Advertisement

Identifying patients who may benefit from adaptive radiotherapy: Does the literature on anatomic and dosimetric changes in head and neck organs at risk during radiotherapy provide information to help?

Open AccessPublished:June 17, 2015DOI:https://doi.org/10.1016/j.radonc.2015.05.018

      Abstract

      In the last decade, many efforts have been made to characterize anatomic changes of head and neck organs at risk (OARs) and the dosimetric consequences during radiotherapy. This review was undertaken to provide an overview of the magnitude and frequency of these effects, and to investigate whether we could find criteria to identify head and neck cancer patients who may benefit from adaptive radiotherapy (ART). Possible relationships between anatomic and dosimetric changes and outcome were explicitly considered. A literature search according to PRISMA guidelines was performed in MEDLINE and EMBASE for studies concerning anatomic or dosimetric changes of head and neck OARs during radiotherapy. Fifty-one eligible studies were found. The majority of papers reported on parotid gland (PG) anatomic and dosimetric changes. In some patients, PG mean dose differences between planning CT and repeat CT scans up to 10 Gy were reported. In other studies, only minor dosimetric effects (i.e. <1 Gy difference in PG mean dose) were observed as a result of significant anatomic changes. Only a few studies reported on the clinical relevance of anatomic and dosimetric changes in terms of complications or quality of life. Numerous potential selection criteria for anatomic and dosimetric changes during radiotherapy were found and listed. The heterogeneity between studies prevented unambiguous conclusions on how to identify patients who may benefit from ART in head and neck cancer. Potential pre-treatment selection criteria identified from this review include tumour location (nasopharyngeal carcinoma), age, body mass index, planned dose to the parotid glands, the initial parotid gland volume, and the overlap volume of the parotid glands with the target volume. These criteria should be further explored in well-designed and well-powered prospective studies, in which possible relationships between anatomic and dosimetric changes and outcome need to be established.

      Keywords

      Radiotherapy is a commonly applied treatment modality in head and neck cancer patients. Intensity modulated radiotherapy treatment plans with steep dose gradients are currently considered standard. These treatment plans are constructed on planning CT images, acquired prior to the start of radiotherapy. To account for patient positioning errors relative to these planning CT images, position verification procedures are generally applied. However, because of different patient postures and anatomic changes during the course of radiotherapy, the dose actually given to the patient can deviate from the planned dose [
      • Yan D.
      • Lockman D.
      • Martinez A.
      • et al.
      Computed tomography guided management of interfractional patient variation.
      ]. These dose differences may lead to underdosage to target volumes and/or overdosage to organs at risk (OARs) [
      • Hansen E.K.
      • Bucci M.K.
      • Quivey J.M.
      • et al.
      Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.
      ].
      Radiation-induced complications have a significant adverse impact on health-related quality of life [
      • Langendijk J.A.
      • Doornaert P.
      • Verdonck-de Leeuw I.M.
      • et al.
      Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy.
      ]. Hence, it is important to monitor radiation doses to OARs during treatment. This is particularly salient in the head and neck area, where OARs are in close proximity to target volumes. However, at present, verification of the dose actually given to the patient is not considered routine clinical practice. Adaptive radiotherapy (ART) could be applied to reduce dose to OARs and eventually to improve quality of life [
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Yan D.
      • Liang J.
      Expected treatment dose construction and adaptive inverse planning optimization: implementation for offline head and neck cancer adaptive radiotherapy.
      ]. ART is a formal approach to correct for daily tumour and normal tissue variations through streamlined online or offline modification of original target volumes and plans [
      • Schwartz D.L.
      Current progress in adaptive radiation therapy for head and neck cancer.
      ,
      • Yan D.
      Adaptive radiotherapy: merging principle into clinical practice.
      ]. Implementation of ART is challenging both from clinical and logistic points of view and generally requires many resources. Clear guidelines are needed on the timing of rescanning and replanning, and an increasing amount of data needs to be acquainted, handled, transferred and stored. It is unlikely that every patient will benefit from ART and therefore tools to select patients who are expected to benefit most from plan adaptation during treatment become increasingly important [
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ].
      In previous studies, it was shown that anatomic changes cause more dose deviations in OARs than in target volumes [
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Duma M.N.
      • Kampfer S.
      • Schuster T.
      • et al.
      Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Shah S.J.
      • et al.
      Adaptive radiotherapy for head and neck cancer-dosimetric results from a prospective clinical trial.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ]. Clinical target volume (CTV) coverage is usually more robust to changes because of the use of the planning target volume (PTV) concept, while planning volumes at risk (PRV) margins are generally applied for the spinal cord and brain stem, but are not common practice for all OARs. Only 13% of the studies in this review reported PRV margins around the spinal cord and/or the brainstem [
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ], and 4% of the studies reported on PRV margins for all OARs [
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ]. In addition, position verification mainly focuses on correcting for set-up errors of targets, and for that reason might lead to increased doses to distant OARs. Therefore, it is expected that the largest gain of ART would be the monitoring and reduction of the dose to OARs.
      For a strategic selection of patients who may benefit from ART, identification of selection criteria that are associated with dosimetric changes and resulting complications is necessary. Patient selection for ART can be realized by selection prior to treatment, i.e. based on pre-treatment characteristics, and by selection during treatment based on geometric and/or dosimetric changes early in treatment, either by non-imaging related factors (e.g. weight loss) or by imaging related factors (e.g. density changes).
      Castadot et al. [
      • Castadot P.
      • Lee J.A.
      • Geets X.
      Adaptive radiotherapy of head and neck cancer.
      ] have summarized the results of seven studies reporting on anatomic modifications of head and neck target volumes and OARs during radiotherapy in 2010. The authors concluded that radiotherapy induces major volumetric and positional changes in CTVs and OARs during treatment. Parotid glands tend to shrink and to shift medially towards the high dose region, potentially jeopardizing parotid sparing [
      • Castadot P.
      • Lee J.A.
      • Geets X.
      Adaptive radiotherapy of head and neck cancer.
      ]. Not all of these studies reported to what extent these anatomic changes actually translate into dosimetric changes. Furthermore, no unambiguous effect of anatomic changes on dose has been found. Since 2010, the amount of studies reporting on anatomic and dosimetric changes has increased dramatically.
      The main objective of this review was to evaluate the current literature on anatomic and dosimetric changes of head and neck OARs during radiotherapy. Furthermore, implications of these changes for the rate and severity of complications and quality of life were reported. In addition, we tried to identify selection criteria for changes during radiotherapy and recommended on the conduction of further studies on this subject. Results of this review could provide useful information for the development of strategies for patient selection in ART.

      Methods

      We performed a literature search in MEDLINE and EMBASE according to PRISMA guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ] using the following keywords: ((synonyms for anatomic changes) OR (synonyms for dosimetric changes)) AND (synonyms for organs at risk) AND (synonyms for head and neck radiotherapy). The search was completed by March 1, 2015.
      In addition, reference lists of papers were screened in order to retrieve additional relevant papers. Both prospective and retrospective studies published in journals part of the Thomson Reuters journal citation reports® were included. Studies in languages other than English, and studies only available in abstract form were excluded from this review.
      Studies had to fulfil the following eligibility criteria to be selected for this review:
      • report on anatomic and/or dosimetric changes of adult head and neck organs at risk during the course of photon radiotherapy, and
      • at least ten patients included.
      We present overviews of anatomic changes, dosimetric changes, and report potential selection criteria of either one. In addition, we report on studies describing the effects of anatomic and dosimetric changes during radiotherapy on side effects and quality of life. The results are presented by volume changes in percentages and dose changes in Gray in order to make comparisons across studies easier to interpret. Associations are presented in five ways; by the Pearson correlation coefficient (R), the coefficient of determination (R2), the Spearman’s rank correlation coefficient (ρ), linear regression analysis (r or r2), and by the odds ratio (OR), according to the study methodology.

      Results

      Literature search

      Fig. 1 presents the outcome of the search strategy. Fifty-two potentially eligible records were found in MEDLINE and EMBASE, and forty-four additional papers were extracted from reference lists. We excluded twenty-eight records as they were conference abstracts, two studies because only the abstract was available [
      • Beltran M.
      • Ramos M.
      • Rovira J.J.
      • et al.
      Dose variations in tumor volumes and organs at risk during IMRT for head-and-neck cancer.
      ,
      • Mavroidis P.
      • Stathakis S.
      • Gutierrez A.
      • et al.
      Expected clinical impact of the differences between planned and delivered dose distributions in helical tomotherapy for treating head and neck cancer using helical megavoltage CT images.
      ], and two papers because their journal was not part of the Thomson Reuters journal citation reports® [
      • Bhandari V.
      • Patel P.
      • Gurjar O.M.G.K.
      Impact of repeat computerized tomography replans in the radiation therapy of head and neck cancers.
      ,
      • Bando R.
      • Ikushima H.
      • Kawanaka T.
      • et al.
      Changes of tumor and normal structures of the neck during radiation therapy for head and neck cancer requires adaptive strategy.
      ]. Furthermore, three papers were excluded as they were general reviews on image guided radiotherapy (IGRT) and ART [
      • Schwartz D.L.
      Current progress in adaptive radiation therapy for head and neck cancer.
      ,
      • Castadot P.
      • Lee J.A.
      • Geets X.
      Adaptive radiotherapy of head and neck cancer.
      ,
      • Dawson L.A.
      • Sharpe M.B.
      Image-guided radiotherapy: rationale, benefits, and limitations.
      ]. Eventually, sixty-one full text articles were assessed for eligibility. Five of these papers did not meet the eligibility criteria since they reported on other subjects and five papers included less than ten patients [
      • Ballivy O.
      • Parker W.
      • Vuong T.
      • et al.
      Impact of geometric uncertainties on dose distribution during intensity modulated radiotherapy of head-and-neck cancer: the need for a planning target volume and a planning organ-at-risk volume.
      ,
      • Han C.
      • Chen Y.-J.
      • Liu A.
      • et al.
      Actual dose variation of parotid glands and spinal cord for nasopharyngeal cancer patients during radiotherapy.
      ,
      • Loo H.
      • Fairfoul J.
      • Chakrabarti A.
      • et al.
      Tumour shrinkage and contour change during radiotherapy increase the dose to organs at risk but not the target volumes for head and neck cancer patients treated on the TomoTherapy HiArt™ system.
      ,
      • Takao S.
      • Tadano S.
      • Taguchi H.
      • et al.
      Accurate analysis of the change in volume, location, and shape of metastatic cervical lymph nodes during radiotherapy.
      ,
      • Elstrøm U.V.
      • Wysocka B.
      • Muren L.P.
      • et al.
      Daily kV cone-beam CT and deformable image registration as a method for studying dosimetric consequences of anatomic changes in adaptive IMRT of head and neck cancer.
      ]. Hence a final number of fifty-one studies could be included in the analyses for this review [
      • Hansen E.K.
      • Bucci M.K.
      • Quivey J.M.
      • et al.
      Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.
      ,
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ,
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Duma M.N.
      • Kampfer S.
      • Schuster T.
      • et al.
      Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Shah S.J.
      • et al.
      Adaptive radiotherapy for head and neck cancer-dosimetric results from a prospective clinical trial.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ,
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      ,
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      ,
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Broggi S.
      • Fiorino C.
      • Dell’Oca I.
      A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.
      ,
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ,
      • Duma M.N.
      • Kampfer S.
      • Wilkens J.J.
      • et al.
      Comparative analysis of an image-guided versus a non-image-guided setup approach in terms of delivered dose to the parotid glands in head-and-neck cancer IMRT.
      ,
      • Fiorentino A.
      • Caivano R.
      • Metallo V.
      • et al.
      Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer.
      ,
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      ,
      • Fung W.W.K.
      • Wu V.W.C.
      • Teo P.M.L.
      Dosimetric evaluation of a three-phase adaptive radiotherapy for nasopharyngeal carcinoma using helical tomotherapy.
      ,
      • Height R.
      • Khoo V.
      • Lawford C.
      • et al.
      The dosimetric consequences of anatomic changes in head and neck radiotherapy patients.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • Lu N.
      • Feng L.-C.
      • Cai B.-N.
      • et al.
      Clinical study on the changes of the tumor target volume and organs at risk in helical tomotherapy for nasopharyngeal carcinoma.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Nichol A.
      • Smith S.L.
      • D’yachkova Y.
      • et al.
      Quantification of masticatory muscle atrophy after high-dose radiotherapy.
      ,
      • Nishimura Y.
      • Nakamatsu K.
      • Shibata T.
      • et al.
      Importance of the initial volume of parotid glands in xerostomia for patients with head and neck cancers treated with IMRT.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ,
      • Popovtzer A.
      • Cao Y.
      • Feng F.Y.
      • et al.
      Anatomical changes in the pharyngeal constrictors after chemo-irradiation of head and neck cancer and their dose–effect relationships: MRI-based study.
      ,
      • Ricchetti F.
      • Wu B.
      • McNutt T.
      • et al.
      Volumetric change of selected organs at risk during IMRT for oropharyngeal cancer.
      ,
      • Senkus-Konefka E.
      • Naczk E.
      • Borowska I.
      • et al.
      Changes in lateral dimensions of irradiated volume and their impact on the accuracy of dose delivery during radiotherapy for head and neck cancer.
      ,
      • Teshima K.
      • Murakami R.
      • Tomitaka E.
      • et al.
      Radiation-induced parotid gland changes in oral cancer patients: correlation between parotid volume and saliva production.
      ,
      • Tomitaka E.
      • Murakami R.
      • Teshima K.
      • et al.
      Longitudinal changes over 2 years in parotid glands of patients treated with preoperative 30-Gy irradiation for oral cancer.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ,
      • Wang W.
      • Yang H.
      • Hu W.
      • et al.
      Clinical study of the necessity of replanning before the 25th fraction during the course of intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      ,
      • You S.H.
      • Kim S.Y.
      • Lee C.G.
      • et al.
      Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia?.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Reali A.
      • Anglesio S.M.
      • Mortellaro G.
      • et al.
      Volumetric and positional changes of planning target volumes and organs at risk using computed tomography imaging during intensity-modulated radiation therapy for head–neck cancer: an “old” adaptive radiation therapy approach.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Cozzolino M.
      • Fiorentino A.
      • Oliviero C.
      • et al.
      Volumetric and dosimetric assessment by cone-beam computed tomography scans in head and neck radiation therapy: a monitoring in four phases of treatment.
      ,
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      ].
      Figure thumbnail gr1
      Fig. 1PRISMA flow diagram of the literature search.

      Reported organs at risk

      In the fifty-one original studies at least one of the following organs at risk was included in the analysis: the parotid gland (PG), submandibular gland, spinal cord, spinal canal, brainstem, mandible, oral cavity, larynx, pharyngeal constrictor muscles, sternocleidomastoid muscles, masticatory muscles, masseter muscles, medial pterygoid muscles, thyroid gland, optic chiasm, optic nerve, eyeball and lens.

      Timing and frequency of imaging during radiation treatment

      OARs were assessed on different time points during radiotherapy (tenth fraction to end of treatment, see also Fig. 2, Table S1–S3) mainly by cone beam CT (CBCT), helical repeat CT and megavoltage CT (MVCT), but also by in-room CT [
      • Schwartz D.L.
      • Garden A.S.
      • Shah S.J.
      • et al.
      Adaptive radiotherapy for head and neck cancer-dosimetric results from a prospective clinical trial.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ] and MR imaging [
      • Popovtzer A.
      • Cao Y.
      • Feng F.Y.
      • et al.
      Anatomical changes in the pharyngeal constrictors after chemo-irradiation of head and neck cancer and their dose–effect relationships: MRI-based study.
      ]. Two studies applied repeat MR imaging in addition to the repeat CT scans [
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ]. In most studies, the re-delineation of OARs was performed manually or automatically using deformable image registration (DIR) with visual inspection and manual corrections if needed. The frequency of imaging varied between studies. Most of the studies reported on multiple time points during radiotherapy. Fourteen studies performed at least weekly repeat imaging [
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ,
      • Ricchetti F.
      • Wu B.
      • McNutt T.
      • et al.
      Volumetric change of selected organs at risk during IMRT for oropharyngeal cancer.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ]. Three of these studies had daily MVCT imaging at their disposal [
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ], and one performed daily in-room CT imaging [
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ]. If results of multiple time points were reported, anatomic and dosimetric changes from the last time point were included in this review.
      Figure thumbnail gr2
      Fig. 2(A) Parotid volume loss vs. patient’s weight loss (22 studies), (B) parotid volume loss vs. planned parotid mean dose (20 studies), (C) parotid mean dose increase (repeat CT – plan CT) vs. weight loss (16 studies), and (D) parotid mean dose increase (repeat CT – plan CT) vs. parotid volume loss (23 studies) during radiotherapy. The size of the data points is proportional to the number of patients included in the study (minimum 10, maximum 87 patients). fx = fraction, tx = treatment. Time point: time of the repeat scan analysed.
      The authors of the different studies reported a variety of time points during treatment that could be optimal for re-scanning and re-planning. There are several indications that anatomic changes are more pronounced in the first half of treatment, and therefore repeated imaging and replanning should be performed in this first time period [
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ].

      Anatomic and dosimetric changes

      Twenty-six papers described both anatomic and dosimetric changes during the course of radiation [
      • Hansen E.K.
      • Bucci M.K.
      • Quivey J.M.
      • et al.
      Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.
      ,
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ,
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Duma M.N.
      • Kampfer S.
      • Schuster T.
      • et al.
      Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      ,
      • Duma M.N.
      • Kampfer S.
      • Wilkens J.J.
      • et al.
      Comparative analysis of an image-guided versus a non-image-guided setup approach in terms of delivered dose to the parotid glands in head-and-neck cancer IMRT.
      ,
      • Fiorentino A.
      • Caivano R.
      • Metallo V.
      • et al.
      Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer.
      ,
      • Fung W.W.K.
      • Wu V.W.C.
      • Teo P.M.L.
      Dosimetric evaluation of a three-phase adaptive radiotherapy for nasopharyngeal carcinoma using helical tomotherapy.
      ,
      • Height R.
      • Khoo V.
      • Lawford C.
      • et al.
      The dosimetric consequences of anatomic changes in head and neck radiotherapy patients.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Senkus-Konefka E.
      • Naczk E.
      • Borowska I.
      • et al.
      Changes in lateral dimensions of irradiated volume and their impact on the accuracy of dose delivery during radiotherapy for head and neck cancer.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • You S.H.
      • Kim S.Y.
      • Lee C.G.
      • et al.
      Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia?.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Cozzolino M.
      • Fiorentino A.
      • Oliviero C.
      • et al.
      Volumetric and dosimetric assessment by cone-beam computed tomography scans in head and neck radiation therapy: a monitoring in four phases of treatment.
      ]. Two studies reported on dosimetric changes without referring to anatomic changes [
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ]. Twenty studies described the relationship between several parameters and anatomic and/or dosimetric changes [
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ,
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      ,
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      ,
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      ,
      • Broggi S.
      • Fiorino C.
      • Dell’Oca I.
      A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.
      ,
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      ,
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Reali A.
      • Anglesio S.M.
      • Mortellaro G.
      • et al.
      Volumetric and positional changes of planning target volumes and organs at risk using computed tomography imaging during intensity-modulated radiation therapy for head–neck cancer: an “old” adaptive radiation therapy approach.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      ] (Table 1, Table 2). Twelve studies reported on the association between anatomic and dosimetric changes with complications and quality of life [
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Nishimura Y.
      • Nakamatsu K.
      • Shibata T.
      • et al.
      Importance of the initial volume of parotid glands in xerostomia for patients with head and neck cancers treated with IMRT.
      ,
      • Senkus-Konefka E.
      • Naczk E.
      • Borowska I.
      • et al.
      Changes in lateral dimensions of irradiated volume and their impact on the accuracy of dose delivery during radiotherapy for head and neck cancer.
      ,
      • Teshima K.
      • Murakami R.
      • Tomitaka E.
      • et al.
      Radiation-induced parotid gland changes in oral cancer patients: correlation between parotid volume and saliva production.
      ,
      • You S.H.
      • Kim S.Y.
      • Lee C.G.
      • et al.
      Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia?.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      ] (Table 3). In two of these studies, a significant reduction of side effects was found when replanning was performed vs. no replanning [
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ]. The findings of specific changes during radiotherapy and the corresponding correlations and associations are summarized per organ in the next paragraphs.
      Table 1Studies reporting on parameters associated with anatomic or dosimetric changes of parotid glands during the course of radiotherapy. Only statistically significant correlations are shown. Results of Spearman correlation are denoted with ρ, Pearson correlation with R, linear regression analysis by r or r2 and odds ratio by OR.
      Study# PtsParameterEndpointCorrelation/associationp value
      Anatomic endpoints
      Ahn et al.
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      23Weight lossPG volume lossR = 0.52–0.67n.r.
      Ajani et al.
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      13Weight lossPG volume lossρ = 0.66p < 0.01
      PG Dmean ⩾ 31 Gy vs. PG Dmean < 31 Gy
      Barker et al.
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      14Weight lossPG centre of mass shiftρ = 0.931, Spearman two-tailed correlationp < 0.01
      Broggi et al.
      • Broggi S.
      • Fiorino C.
      • Dell’Oca I.
      A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.
      Only the strongest associations were listed.
      87Weight lossPG volume loss (cc)OR = 0.845 (0.78–0.92), univariable analysisp = 0.0001
      ΔBody thickness (cc)OR = 0.181 (0.078–0.422), “p = 0.0001
      OVPOR = 1.191 (1.086–1.306), “p = 0.0002
      PG V40OR = 1.038 (1.011–1.066), “p = 0.006
      Overall treatment timeOR = 1.059 (1.018–1.100), “p = 0.004
      Initial PG volumeOR = 1.100 (1.056–1.158), multivariable analysisp = 0.0002
      PG DmeanOR = 1.059 (1.003–1.118), “p = 0.038
      PG V40PG volume loss (%)OR = 1.034 (1.0075–1.061), multivariable analysisp = 0.012
      ΔBody thickness (%)OR = 0.863 (0.809–0.921), “p < 0.00001
      Fiorino et al.
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      84PG density decreasePG volume lossρ = 0.23p = 0.003
      Ho et al.
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      10Weight lossPG volume lossρ = 0.83p < 0.0001
      Reali et al.
      • Reali A.
      • Anglesio S.M.
      • Mortellaro G.
      • et al.
      Volumetric and positional changes of planning target volumes and organs at risk using computed tomography imaging during intensity-modulated radiation therapy for head–neck cancer: an “old” adaptive radiation therapy approach.
      10PG DmeanPG volume lossr2 = 0.31, 0.41 (left, right PG)p < 0.001
      Sanguineti et al.
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      85Weight lossPG volume lossOR = 1.160 (1.04–1.29), multivariable analysisp = 0.007
      PG DmeanOR = 1.080 (1.01–1.17), “p = 0.038
      AgeOR = 0.960 (0.93–0.99), “p = 0.033
      Sanguineti et al.
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      85Body mass indexPG volume lossρ = −0.234p = 0.031
      PG Dmeanρ = 0.258p = 0.017
      Schwartz et al.
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      24Weight lossPG volume lossn.r.p = 0.04
      Vasquez-Osorio et al.
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      10PG DmeanPG volume lossr = 0.68p < 0.001
      Wang et al.
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      82PG DmeanPG volume lossr = 0.41p < 0.001
      SMG DmeanSMG volume lossr = 0.39p < 0.001
      Wang et al.
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      15Weight lossPG volume lossρ = 0.93, 0.85 (left, right PG)p < 0.001
      Dosimetric endpoints
      Ahn et al.
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      23Cochlea vector increasePG D50% increaseR = 0.41n.r.
      Mandible vector increaseR = 0.42n.r.
      Reduction of lateral neck diameter at mandibular jointR = 0.22–0.39n.r.
      Reduction of lateral neck diameter at C1–C5R = 0.17–0.28n.r.
      Parotid volume decreaseR = 0.22n.r.
      Weight lossR = 0.30–0.35n.r.
      Anatomic isocentre APPG D50% overdose (D50% > 26 Gy)n.r.p = 0.002
      Mandible vector, AP, SIn.r.p = 0.001–0.006
      Reduction of lateral neck diameter at C2–C3n.r.p = 0.07–0.08
      Capelle et al.
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      Only the strongest associations were listed.
      20Reduction of neck diameter mid-PTV levelCombined PG mean dose increaseρ = 0.64p = 0.002
      Castadot et al.
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      10Contralateral PG shrinkage slope (cc/day)Contralateral PG mean dose increase0.62, correlation measure n.r.p = 0.006
      Castelli et al.
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      15CTV70 shrinkagePG mean dose increasen.r., Linear mixed effect modelp < 0.01
      Reduction of neck diameter
      Hunter et al.
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      18PG mean dose difference first fraction (Gy)PG mean dose difference (end of treatment)ρ = 0.92p < 0.001
      Lee et al.
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      10PG COM distance decreasePG mean dose increaser2 = 0.88n.r.
      Weight lossr2 = 0.58n.r.
      Marzi et al.
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      15ΔGTV (cm3)PG mean dose increaser2 = 0.43, Stepwise multiple regressionp = 0.015
      Wang et al.
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      15Weight lossPG mean dose increaseρ = 0.85p < 0.001
      Pts = patients, PG = parotid gland, ipsi = ipsilateral, contra = contralateral, n.r. = not reported, AP = anterior–posterior, SI = superior–inferior, OVP = overlap volume parotid gland and lymphnodal tumour, COM = centre of mass, OR = odds ratio (95% confidence intervals).
      low asterisk Only the strongest associations were listed.
      Table 2Studies reporting on parameters associated with contour reduction (anatomic endpoints) and dosimetric changes of spinal cord and mandible (dosimetric endpoints) during the course of radiotherapy. Only statistically significant correlations are shown. Results of Spearman correlation were denoted with ρ, Pearson correlation with R.
      Study# PtsParameterEndpointCorrelation/associationp value
      Anatomic endpoints
      Barker et al.
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      14Weight lossExternal contour volume reduction at level of C2 and at base of skullρ = 0.917 and 0.936, respectively, Spearman two-tailed correlationp < 0.01
      Fiorino et al.
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      84PG density decreaseAbsolute neck thickness reduction at C2 levelρ = 0.27p = 0.0005
      Dosimetric endpoints
      Ahn et al.
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      23Mandible vector increaseSpinal cord Dmax increaseR = 0.27n.r.
      Reduction of lateral neck diameter at mandibular jointR = 0.30n.r.
      Reduction of lateral neck diameter at C4–C6R = 0.17–0.27n.r.
      Reduction of lateral neck diameter at mid tumor levelR = 0.18n.r.
      ΔGTV (cm3)Mandible V60 increaseR = 0.26n.r.
      Cochlea/incisive roll, pitch, RL, APSpinal cord Dmax overdose (Dmax > 45 Gy)n.r.p = 0.024–0.054
      Mandible roll, yawn.r.p = 0.034
      C3–C7 vectorn.r.p = 0.002–0.043
      C2–6 pitchn.r.p = 0.001–0.005
      C2–C5 APn.r.p = 0.001
      Lordosisn.r.p = 0.001
      Anatomic isocentre vector RLMandible overdosen.r.p = 0.001–0.002
      Cochlea/incisive AP, RL, rolln.r.p = 0.013–0.039
      Mandible vector/yaw/roll/pitchn.r.p = 0.004–0.028
      Capelle et al.
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      Only the most predictive parameters were listed.
      20Reduction of lateral neck diameter at the level of the thyroid notchSpinal cord Dmax increaseρ = 0.73p < 0.0001
      Normal tissue V50 increaseρ = 0.71p < 0.0001
      Castadot et al.
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      10GTV shrinkage slope (cc/day)Spinal cord D2% increase0.75, correlation measure n.r.p = 0.001
      Nishi et al.
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      20ΔGTVp (cm3)Spinal cord D2% increaseρ = 0.91n.r.
      Wang et al.
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      15Weight lossSpinal cord Dmax increaseρ = 0.652p < 0.05
      Pts = patients, PG = parotid gland, n.r. = not reported, AP = anterior–posterior, SI = superior–inferior, RL = right-left, GTVp = the volume of primary gross tumour.
      low asterisk Only the most predictive parameters were listed.
      Table 3Studies reporting on side effects or quality of life in relation to anatomic or dosimetric alterations during radiotherapy. Only significant associations are shown. Results of Spearman correlation were denoted with ρ, linear regression analysis with r or r2 and odds ratio by OR.
      Study# PtsParameterEndpointAssociationp-value
      Anatomic parameters
      Belli et al.
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      46ΔPG rate (mm3/day)Mean xerostomia (CTC v3.0) score (treatment course) ⩾ 1.57OR = 0.10 (0.03–0.93)p = 0.02
      ΔDensity rate PG (HU/day)OR = 0.15 (0.99–1.00),

      Logistic univariable analysis
      p = 0.04
      Marzi et al.
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      15ΔGTV (cm3)ΔNTCP grade 3 or higher RTOG toxicity 12 months after RT
      Hypothetical difference in NTCP, assessed by LKB model.
      r2 = 0.609, stepwise multiple regressionp = 0.074
      ΔPG (%)p = 0.010
      Nishimura et al.
      • Nishimura Y.
      • Nakamatsu K.
      • Shibata T.
      • et al.
      Importance of the initial volume of parotid glands in xerostomia for patients with head and neck cancers treated with IMRT.
      33Initial volume of PG ΔPG (%)Xerostomia score at 3–4 monthsρ = n.r.

      ρ = n.r.
      p = 0.040

      p = 0.186
      Teshima et al.
      • Teshima K.
      • Murakami R.
      • Tomitaka E.
      • et al.
      Radiation-induced parotid gland changes in oral cancer patients: correlation between parotid volume and saliva production.
      20PG volume ratio post-RT/pre-RT (%)Saliva reduction amount (g)ρ = −0.79, Spearman rank correlation and Fisher exact testp < 0.01
      Sanguineti et al.
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      85ΔPG (%) mid treatmentTime to reduction of the acute xerostomia grade (CTCAE v3.0) (from ⩾grade 2 to grade 1)HR = 1.034 (1.004–1.064), multivariable analysisp = 0.024
      Schwartz et al.
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      24PG shrinkage (%) end of treatmentDuration of PEG tube useρ = n.r., two-tailed nonparametric Spearmanp = 0.025
      Senkus-Konefka et al.
      • Senkus-Konefka E.
      • Naczk E.
      • Borowska I.
      • et al.
      Changes in lateral dimensions of irradiated volume and their impact on the accuracy of dose delivery during radiotherapy for head and neck cancer.
      33Lateral dimension changes at beam axisDegree of mucositisr = n.r.p = 0.017
      You et al.
      • You S.H.
      • Kim S.Y.
      • Lee C.G.
      • et al.
      Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia?.
      31Weight loss >5% and/or decrease of neck diameter >10%Acute xerostomia ⩽grade 1 vs. grade 2n.r.p = 0.02, t-test
      Dosimetric parameters
      Castelli et al.
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      15IMRT replanning vs. no replanning in over-irradiated PG groupXerostomia risk
      Hypothetical difference in NTCP, assessed by LKB model.
      n.r.p < 0.01
      Hunter et al.
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      18PG Dmean (planned)Stimulated selective PG salivary output 6 months post-treatment (cc/min)ρ = −0.55p < 0.0007
      PG Dmean (delivered)ρ = −0.57p < 0.0004
      Yang et al.
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      129IMRT replanning vs. no replanningGlobal quality of life
      EORTC QLQ-C30 scales role functioning, social functioning, dyspnoea, appetite loss, constipation and diarrhoea all statistically significant. PG=parotid gland, Pts=patients, n.r.=not reported, OR=odds ratio (95% confidence intervals).
      n.r.p = 0.012, ANOVA
      Speech problemsn.r.p = 0.000
      Trouble with social contactn.r.p = 0.000
      Teethn.r.p = 0.031
      Opening mouthn.r.p = 0.000
      Dry mouthn.r.p = 0.000
      Sticky salivan.r.p = 0.015
      Zhao et al.
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      33TxN2,3 replanning vs. no replanningMucosan.r.p = 0.05, Mann Whitney Wilcoxon
      Xerostomian.r.p = 0.04
      low asterisk Hypothetical difference in NTCP, assessed by LKB model.
      low asterisklow asterisk EORTC QLQ-C30 scales role functioning, social functioning, dyspnoea, appetite loss, constipation and diarrhoea all statistically significant. PG = parotid gland, Pts = patients, n.r. = not reported, OR = odds ratio (95% confidence intervals).

      Parotid gland

      The majority of the studies included anatomic and/or dosimetric changes of the parotid glands (PGs). This interest for PG changes during radiotherapy can be explained by the fact that radiation dose to the PGs was associated with reduced saliva production [
      • Dijkema T.
      • Raaijmakers C.P.J.
      • Ten Haken R.K.
      • et al.
      Parotid gland function after radiotherapy: the combined Michigan and Utrecht experience.
      ] and xerostomia [
      • Beetz I.
      • Schilstra C.
      • van der Schaaf A.
      • et al.
      NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: the role of dosimetric and clinical factors.
      ,
      • Deasy J.O.
      • Moiseenko V.
      • Marks L.
      • et al.
      Radiotherapy dose–volume effects on salivary gland function.
      ].
      When all studies were taken into account, the average volume decrease of the PGs during radiotherapy was 26 ± 11% (note: volume loss reported on different time points during radiotherapy, Table S1). Some studies presented the PG shrinkage rate per treatment day or treatment week [
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ]. Sanguineti et al. [
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ] studied weekly CT scans of eighty-five patients and concluded that the PG shrinkage is not linear (PGs shrunk most during the first half of treatment).
      Thirty-eight papers reported on PG anatomic changes [
      • Hansen E.K.
      • Bucci M.K.
      • Quivey J.M.
      • et al.
      Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.
      ,
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Schwartz D.L.
      Current progress in adaptive radiation therapy for head and neck cancer.
      ,
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Duma M.N.
      • Kampfer S.
      • Schuster T.
      • et al.
      Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      ,
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      ,
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Broggi S.
      • Fiorino C.
      • Dell’Oca I.
      A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.
      ,
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ,
      • Duma M.N.
      • Kampfer S.
      • Wilkens J.J.
      • et al.
      Comparative analysis of an image-guided versus a non-image-guided setup approach in terms of delivered dose to the parotid glands in head-and-neck cancer IMRT.
      ,
      • Fiorentino A.
      • Caivano R.
      • Metallo V.
      • et al.
      Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer.
      ,
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      ,
      • Fung W.W.K.
      • Wu V.W.C.
      • Teo P.M.L.
      Dosimetric evaluation of a three-phase adaptive radiotherapy for nasopharyngeal carcinoma using helical tomotherapy.
      ,
      • Height R.
      • Khoo V.
      • Lawford C.
      • et al.
      The dosimetric consequences of anatomic changes in head and neck radiotherapy patients.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.
      ,
      • Lu N.
      • Feng L.-C.
      • Cai B.-N.
      • et al.
      Clinical study on the changes of the tumor target volume and organs at risk in helical tomotherapy for nasopharyngeal carcinoma.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Nishimura Y.
      • Nakamatsu K.
      • Shibata T.
      • et al.
      Importance of the initial volume of parotid glands in xerostomia for patients with head and neck cancers treated with IMRT.
      ,
      • Ricchetti F.
      • Wu B.
      • McNutt T.
      • et al.
      Volumetric change of selected organs at risk during IMRT for oropharyngeal cancer.
      ,
      • Tomitaka E.
      • Murakami R.
      • Teshima K.
      • et al.
      Longitudinal changes over 2 years in parotid glands of patients treated with preoperative 30-Gy irradiation for oral cancer.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ,
      • Castelli J.
      • Simon A.
      • Louvel G.
      • et al.
      Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia.
      ,
      • Reali A.
      • Anglesio S.M.
      • Mortellaro G.
      • et al.
      Volumetric and positional changes of planning target volumes and organs at risk using computed tomography imaging during intensity-modulated radiation therapy for head–neck cancer: an “old” adaptive radiation therapy approach.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Cozzolino M.
      • Fiorentino A.
      • Oliviero C.
      • et al.
      Volumetric and dosimetric assessment by cone-beam computed tomography scans in head and neck radiation therapy: a monitoring in four phases of treatment.
      ]. The most common reported anatomic changes were volume loss (Table S1) and medial shifts of the PGs [
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      ,
      • Barker J.L.
      • Garden A.S.
      • Ang K.K.
      • et al.
      Quantification of volumetric and geometric changes occurring during fractionated radiotherapy for head-and-neck cancer using an integrated CT/linear accelerator system.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ,
      • Height R.
      • Khoo V.
      • Lawford C.
      • et al.
      The dosimetric consequences of anatomic changes in head and neck radiotherapy patients.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Evaluation of geometric changes of parotid glands during head and neck cancer radiotherapy using daily MVCT and automatic deformable registration.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • Reali A.
      • Anglesio S.M.
      • Mortellaro G.
      • et al.
      Volumetric and positional changes of planning target volumes and organs at risk using computed tomography imaging during intensity-modulated radiation therapy for head–neck cancer: an “old” adaptive radiation therapy approach.
      ]. Jensen et al. [
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ] found a medial, cranial, and dorsal shift of the PG centre of mass from its original position. In general, a medial shift was observed of the medial and lateral aspects of both PGs [
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Ajani A.A.
      • Qureshi M.M.
      • Kovalchuk N.
      A quantitative assessment of volumetric and anatomic changes of the parotid gland during intensity-modulated radiotherapy for head and neck cancer using serial computed tomography.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ]. Vasquez-Osorio et al. [
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.
      Local anatomic changes in parotid and submandibular glands during radiotherapy for oropharynx cancer and correlation with dose, studied in detail with nonrigid registration.
      ] reported on shape and position changes of six sub-regions of the PG. The medial translation of the inferior region of the irradiated PGs was similar to that of the lateral region (3 ± 4 mm). Fiorino et al. [
      • Fiorino C.
      • Rizzo G.
      • Scalco E.
      • et al.
      Density variation of parotid glands during IMRT for head-neck cancer: correlation with treatment and anatomical parameters.
      ] and Belli et al. [
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      ] found reduced PG densities during IMRT.
      Twenty-four papers reported on dosimetric changes of the PGs [
      • Hansen E.K.
      • Bucci M.K.
      • Quivey J.M.
      • et al.
      Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer.
      ,
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Adaptive functional image-guided IMRT in pharyngo-laryngeal squamous cell carcinoma: is the gain in dose distribution worth the effort?.
      ,
      • Wu Q.
      • Chi Y.
      • Chen P.Y.
      • et al.
      Adaptive replanning strategies accounting for shrinkage in head and neck IMRT.
      ,
      • Duma M.N.
      • Kampfer S.
      • Schuster T.
      • et al.
      Adaptive radiotherapy for soft tissue changes during helical tomotherapy for head and neck cancer.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Robar J.L.
      • Day A.
      • Clancey J.
      • et al.
      Spatial and dosimetric variability of organs at risk in Head-and-Neck Intensity-Modulated Radiotherapy.
      ,
      • Graff P.
      • Hu W.
      • Yom S.S.
      • et al.
      Does IGRT ensure target dose coverage of head and neck IMRT patients?.
      ,
      • Ahn P.H.
      • Chen C.-C.
      • Ahn A.I.
      • et al.
      Adaptive planning in intensity-modulated radiation therapy for head and neck cancers: single-institution experience and clinical implications.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Capelle L.
      • Mackenzie M.
      • Field C.
      • et al.
      Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.
      ,
      • Duma M.N.
      • Kampfer S.
      • Wilkens J.J.
      • et al.
      Comparative analysis of an image-guided versus a non-image-guided setup approach in terms of delivered dose to the parotid glands in head-and-neck cancer IMRT.
      ,
      • Fung W.W.K.
      • Wu V.W.C.
      • Teo P.M.L.
      Dosimetric evaluation of a three-phase adaptive radiotherapy for nasopharyngeal carcinoma using helical tomotherapy.
      ,
      • Height R.
      • Khoo V.
      • Lawford C.
      • et al.
      The dosimetric consequences of anatomic changes in head and neck radiotherapy patients.
      ,
      • Ho K.F.
      • Marchant T.
      • Moore C.
      • et al.
      Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.
      ,
      • Jensen A.D.
      • Nill S.
      • Huber P.E.
      • et al.
      A clinical concept for interfractional adaptive radiation therapy in the treatment of head and neck cancer.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • O’Daniel J.C.
      • Garden A.S.
      • Schwartz D.L.
      • et al.
      Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?.
      ,
      • Wang X.
      • Lu J.
      • Xiong X.
      • et al.
      Anatomic and dosimetric changes during the treatment course of intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma.
      ,
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ,
      • Cozzolino M.
      • Fiorentino A.
      • Oliviero C.
      • et al.
      Volumetric and dosimetric assessment by cone-beam computed tomography scans in head and neck radiation therapy: a monitoring in four phases of treatment.
      ]. On average, the PG mean dose increased with 2.2 ± 2.6 Gy as compared to the dose calculated on the planning CT at baseline. Not all papers reported on absolute dose values. The studies that reported the highest dose increase consisted of (a majority of) (naso)pharyngeal carcinoma patients [
      • Nishi T.
      • Nishimura Y.
      • Shibata T.
      • et al.
      Volume and dosimetric changes and initial clinical experience of a two-step adaptive intensity modulated radiation therapy (IMRT) scheme for head and neck cancer.
      ,
      • Zhao L.
      • Wan Q.
      • Zhou Y.
      • et al.
      The role of replanning in fractionated intensity modulated radiotherapy for nasopharyngeal carcinoma.
      ,
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ,
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ,
      • Bhide S.A.
      • Davies M.
      • Burke K.
      Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: a prospective observational study.
      ,
      • Lee C.
      • Langen K.M.
      • Lu W.
      • et al.
      Assessment of parotid gland dose changes during head and neck cancer radiotherapy using daily megavoltage computed tomography and deformable image registration.
      ,
      • Wang W.
      • Yang H.
      • Hu W.
      • et al.
      Clinical study of the necessity of replanning before the 25th fraction during the course of intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.
      ]. The largest PG dose increase was found by Chen et al. [
      • Chen C.
      • Lin X.
      • Pan J.
      • et al.
      Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma?.
      ] and Cheng et al. [
      • Cheng H.C.Y.
      • Wu V.W.C.
      • Ngan R.K.C.
      • et al.
      A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients.
      ] (on average an increase of the mean dose of 10.4 Gy in the sixth week of radiotherapy, and an increase of the median dose of 7.8 Gy at the twenty fifth fraction, respectively). Both prospective studies included stage III–IV nasopharyngeal carcinoma patients.

      Factors correlating with parotid gland volume loss and parotid mean dose increase

      Eighteen studies reported on factors that correlated significantly with PG anatomic and/or dosimetric changes (Table 1). The most frequently reported factors were weight loss, PG dose and PG volume loss. All data available are presented in Fig. 2. On average, no clear relation between these factors and changes was found. The strongest association found was between PG dose and PG volume loss; three of the larger studies (more than eighty patients included) reported a significant correlation of PG dose with PG volume loss [
      • Broggi S.
      • Fiorino C.
      • Dell’Oca I.
      A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.
      ,
      • Wang Z.-H.
      • Yan C.
      • Zhang Z.-Y.
      • et al.
      Radiation-induced volume changes in parotid and submandibular glands in patients with head and neck cancer receiving postoperative radiotherapy: a longitudinal study.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Thomas O.
      • et al.
      Pattern and predictors of volumetric change of parotid glands during intensity modulated radiotherapy.
      ]. Still, a large variety of volume loss was observed between studies (Fig. 2B).
      Details of correlations on individual study level can be found in the Supplementary Material. Table 1 includes all factors that demonstrated significant correlations (p < 0.05) with corresponding correlation/association measures.

      Anatomic and dosimetric changes of the parotid gland and outcome

      Significant associations between PG volume change and the occurrence of complications were found in five studies [
      • Schwartz D.L.
      • Garden A.S.
      • Thomas J.
      • et al.
      Adaptive radiotherapy for head-and-neck cancer: initial clinical outcomes from a prospective trial.
      ,
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Teshima K.
      • Murakami R.
      • Tomitaka E.
      • et al.
      Radiation-induced parotid gland changes in oral cancer patients: correlation between parotid volume and saliva production.
      ,
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      ,
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      ] (Table 3). In general, more PG shrinkage was associated with higher complication rates [
      • Marzi S.
      • Pinnarò P.
      • D’Alessio D.
      • et al.
      Anatomical and dose changes of gross tumour volume and parotid glands for head and neck cancer patients during intensity-modulated radiotherapy: effect on the probability of xerostomia incidence.
      ,
      • Belli M.L.
      • Scalco E.
      • Sanguineti G.
      • et al.
      Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia.
      ]. On the contrary, Sanguineti et al. [
      • Sanguineti G.
      • Ricchetti F.
      • Wu B.
      • et al.
      Parotid gland shrinkage during IMRT predicts the time to xerostomia resolution.
      ] observed that the patients who received mean doses over 35.7 Gy to the PG developed more physician-reported GR2+ xerostomia if the shrinkage of the combined volume of parotid glands was lower than 19.6%. Nishimura et al. [
      • Nishimura Y.
      • Nakamatsu K.
      • Shibata T.
      • et al.
      Importance of the initial volume of parotid glands in xerostomia for patients with head and neck cancers treated with IMRT.
      ] found out that the patients with initially small parotid glands (⩽38.8 ml) had significantly more severe xerostomia three to four months after the start of IMRT than patients with initially larger parotid glands (p = 0.040), while the correlation between the shrinkage of PG and the grade of xerostomia was not significant (p = 0.186) (Table 3). Belli et al. found that apart from volume decrease, also early density decrease was associated with significantly higher acute xerostomia scores (Table 3). Weight loss >5% and/or decrease of neck diameter >10% was associated with higher xerostomia scores in the study of You et al. [
      • You S.H.
      • Kim S.Y.
      • Lee C.G.
      • et al.
      Is there a clinical benefit to adaptive planning during tomotherapy in patients with head and neck cancer at risk for xerostomia?.
      ]. Hunter et al. concluded that dosimetric changes were small relative to the standard deviations of the dose and saliva flow data [
      • Hunter K.U.
      • Fernandes L.L.
      • Vineberg K.A.
      Parotid glands dose–effect relationships based on their actually delivered doses: implications for adaptive replanning in radiation therapy of head-and-neck cancer.
      ].
      Yang et al. [
      • Yang H.
      • Hu W.
      • Wang W.
      • et al.
      Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma.
      ] studied global quality of life in addition to the different side effects for IMRT replanning vs. no replanning, and reported better quality of life and less side effects for the IMRT replanning group (Table 3).

      Submandibular glands

      In contrast to the parotid glands, information on anatomic and dosimetric changes of the submandibular glands is scarce. On average, a submandibular gland volume reduction of 22% (15–32%) was found [
      • Castadot P.
      • Geets X.
      • Lee J.A.
      • et al.
      Assessment by a deformable registration method of the volumetric and positional changes of target volumes and organs at risk in pharyngo-laryngeal tumors treated with concomitant chemo-radiation.
      ,
      • Vásquez Osorio E.M.
      • Hoogeman M.S.
      • Al-Mamgani A.
      • et al.