging.
      5012b0-100-800-1000, 3TADCpost6Positive<0.00011.045 × 10−3100753510078
      Pooled data31524ADCpost7872479174
      20419ΔADCpost (%)8078469478
      27420VDWIpost6596809290
      37424ΔVpost (%)8386659485
      Qualitative analysis
      Engin
      • Engin G.
      • Sharifov R.
      • Güral Z.
      • et al.
      Can diffusion-weighted MRI determine complete responders after neoadjuvant chemoradiation for locally advanced rectal cancer?.
      3030b50-400-800, 1.5TSignal intensity8221001007577
      Song
      • Song I.
      • Kim S.H.
      • Lee S.J.
      • Choi J.Y.
      • Kim M.J.
      • Rhim H.
      Value of diffusion-weighted imaging in the detection of viable tumour after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging.
      5012b0-100-800-1000, 3TVRS R163398679290
      VRS R25091439386
      Lambregts
      • Lambregts D.M.
      • Vandecaveye V.
      • Barbaro B.
      • et al.
      Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study.
      12019b0-1000, 1.5TVRS R15–105694708986
      VRS R26490629084
      VRS R35297818988
      Sassen
      • Sassen S.
      • de Booij M.
      • Sosef M.
      • et al.
      Locally advanced rectal cancer: is diffusion weighted MRI helpful for the identification of complete responders (ypT0N0) after neoadjuvant chemoradiation therapy?.
      7014b0-300-1100 (n = 59)

      b0-500-100 (n = 11), 1.5T
      VRS R167093649590
      VRS R24098809190
      Pooled data630
      Cutoff values of ADC are in mm2/s, cutoff values of volumes are in cm3.
      18Qualitative analysis5394689087
      Acc = accuracy; ADC = apparent diffusion coefficient; DWI = diffusion weighted imaging; N = number of patients; NA = not available; NPV = negative predictive value; pCR = pathologic complete response; PPV = positive predictive value; R = radiologist; RCT = radiochemotherapy; Sens = sensitivity; Spec = specificity; T = Tesla; V = volume; VRS = visual response score.
      low asterisk Cutoff values of ADC are in mm2/s, cutoff values of volumes are in cm3.
      In one patient, ADC measurements were not obtained because the tumor had an entirely mucinous aspect.
      Four articles demonstrate that late qualitative DWI assessment can predict pCR with a pooled specificity of 94% and an overall accuracy of 87%, thereby outperforming quantitative DWI measurements [
      • Engin G.
      • Sharifov R.
      • Güral Z.
      • et al.
      Can diffusion-weighted MRI determine complete responders after neoadjuvant chemoradiation for locally advanced rectal cancer?.
      ,
      • Song I.
      • Kim S.H.
      • Lee S.J.
      • Choi J.Y.
      • Kim M.J.
      • Rhim H.
      Value of diffusion-weighted imaging in the detection of viable tumour after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging.
      ,
      • Lambregts D.M.
      • Vandecaveye V.
      • Barbaro B.
      • et al.
      Diffusion-weighted MRI for selection of complete responders after chemoradiation for locally advanced rectal cancer: a multicenter study.
      ,
      • Sassen S.
      • de Booij M.
      • Sosef M.
      • et al.
      Locally advanced rectal cancer: is diffusion weighted MRI helpful for the identification of complete responders (ypT0N0) after neoadjuvant chemoradiation therapy?.
      ].
      Thirteen papers reported on the performance of SUVmaxpre or SUVmeanpre in the prediction of pCR (Table 3). Only one article found a statistically significant correlation between a low SUVmaxpre and pCR [
      • Perez RO
      • Habr-Gama A
      • São Julião GP
      Predicting complete response to neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.
      ]. Individual patient data from two studies demonstrate that SUVmaxpre predicts pCR with a specificity and overall accuracy of only 35% and 44% respectively [
      • Palma P.
      • Conde-Muíño R.
      • Rodríguez-Fernández A.
      • et al.
      The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer.
      ,
      • Martoni A.A.
      • Di Fabio F.
      • Pinto C.
      • et al.
      Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer.
      ]. Early response prediction by 18F-FDG PET/CT during RCT seems more promising (Table 4). Based on PET data after 10–12 fractions, our group demonstrated that a RI SUVmax threshold value of 40% correctly identified all patients who achieved pCR [
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      ]. Recently, Goldberg et al. found that only after one week a decrease in SUVmax of more than 32% could predict the achievement of pCR with a sensitivity of 75% and a specificity of 100% [
      • Goldberg N.
      • Kundel Y.
      • Purim O.
      • et al.
      Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18F-FDG PET-CT imaging. A prospective clinical study.
      ]. Pooled analysis shows a PPV and overall accuracy of 69% and 88% respectively for SUV measurements during RCT.
      Table 3Early pCR prediction with 18F-FDG-PET/CT.
      StudyNpCR (%)PET parameterCorrelation PET and pCRp-ValueCutoffSens

      (%)
      Spec

      (%)
      PPV

      (%)
      NPV

      (%)
      Acc

      (%)
      Perez
      • Perez RO
      • Habr-Gama A
      • São Julião GP
      Predicting complete response to neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.
      997SUVmaxpreNegative0.043
      Konski
      • Konski A.
      • Li T.
      • Sigurdson E.
      • et al.
      Use of molecular imaging to predict clinical outcome in patients with rectal cancer after preoperative chemotherapy and radiation.
      5330SUVmaxprePositive0.71
      Capirci
      • Capirci C.
      • Rubello D.
      • Pasini F.
      • et al.
      The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.
      8127SUVmaxprePositive0.09713.9
      Palma
      • Palma P.
      • Conde-Muíño R.
      • Rodríguez-Fernández A.
      • et al.
      The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer.
      5022SUVmaxpreNegative0.14910.144674338368
      Martoni
      • Martoni A.A.
      • Di Fabio F.
      • Pinto C.
      • et al.
      Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer.
      8020SUVmaxpreNegativeNA27100112010029
      Hur
      • Hur H.
      • Kim N.K.
      • Yun M.
      • et al.
      18Fluoro-deoxy-glucose positron emission tomography in assessing tumor response to preoperative chemoradiation therapy for locally advanced rectal cancer.
      3735SUVmaxpreNegative0.838
      Shanmugan
      • Shanmugan S.
      • Arrongoiz R.
      • Nitzorkski J.R.
      • et al.
      Predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using 18FDG-PET/CT.
      7026SUVmaxprePositive0.6
      Goldberg
      • Goldberg N.
      • Kundel Y.
      • Purim O.
      • et al.
      Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18F-FDG PET-CT imaging. A prospective clinical study.
      1921SUVmaxprePositive0.617
      Guillem
      • Guillem J.G.
      • Ruby J.A.
      • Leibold T.
      • et al.
      Neither FDG-PET Nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study.
      12121SUVmaxpreNAn.s.
      SUVmeanpreNAn.s.
      Kim
      • Kim J.W.
      • Kim H.C.
      • Park J.W.
      • et al.
      Predictive value of (18)FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy.
      15113SUVmaxpreNegative0.064
      Lee
      • Lee S.J.
      • Kim J.G.
      • Lee S.W.
      • et al.
      Clinical implications of initial FDG-PET/CT in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.
      816SUVmaxpreNegative0.675
      SUVmeanpreNegative0.675
      Bampo
      • Bampo C.
      • Alessi A.
      • Fantini S.
      • et al.
      Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?.
      3030SUVmaxpreNegative0.08
      Van Stiphout
      • van Stiphout R.G.
      • Lammering G.
      • Buijsen J.
      • et al.
      Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging.
      11421SUVmaxpreNegative0.29
      Pooled data13021SUVmaxpre7835248644
      Acc = accuracy; NPV = negative predictive value; N = number of patients; NA = not available; n.s. = not significant; pCR = pathologic complete response; PET = positron emission tomography; PPV = positive predictive value; Sens = sensitivity; Spec = specificity; SUV = standardized uptake value.
      Table 4pCR prediction during RCT with 18F-FDG-PET/CT.
      StudyNpCR (%)PET parameterCorrelation PET and pCRTiming PETp-ValueCutoffSens

      (%)
      Spec

      (%)
      PPV

      (%)
      NPV

      (%)
      Acc

      (%)
      Lambrecht
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      2227RI SUVmaxduringPositiveAfter 10–12 fractions0.003640%100756010082
      Goldberg
      • Goldberg N.
      • Kundel Y.
      • Purim O.
      • et al.
      Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18F-FDG PET-CT imaging. A prospective clinical study.
      1921SUVmaxduringPositiveAfter 8 days0.841
      RI SUVmaxduringPositiveAfter 8 days0.04632%751001009495
      Bampo
      • Bampo C.
      • Alessi A.
      • Fantini S.
      • et al.
      Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?.
      3030SUVmaxduringNegativeAfter 2 weeks0.32
      RI SUVmaxduringPositive0.23
      Pooled data4124RI SUVmaxduring9087699688
      Acc = accuracy; NPV = negative predictive value; N = number of patients; pCR = pathologic complete response; PET = positron emission tomography; PPV = positive predictive value; RCT = radiochemotherapy; RI = response index; Sens = sensitivity; Spec = specificity; SUV = standardized uptake value.
      We found 14 articles reporting on posttreatment SUV as a semi-quantitative parameter for the assessment of pCR (Table 5). SUVmaxpost tends to be lower in patients without residual tumor cells than in patients with suboptimal treatment response. Optimal cutoff points to discriminate patients who achieve pCR from those who do not, vary between 3.35 and 5.4 [
      • Capirci C.
      • Rubello D.
      • Pasini F.
      • et al.
      The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.
      ,
      • Palma P.
      • Conde-Muíño R.
      • Rodríguez-Fernández A.
      • et al.
      The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer.
      ,
      • Martoni A.A.
      • Di Fabio F.
      • Pinto C.
      • et al.
      Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer.
      ,
      • Hur H.
      • Kim N.K.
      • Yun M.
      • et al.
      18Fluoro-deoxy-glucose positron emission tomography in assessing tumor response to preoperative chemoradiation therapy for locally advanced rectal cancer.
      ,
      • Shanmugan S.
      • Arrongoiz R.
      • Nitzorkski J.R.
      • et al.
      Predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using 18FDG-PET/CT.
      ,
      • Kim J.W.
      • Kim H.C.
      • Park J.W.
      • et al.
      Predictive value of (18)FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy.
      ,
      • Bampo C.
      • Alessi A.
      • Fantini S.
      • et al.
      Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?.
      ].
      Table 5Late pCR assessment with 18F-FDG-PET/CT.
      StudyNpCR (%)PET parameterCorrelation PET and pCRInterval RCT-PET (weeks)p-ValueCutoffSens

      (%)
      Spec

      (%)
      PPV

      (%)
      NPV

      (%)
      Acc

      (%)
      Quantitative analysis
      Lambrecht
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      2227RI SUVmaxpostPositive50.01376%100756010082
      Perez
      • Perez RO
      • Habr-Gama A
      • São Julião GP
      Predicting complete response to neoadjuvant CRT for distal rectal cancer using sequential PET/CT imaging.
      997SUVmaxpostNegative60.23
      SUVmaxpostNegative120.15
      RI SUVmaxpostNegative60.87
      RI SUVmaxpostNegative120.96
      Konski
      • Konski A.
      • Li T.
      • Sigurdson E.
      • et al.
      Use of molecular imaging to predict clinical outcome in patients with rectal cancer after preoperative chemotherapy and radiation.
      5330SUVmaxpostPositive3–40.18
      RI SUVmaxpostPositive5–60.08
      Capirci
      • Capirci C.
      • Rubello D.
      • Pasini F.
      • et al.
      The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.
      8127SUVmaxpostNegative<0.00015.2
      RI SUVmaxpostPositive<0.000145.90%
      ΔSUVmaxPositive0.2966.4
      Palma
      • Palma P.
      • Conde-Muíño R.
      • Rodríguez-Fernández A.
      • et al.
      The value of metabolic imaging to predict tumour response after chemoradiation in locally advanced rectal cancer.
      5022SUVmaxpostNegative5–70.0134.076474418872
      RI SUVmaxpostPositive0.35469.67%4674338368
      ΔSUVmaxNegative0.594
      Martoni
      • Martoni A.A.
      • Di Fabio F.
      • Pinto C.
      • et al.
      Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer.
      8020SUVmaxpostNegative6–7NA58834259045
      RI SUVmaxpostPositiveNA66.10%9431259544
      Hur
      • Hur H.
      • Kim N.K.
      • Yun M.
      • et al.
      18Fluoro-deoxy-glucose positron emission tomography in assessing tumor response to preoperative chemoradiation therapy for locally advanced rectal cancer.
      3735SUVmaxpostNegative4<0.0013.358579699181
      RI SUVmaxpostPositive0.00975.00%6983698378
      ΔSUVmaxPositive0.404
      Shanmugan
      • Shanmugan S.
      • Arrongoiz R.
      • Nitzorkski J.R.
      • et al.
      Predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using 18FDG-PET/CT.
      7026SUVmaxpostNegative40.0147858398863
      RI SUVmaxpostPositive0.00263.00%8360429166
      Guillem
      • Guillem J.G.
      • Ruby J.A.
      • Leibold T.
      • et al.
      Neither FDG-PET Nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study.
      12121RI SUVmaxpostNA4–6n.s.
      RI SUVmeanpostNAn.s.
      Kim
      • Kim J.W.
      • Kim H.C.
      • Park J.W.
      • et al.
      Predictive value of (18)FDG PET-CT for tumour response in patients with locally advanced rectal cancer treated by preoperative chemoradiotherapy.
      15113SUVmaxpostNegative5–7<0.0013.557464239465
      RI SUVmaxpostPositive0.19
      ΔSUVmaxNegative0.312
      Bampo
      • Bampo C.
      • Alessi A.
      • Fantini S.
      • et al.
      Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?.
      3030SUVmaxpostNegative60.015.4100816910087
      RI SUVmaxpostPositive0.035
      Van Stiphout
      • van Stiphout R.G.
      • Lammering G.
      • Buijsen J.
      • et al.
      Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging.
      11421SUVmaxpostNegative<0.001
      RI SUVmaxpostPositive<0.001
      Sun
      • Sun W.
      • Xu J.
      • Hu W.
      • Zhang Z.
      • Shen W.
      The role of sequential 18(F)-FDG PET/CT in predicting tumour response after preoperative chemoradiation for rectal cancer.
      3531RI SUVmaxpostPositive10.932
      RI SUVmaxpostPositive5–70.045
      RI SUVmeanpostPositive10.444
      RI SUVmeanpostPositive5–70.019
      Huh
      • Huh JW
      • Kwon SY
      • Lee JH
      • Kim HR
      Comparison of restaging accuracy of repeat FDG-PET/CT with pelvic MRI after preoperative chemoradiation in patients with rectal cancer.
      18114RI SUVmaxpostPositive5NA63.60%7365269466
      Pooled data41821SUVmaxpost8061359265
      44020RI SUVmaxpost7760429164
      Qualitative analysis
      Lambrecht
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      2227VRS55088608277
      Song
      • Song I.
      • Kim S.H.
      • Lee S.J.
      • Choi J.Y.
      • Kim M.J.
      • Rhim H.
      Value of diffusion-weighted imaging in the detection of viable tumour after neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer: comparison with T2 weighted and PET/CT imaging.
      5012VRS68343179548
      Guillem
      • Guillem J.G.
      • Ruby J.A.
      • Leibold T.
      • et al.
      Neither FDG-PET Nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study.
      12121VRS4–65466308464
      Capirci
      • Capirci C.
      • Rubello D.
      • Chierchetti F.
      • et al.
      Restaging after neoadjuvant chemoradiotherapy for rectal adenocarcinoma: role of F18-FDG PET.
      8135VRS47945438057
      Kalff
      • Kalff V.
      • Duong C.
      • Drummond E.G.
      • Matthews J.P.
      • Hicks R.J.
      Findings on 18F-FDG PET scans after neoadjuvant chemoradiation provides prognostic stratification in patients with locally advanced rectal carcinoma subsequently treated by radical surgery.
      3020VRS3–48350299257
      Vliegen
      • Vliegen R.F.
      • Beets-Tan R.G.
      • Vanhauten B.
      • et al.
      Can an FDG-PET/CT predict tumor clearance of the mesorectal fascia after preoperative chemoradiation of locally advanced rectal cancer?.
      2010VRS6.35094509490
      Kristiansen
      • Kristiansen C.
      • Loft A.
      • Berthelsen A.K.
      • et al.
      PET/CT and histopathologic response to preoperative chemoradiation therapy in locally advanced rectal cancer.
      3027VRS77546338353
      Kalff
      • Kalff V.
      • Ware R.
      • Heriot A.
      • Chao M.
      • Drummond E.
      • Hicks R.J.
      Radiation changes do not interfere with postchemoradiation restaging of patients with rectal cancer by FDG PET/CT before curative surgical therapy.
      6316VRS4–58062299465
      Cho
      • Cho Y.B.
      • Chun H.K.
      • Kim M.J.
      • et al.
      Accuracy of MRI and 18F-FDG PET/CT for restaging after preoperative concurrent chemoradiotherapy for rectal cancer.
      3013VRS67585439683
      Mak
      • Mak D.
      • Joon D.L.
      • Chao M.
      • et al.
      The use of PET in assessing tumor response after neoadjuvant chemoradiation for rectal cancer.
      2035VRS3–67185718580
      Murcia Duréndez
      • Murcia Duréndez MJ
      • Frutos Esteban L
      • Luján J
      The value of 18F-FDG PET/CT for assessing the response to neoadjuvant therapy in locally advanced rectal cancer.
      4120VRS7100765010081
      Pooled data50822VRS7263358965
      Acc = accuracy; NPV = negative predictive value; N = number of patients; NA = not available; n.s. = not significant; pCR = pathologic complete response; PET = positron emission tomography; PPV = positive predictive value; RCT = radiochemotherapy; RI = response index; Sens = sensitivity; Spec = specificity; SUV = standardized uptake value; VRS = visual response score.
      The most studied PET parameter in late response prediction is the relative change in SUV measured before and after RCT (RI SUVmaxpost and RI SUVmeanpost). A higher decrease in SUV was found predictive for pCR by seven authors [
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      ,
      • Capirci C.
      • Rubello D.
      • Pasini F.
      • et al.
      The role of dual-time combined 18-fluorodeoxyglucose positron emission tomography and computed tomography in the staging and restaging workup of locally advanced rectal cancer, treated with preoperative chemoradiation therapy and radical surgery.
      ,
      • Hur H.
      • Kim N.K.
      • Yun M.
      • et al.
      18Fluoro-deoxy-glucose positron emission tomography in assessing tumor response to preoperative chemoradiation therapy for locally advanced rectal cancer.
      ,
      • Shanmugan S.
      • Arrongoiz R.
      • Nitzorkski J.R.
      • et al.
      Predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer using 18FDG-PET/CT.
      ,
      • Bampo C.
      • Alessi A.
      • Fantini S.
      • et al.
      Is the standardized uptake value of FDG-PET/CT predictive of pathological complete response in locally advanced rectal cancer treated with capecitabine-based neoadjuvant chemoradiation?.
      ,
      • van Stiphout R.G.
      • Lammering G.
      • Buijsen J.
      • et al.
      Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging.
      ,
      • Sun W.
      • Xu J.
      • Hu W.
      • Zhang Z.
      • Shen W.
      The role of sequential 18(F)-FDG PET/CT in predicting tumour response after preoperative chemoradiation for rectal cancer.
      ]. Optimal cutoff values for RI SUVmaxpost vary from 45.9% to 76%.
      In eleven studies, 18F-FDG PET/CT scans were interpreted subjectively by visual inspection. Pooled data show qualitative analysis after RCT is able to assess pCR with a negative predictive value of 89% and an overall accuracy of 65%, which is comparable to the quantitative SUV measurements post-RCT. Three articles investigated changes in MTV and TLG as a response parameter, but only Sun and co-workers found a relative decrease in MTV and TLG after 5–7 weeks significantly predictive for pCR [
      • Guillem J.G.
      • Ruby J.A.
      • Leibold T.
      • et al.
      Neither FDG-PET Nor CT can distinguish between a pathological complete response and an incomplete response after neoadjuvant chemoradiation in locally advanced rectal cancer: a prospective study.
      ,
      • Lee S.J.
      • Kim J.G.
      • Lee S.W.
      • et al.
      Clinical implications of initial FDG-PET/CT in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.
      ,
      • Sun W.
      • Xu J.
      • Hu W.
      • Zhang Z.
      • Shen W.
      The role of sequential 18(F)-FDG PET/CT in predicting tumour response after preoperative chemoradiation for rectal cancer.
      ].

      Discussion

      In this systematic review, we collect the current evidence of the role of DWI and 18F-FDG PET/CT in the prediction of pCR before, during and after RCT for rectal cancer (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Overview of the sensitivity and specificity of DWI and 18F-FDG PET/CT in the prediction of pathological complete response. Solid bars represent DWI-based parameters, while 18F-FDG PET/CT parameters are depicted by hatched bars. Parameters based on pre-RCT imaging and those based on imaging during or after RCT are depicted on the left and the right side respectively. Parameters are represented in the order of decreasing sensitivity in the prediction of pathological complete response.
      Response assessment during RCT could possibly re-orientate non-responding patients to a different treatment modality (e.g. surgery) or to treatment intensification (e.g. dose escalation or addition of targeted agents) [
      • Burbach JP
      • den Harder AM
      • Intven M
      • van Vulpen M
      • Verkooijen HM
      • Reerink O
      Impact of radiotherapy boost on pathological complete response in patients with locally advanced rectal cancer: A systematic review and meta-analysis.
      ]. Some authors found that a low pretreatment ADC was correlated with a good response to treatment. Similar findings have been reported in brain tumors [
      • Mardor Y.
      • Roth Y.
      • Ochershvilli A.
      • et al.
      Pretreatment prediction of brain tumors’ response to radiation therapy using high b-value diffusion-weighted MRI.
      ] and in hepatic metastases of colorectal cancer [
      • Koh D.M.
      • Scurr E.
      • Collins D.
      • et al.
      Predicting response of colorectal hepatic metastasis: value of pretreatment apparent diffusion coefficients.
      ]. The association between the pretreatment ADC and tumor response is hypothesized to be correlated to the presence of necrotic areas (characterized by a high ADC), in which tumor cells are exposed to a more acidic and hypoxic environment, diminishing the effectiveness of radiation therapy and chemotherapeutic agents [
      • Koh D.M.
      • Scurr E.
      • Collins D.
      • et al.
      Predicting response of colorectal hepatic metastasis: value of pretreatment apparent diffusion coefficients.
      ,
      • Harrison L.
      • Blackwell K.
      Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?.
      ]. However, coagulative necrosis without cell liquefaction may not increase ADC and this might be the reason why tumors do not respond well to neoadjuvant RCT, although they have a low pretreatment ADC. It should be stressed however that this hypothesis has not yet been confirmed by radiological-pathological correlative studies. While baseline 18F-FDG PET/CT itself has limited value in response prediction, the relative change in SUVmax during RCT seems more promising. A higher decrease in FDG-uptake represents a smaller amount of metabolically active tumor cells, indicating response to treatment.
      Response assessment before surgery enables physicians to offer patients who achieve a clinical complete response less extensive surgery or even a ‘wait-and-see’ policy. Pooled analysis showed that qualitative DWI assessment had a higher accuracy in pCR prediction than quantitative analysis (87% vs. 74–78%). However, with respect to sensitivity, ADC measurements outperformed subjective visual assessment (78–80% vs. 53%), indicating that quantitative analysis is more accurate in detecting patients with pCR. Quantitative and qualitative 18F-FDG PET/CT evaluations are equally performant in the preoperative assessment of complete response.
      Most studies suffer from a retrospective design and a low number of patients. In an attempt to assess the performance of the different imaging parameters, we pooled the available individual patient data. Most authors provide cutoff values based on ROC analysis, which aims at the maximal accuracy of response prediction. However, this maximal accuracy may not necessarily represent the most desirable clinical parameter. For instance, we believe a high PPV and specificity are mandatory if alteration of the surgical strategy is considered. A low specificity and PPV may correlate with many false positives, corresponding to residual tumor on pathology whereas the DWI or 18F-FDG PET/CT images show no evidence of disease. In general, DWI and 18F-FDG PET/CT had a high NPV in the prediction of pCR, making these functional imaging techniques potential valuable tools to deselect patients for a conservative treatment approach. Unfortunately, both imaging modalities lack the specificity and PPV needed to safely select patients for a ‘wait-and-see’ policy.
      The combination of different functional imaging techniques at different time points may increase the specificity for pCR prediction. Our group previously showed that the combination of early and late RI SUVmaxpost thresholds increased the specificity in the prediction of pCR (75% for the individual threshold values vs. 94% when combined) [
      • Lambrecht M.
      • Deroose C.
      • Roels S.
      • et al.
      The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer.
      ]. We also demonstrated that the combination of 18F-FDG PET/CT with pretreatment DWI may further increase the specificity of response assessment. Although this study only included 22 patients, the combination of different imaging modalities at different time intervals is at least hypothesis-generating and deserves further investigation. Combined PET/MRI cameras might make these evaluations logistically less cumbersome. Van Stiphout et al. demonstrated that the integration of functional imaging and clinical data might also contribute to the accuracy of pCR assessment [
      • van Stiphout R.G.
      • Lammering G.
      • Buijsen J.
      • et al.
      Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging.
      ]. This group developed and validated a nomogram for pCR prediction by collecting population-based databases of 953 patients from 4 different institutes. These databases were divided into three groups: clinical factors (762 patients), pre-RCT 18F-FDG PET-CT (151 patients) and post-RCT 18F-FDG PET-CT (162 patients). The model’s performance was evaluated by ROC analysis. The AUC increased from 0.68 to 0.86 when post-RCT PET data were added to the clinical and pre-RCT PET variable set. The integration of blood and tissue biomarkers appears also useful in pCR prediction after RCT for rectal cancer [
      • Buijsen J.
      • van Stiphout R.G.
      • Menheere P.P.
      • Lammering G.
      • Lambin P.
      Blood biomarkers are helpful in the prediction of response to chemoradiation in rectal cancer: a prospective, hypothesis driven study on patients with locally advanced rectal cancer.
      ,
      • Hur H.
      • Kim N.K.
      • Min B.S.
      Can a biomarker-based scoring system predict pathologic complete response after preoperative chemoradiotherapy for rectal cancer?.
      ,
      • Edden Y.
      • Wexner S.D.
      • Berho M.
      The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma.
      ].
      The ability of functional imaging to predict pCR is affected by the interval between the end of RCT, the post-treatment scan and surgery. In most studies, post-treatment 18F-FDG PET/CT and DWI scans were performed 4–8 weeks after the end of RCT. A longer time interval between the end of RCT and surgery has shown to increase pCR rates [
      • Tulchinsky H.
      • Shmueli E.
      • Figer A.
      • Klausner J.M.
      • Rabau M.
      An interval >7 weeks between neoadjuvant therapy and surgery improves pathologic complete response and disease-free survival in patients with locally advanced rectal cancer.
      ,
      • Wolthuis A.M.
      • Penninckx F.
      • Haustermans K.
      • et al.
      Impact of interval between neoadjuvant chemoradiotherapy and TME for locally advanced rectal cancer on pathologic response and oncologic outcome.
      ]. However, Perez et al. reported that not all patients benefit from this prolonged interval [
      • Harrison L.
      • Blackwell K.
      Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?.
      ]. These authors showed that the increase between early (1 h) and late (3 h) SUVmax at 6-weeks 18F-FDG PET/CT scans was a significant predictor of poor response. Patients who have such an increase in SUVmax do not benefit from a longer time interval between RCT and surgery. It is known that the interpretation of functional imaging scans during and early after the end of RCT can be confounded by treatment-induced tissue alterations. This is especially the case for 18F-FDG PET/CT in which RCT-induced inflammation can cause FDG-uptake.
      A number of limitations of this analysis must be recognized. Most papers report on a limited number of patients, yielding large 95% confidence intervals around the diagnostic accuracy parameters, thereby providing cutoff thresholds that are not sufficiently robust for clinical use. Few papers provided enough data to construct individual 2 × 2 contingency tables. However, by pooling individual patient data, we were able to evaluate the performance of DWI and 18F-FDG PET/CT in a larger patient group. Because of the heterogeneity within the included studies with respect to patient selection, neoadjuvant treatment and imaging protocols and analyses, this pooled analysis should be regarded as an indicator of the general performance of DWI and 18F-FDG PET/CT in the prediction of pCR. Furthermore, the results on functional imaging prediction are restricted to monocentric studies conducted in ultra-specialized centers. Validation and implementation in a multicenter setting are still awaited. Standardization through protocols for both image acquisition and data analysis is necessary to ensure reproducibility of the results and enable widespread implementation.
      In conclusion, data on the role of 18F-FDG PET/CT and DWI in response prediction before, during and after RCT for locally advanced rectal cancer are emerging. In general, a low pretreatment ADC, an increase in ADC and decrease in SUV are associated with better response to RCT. Pooled analysis shows qualitative DWI assessment 5–10 weeks after the end of RCT outperforms ADC-based DWI-parameters. Although little data are available, early changes in FDG-uptake seem promising and the role of 18F-FDG PET/CT during RCT should be further investigated. Multicenter studies using large patient populations are needed to validate the role of functional imaging in order to identify those patients who may benefit from a less aggressive therapeutic approach after RCT. Up to now, DWI and 18F-FDG PET/CT are not accurate enough to safely select patients for organ preservation. Future research must focus on the integration of functional imaging with clinical data and molecular biomarkers.

      Conflict of interest

      None declared.

      Appendix A. Supplementary data

      Figure thumbnail fx1
      Supplementary Figure 1Performance parameters. Abbreviations: cCR = clinical complete response; FN = false negatives; FP = false positives; NPV = negative predictive value; pCR = pathological complete response; PPV = positive predictive value; TN = true negatives; TP = true positives.

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