Radiotherapy Dose–Volume Effects on Salivary Gland Function
2010; Elsevier BV; Volume: 76; Issue: 3 Linguagem: Inglês
10.1016/j.ijrobp.2009.06.090
ISSN1879-355X
AutoresJoseph O. Deasy, Vitali Moiseenko, Lawrence B. Marks, K. S. Clifford Chao, Jiho Nam, Avraham Eisbruch,
Tópico(s)Salivary Gland Disorders and Functions
ResumoPublications relating parotid dose–volume characteristics to radiotherapy-induced salivary toxicity were reviewed. Late salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia (defined as long-term salivary function of <25% of baseline) is usually avoided if at least one parotid gland is spared to a mean dose of less than ≈20 Gy or if both glands are spared to less than ≈25 Gy (mean dose). For complex, partial-volume RT patterns (e.g., intensity-modulated radiotherapy), each parotid mean dose should be kept as low as possible, consistent with the desired clinical target volume coverage. A lower parotid mean dose usually results in better function. Submandibular gland sparing also significantly decreases the risk of xerostomia. The currently available predictive models are imprecise, and additional study is required to identify more accurate models of xerostomia risk. Publications relating parotid dose–volume characteristics to radiotherapy-induced salivary toxicity were reviewed. Late salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time. Severe xerostomia (defined as long-term salivary function of 100%) in salivary function can occur (8Maes A. Weltens C. Flamen P. et al.Preservation of parotid function with uncomplicated conformal radiotherapy.Radiother Oncol. 2002; 63: 203-211Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Li Y. Taylor J. Ten Haken R. et al.The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy.Int J Radiat Oncol Biol Phys. 2007; 67: 660-669Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Braam et al.(10Braam P.M. Roesink J.M. Raaijmakers C.P. et al.Quality of life and salivary output in patients with head-and-neck cancer five years after radiotherapy.Radiat Oncol. 2007; 2: 3Crossref PubMed Scopus (62) Google Scholar) reported that recovery in parotid flow correlated significantly with a reduction in patient-reported dry mouth symptoms. Parotid and submandibular salivary glands can be adequately delineated on contrast-enhanced computed tomography images. However, irradiated parotid glands typically shrink during RT, presumably owing to cell loss. On the basis of weekly computed tomography scans of 15 patients, Robar et al.(11Robar J.L. Day A. Clancey J. et al.Spatial and dosimetric variability of organs at risk in head-and-neck intensity-modulated radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 68: 1121-1130Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) reported little change in the medial parotid gland position during RT. However, the lateral edges shrank, on average, ≈1 mm/wk during RT (average displacements of 4–6 mm during the RT course), resulting in decreasing gland sparing A variety of salivary endpoints have been correlated with the dosimetric dose–volume parameters, including subjective xerostomia and objective stimulated/unstimulated salivary flow. In particular, the mean parotid gland dose (6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 8Maes A. Weltens C. Flamen P. et al.Preservation of parotid function with uncomplicated conformal radiotherapy.Radiother Oncol. 2002; 63: 203-211Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 9Li Y. Taylor J. Ten Haken R. et al.The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy.Int J Radiat Oncol Biol Phys. 2007; 67: 660-669Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 11Robar J.L. Day A. Clancey J. et al.Spatial and dosimetric variability of organs at risk in head-and-neck intensity-modulated radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 68: 1121-1130Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) has been correlated with whole mouth or individual gland salivary production. Table 1 summarizes the reported dose–volume predictors for salivary flow, the incidence of complications, and salivary function recovery.Table 1Dosimetric predictors of xerostomia.Dose–volume parametersInvestigatorPatients (n)/follow-up (mo)Total prescribed target dose (Gy)∗All ≈1.8–2.0 Gy/fraction.“Functional” endpoints assessedUnstimulatedStimulatedBlanco et al.6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 200555/6; 29/1250–71†1.5–1.8-Gy fractions in low-risk target volumes for intensity-modulated radiotherapy patients.Stimulated saliva flow‡Grade 4 xerostomia using subjective, objective, management, analytic (SOMA) method; ≤25% of pretreatment level defined as event.Mean dose <25.8 Gy§Mean dose to single parotid gland to reduce stimulated salivary flow from that gland to <25% of pre-RT saliva.Eisbruch et al.7Eisbruch A. Kim K.M. Terrell J.E. et al.Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 695-704Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar, 199988/1–1258–72Saliva flow, stimulated and unstimulatedMean dose ≤22–25 Gy¶24 Gy at 1 and 3 months, 22 Gy at 6 months, and 25 Gy at 12 months; threshold dose defined as mean dose above which saliva production appeared to abruptly approach 0.Mean dose ≤25–26 Gy‖26 Gy at 1, 3, and 6 months, 25 Gy at 12 months; threshold dose defined as mean dose above which saliva production appeared to abruptly approach 0.V15 <66%V30 <43%V45 <26%V15 <67%V30 <45%V45 <24%Li et al.9Li Y. Taylor J. Ten Haken R. et al.The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy.Int J Radiat Oncol Biol Phys. 2007; 67: 660-669Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 2007142/1–2460–75Saliva flow; stimulated and unstimulated#Predictors defined as mean doses below which efficient function recovery occurs with time, returning to pre-RT levels by 24 months.Mean dose <25–30 GyMean dose <25–30 GyMaes et al.8Maes A. Weltens C. Flamen P. et al.Preservation of parotid function with uncomplicated conformal radiotherapy.Radiother Oncol. 2002; 63: 203-211Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 200239/1–466–7066–70 Gy to primary tumor and pathologic nodes; 50–70 Gy to tumor bed if postoperatively; 46–50 Gy to elective nodes.SEFSEF loss ≥50% defined as event.; stimulated flow, 99mTc-pertechnetate scintigraphyMean dose ≤20 GyCorresponded to probability of 70% that SEF loss was x Gy; 99mTc = technetium-99 m; SEF = salivary excretion fraction; RT = radiotherapy.∗ All ≈1.8–2.0 Gy/fraction.† 1.5–1.8-Gy fractions in low-risk target volumes for intensity-modulated radiotherapy patients.‡ Grade 4 xerostomia using subjective, objective, management, analytic (SOMA) method; ≤25% of pretreatment level defined as event.§ Mean dose to single parotid gland to reduce stimulated salivary flow from that gland to <25% of pre-RT saliva.¶ 24 Gy at 1 and 3 months, 22 Gy at 6 months, and 25 Gy at 12 months; threshold dose defined as mean dose above which saliva production appeared to abruptly approach 0.‖ 26 Gy at 1, 3, and 6 months, 25 Gy at 12 months; threshold dose defined as mean dose above which saliva production appeared to abruptly approach 0.# Predictors defined as mean doses below which efficient function recovery occurs with time, returning to pre-RT levels by 24 months.∗∗ 66–70 Gy to primary tumor and pathologic nodes; 50–70 Gy to tumor bed if postoperatively; 46–50 Gy to elective nodes.†† SEF loss ≥50% defined as event.‡‡ Corresponded to probability of 70% that SEF loss was x Gy; 99mTc = technetium-99 m; SEF = salivary excretion fraction; RT = radiotherapy. Minimal gland function reduction occurs at 75%) at >40 Gy (Fig. 1) (4Chao K.S.C. Deasy J.O. Markman J. et al.A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results.Int J Radiat Oncol Biol Phys. 2001; 49: 907-916Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar, 6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). Xerostomia risk is reduced with sparing of at least one parotid gland or even one submandibular gland (12Saarilahti K. Kouri M. Collan J. et al.Sparing of the submandibular glands by intensity modulated radiotherapy in the treatment of head and neck cancer.Radiother Oncol. 2006; 78: 270-275Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). In one study, patients receiving <30 Gy to the contralateral parotid reported no or mild subjective xerostomia (13Portaluri M. Fucilli F. Castagna R. et al.Three-dimensional conformal radiotherapy for locally advanced (stage II and worse) head-and-neck cancer: Dosimetric and clinical evaluation.Int J Radiat Oncol Biol Phys. 2006; 66: 1036-1043Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Some recovery of function occurs with time, with the tissue dose required for a 50% response (TD50) increasing (i.e., more dose needed for the same level of injury) at longer follow-up times (Fig. 2) (8Maes A. Weltens C. Flamen P. et al.Preservation of parotid function with uncomplicated conformal radiotherapy.Radiother Oncol. 2002; 63: 203-211Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 10Braam P.M. Roesink J.M. Raaijmakers C.P. et al.Quality of life and salivary output in patients with head-and-neck cancer five years after radiotherapy.Radiat Oncol. 2007; 2: 3Crossref PubMed Scopus (62) Google Scholar, 12Saarilahti K. Kouri M. Collan J. et al.Sparing of the submandibular glands by intensity modulated radiotherapy in the treatment of head and neck cancer.Radiother Oncol. 2006; 78: 270-275Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 14Roesink J.M. Moerland M.A. Battermann J.J. et al.Quantitative dose–volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.Int J Radiat Oncol Biol Phys. 2001; 51: 938-946Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 15Roesink J.M. Moerland M.A. Hoekstra A. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: A prospective study of dose–volume response relationships.Int J Radiat Oncol Biol Phys. 2004; 58: 1451-1460Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 16Bussels B. Maes A. Flamen P. et al.Dose–response relationships within the parotid gland after radiotherapy for head and neck cancer.Radiother Oncol. 2004; 73: 297-306Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Figure 3 summarizes the existing published data regarding TD50 (dose resulting in 50% incidence) for a reduction in stimulated saliva by 50–75% (2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 10Braam P.M. Roesink J.M. Raaijmakers C.P. et al.Quality of life and salivary output in patients with head-and-neck cancer five years after radiotherapy.Radiat Oncol. 2007; 2: 3Crossref PubMed Scopus (62) Google Scholar, 14Roesink J.M. Moerland M.A. Battermann J.J. et al.Quantitative dose–volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.Int J Radiat Oncol Biol Phys. 2001; 51: 938-946Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 15Roesink J.M. Moerland M.A. Hoekstra A. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: A prospective study of dose–volume response relationships.Int J Radiat Oncol Biol Phys. 2004; 58: 1451-1460Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 16Bussels B. Maes A. Flamen P. et al.Dose–response relationships within the parotid gland after radiotherapy for head and neck cancer.Radiother Oncol. 2004; 73: 297-306Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 17Eisbruch A. Ten Haken R. Kim H. et al.Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.Int J Radiat Oncol Biol Phys. 1999; 45: 577-587Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar, 18Munter M.W. Karger C.P. Hoffner S.G. et al.Evaluation of salivary gland function after treatment of head-and-neck tumors with intensity-modulated radiotherapy by quantitative pertechnetate scintigraphy.Int J Radiat Oncol Biol Phys. 2007; 58: 175-184Abstract Full Text Full Text PDF Scopus (129) Google Scholar, 19Munter M.W. Hoffner S. Hof H. et al.Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: Comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without amifostine.Int J Radiat Oncol Biol Phys. 2007; 67: 651-659Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 20Rudat V. Munter M. Rades D. et al.The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy.Radiother Oncol. 2008; 89: 71-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Whole mouth or ipsilateral salivary measurement-based TD50s tend to be lower than scintigraphy-based TD50s (≈25–45 Gy). Consistent with this, the image-based data shown in Fig. 4 implies a greater TD50 compared with the salivary flow data in Fig. 1. The wide variation in the reported TD50 values is unexplained but could result from several factors, including differences in dose distributions, salivary measurement methods, segmentation, intragland sensitivity, and so forth.Fig. 3Reported tissue dose required for 50% response for loss of stimulated saliva flow after radiotherapy (RT) (2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 10Braam P.M. Roesink J.M. Raaijmakers C.P. et al.Quality of life and salivary output in patients with head-and-neck cancer five years after radiotherapy.Radiat Oncol. 2007; 2: 3Crossref PubMed Scopus (62) Google Scholar, 14Roesink J.M. Moerland M.A. Battermann J.J. et al.Quantitative dose–volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.Int J Radiat Oncol Biol Phys. 2001; 51: 938-946Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 15Roesink J.M. Moerland M.A. Hoekstra A. Scintigraphic assessment of early and late parotid gland function after radiotherapy for head-and-neck cancer: A prospective study of dose–volume response relationships.Int J Radiat Oncol Biol Phys. 2004; 58: 1451-1460Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 16Bussels B. Maes A. Flamen P. et al.Dose–response relationships within the parotid gland after radiotherapy for head and neck cancer.Radiother Oncol. 2004; 73: 297-306Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 17Eisbruch A. Ten Haken R. Kim H. et al.Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.Int J Radiat Oncol Biol Phys. 1999; 45: 577-587Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar, 18Munter M.W. Karger C.P. Hoffner S.G. et al.Evaluation of salivary gland function after treatment of head-and-neck tumors with intensity-modulated radiotherapy by quantitative pertechnetate scintigraphy.Int J Radiat Oncol Biol Phys. 2007; 58: 175-184Abstract Full Text Full Text PDF Scopus (129) Google Scholar, 19Munter M.W. Hoffner S. Hof H. et al.Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: Comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without amifostine.Int J Radiat Oncol Biol Phys. 2007; 67: 651-659Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 20Rudat V. Munter M. Rades D. et al.The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy.Radiother Oncol. 2008; 89: 71-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) for single parotid gland. Endpoint considered in reports was salivary flow reduction to <25% (black symbols) or <50% (gray symbols) of pretreatment value. Tissue dose required for 50% response defined as dose at which 50% of patients developed complications. Error bars (if shown) indicate 95% confidence intervals; refer to original publications for exact meaning. 95% Confidence intervals for studies by Munter et al.(19Munter M.W. Hoffner S. Hof H. et al.Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: Comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without amifostine.Int J Radiat Oncol Biol Phys. 2007; 67: 651-659Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 20Rudat V. Munter M. Rades D. et al.The effect of amifostine or IMRT to preserve the parotid function after radiotherapy of the head and neck region measured by quantitative salivary gland scintigraphy.Radiother Oncol. 2008; 89: 71-80Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar) were estimated from standard errors provided. Lines connect points from data sets with measurements taken at more than one interval after radiotherapy. Most studies used salivary gland scintigraphy. Some studies measured physical production (ipsilateral salivary flow or whole salivary flow; marked with “I” or “W”, respectively). Data from Buus et al.(2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar) (which did not include preradiotherapy assessments) derived by comparing different regions of parotid gland that had received different doses. Each label gives number of patients. Note, most imaging-derived endpoint data had greater values for tissue dose required for 50% response (TD50) than measured salivary data. CRT = conformal radiotherapy; IMRT = intensity-modulated radiotherapy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 4Population-based dose vs. local function response (salivary function at rest) from imaging study by Buus et al.(2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Local functional decline in metabolic clearance of parotid salivary glands vs. local dose, according to voxel-by-voxel estimated time-activity curves of intravenously injected C11-methionine. Data points from 12 patients shown, along with best-fit curve and 95% confidence intervals of curve fit. Individual gland curves reported by Buus et al.(2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar) deviated significantly from this population average curve (reproduced from Buus et al.[2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar], used with permission.) This population curve demonstrated functional decline in salivary function even at low doses.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Non-dose–volume factors could affect the risk of xerostomia. Nondosimetric patient factors (e.g., gender and age) and the use of chemotherapy have typically not correlated with xerostomia risk. However, pretreatment salivary function and medications affecting salivary function can affect the risk of xerostomia. Several investigators have tried to fit dose, volume, and complication risk data to a sigmoidal response function. This mirrors the local function curve derived from imaging measurements (Fig. 4). The Lyman-Kutcher-Burman volume effect parameter, n, is typically set to 1, although the best-fit value of n has sometimes been reported to be either less (6Blanco A.I. Chao K.S.C. El Naqa I. et al.Dose-volume modeling of salivary function in patients with head-and-neck cancer receiving radiotherapy.Int J Radiat Oncol Biol Phys. 2005; 62: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar) or greater (14Roesink J.M. Moerland M.A. Battermann J.J. et al.Quantitative dose–volume response analysis of changes in parotid gland function after radiotherapy in the head-and-neck region.Int J Radiat Oncol Biol Phys. 2001; 51: 938-946Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar) than 1. Chao et al.(4Chao K.S.C. Deasy J.O. Markman J. et al.A prospective study of salivary function sparing in patients with head-and-neck cancers receiving intensity-modulated or three-dimensional radiation therapy: Initial results.Int J Radiat Oncol Biol Phys. 2001; 49: 907-916Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar) fit stimulated whole mouth salivary function to a sum of two exponentials, representing contributions from both glands. Single gland function at 6 months was approximately given by exp(−0.054 × mean gland dose) (2Buus S. Grau C. Munk O. et al.Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET.Radiother Oncol. 2006; 78: 262-269Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). This model neglects the known submandibular gland contributions, however, which might cause it to overestimate the reduction at low mean doses (mean dose, 40 Gy. It is, therefore, not clear whether the parotid and submandibular glands have the same dose–volume response characteristics. The mean dose to the oral cavity (containing minor salivary glands) has been found to be an independent risk factor in some data sets (7Eisbruch A. Kim K.M. Terrell J.E. et al.Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 695-704Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar) but not others (25Lombaert I.M. Brunsting J.F. Wierenga P.K. et al.Rescue of salivary gland function after stem cell transplantation in irradiated glands.PLoS ONE. 2008; 3: e2063Crossref PubMed Scopus (324) Google Scholar), probably because of technique differences. The chemical modifier amifostine, is a radioprotector and has recently been shown to reduce the rates of xerostomia. Although quantitative data are sparse, Munter et al.(31Munter M.W. Hoffner S. Hof H. et al.Changes in salivary gland function after radiotherapy of head and neck tumors measured by quantitative pertechnetate scintigraphy: Comparison of intensity-modulated radiotherapy and conventional radiation therapy with and without amifostine.Int J Radiat Oncol Biol Phys. 2007; 67: 651-659Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) noted that amifostine significantly increased the combined parotid and submandibular gland tolerance dose for scintigraphically measured clearance dysfunction, by a mean dose of approximately 9 Gy. Sparing at least one parotid gland appears to eliminate xerostomia (Fig. 1), and sparing at least one submandibular gland also appears to reduce xerostomia risk and increase stimulated and unstimulated salivary function. Some of the reduction in stimulated salivary function in Fig. 1 also resulted from consistently irradiated submandibular glands. Severe xerostomia (long-term salivary function <25% of baseline) can usually be avoided if at least one parotid gland has been spared to a mean dose of less than ≈20 Gy or if both glands have been spared to a mean dose of less than ≈25 Gy. For complex partial volume RT patterns (e.g., intensity-modulated RT), the mean dose to each parotid gland should be kept as low as possible, consistent with the desired clinical target volume coverage. A lower mean dose to the parotid gland usually results in better function, even for relatively low mean doses (<10 Gy). Similarly, the mean dose to the parotid gland should still be minimized, consistent with adequate target coverage, even if one or both cannot be kept to a threshold of <20 or <25 Gy. Published variations in response among different patient cohorts were probably related to the lack of an accurate model that correctly includes the effects of multiple salivary glands and intragland sensitivity variations. When it can be deemed oncologically safe, submandibular gland sparing to modest mean doses (<35 Gy to see any effect) might reduce xerostomia symptoms. To improve patient-specific predictions, several questions need additional research:1.Whether partial sparing (achievable with intensity-modulated RT) of the submandibular glands or minor glands within the oral cavity will have a positive effect on patients' QOL2.Whether the (arbitrary) 25% salivary threshold is the best quantitative measure with respect to the affects on patient QOL3.Whether spatial/anatomic variations exist in the local radiation effect4.Whether parotid gland shrinkage during RT should be explicitly accounted for in functional predictions5.How submandibular sparing should be incorporated into predictive salivary function models6.The quantitative effect on xerostomia of oral cavity sparing7.The effect of the radioprotector amifostine on whole mouth salivary function8.The reason imaging endpoints result in greater TD50 values than direct salivary measurements An overarching goal is the validation of an accurate predictive salivary function model. This will probably require combining multiple institutional or cooperative group data sets. To best define xerostomia, we recommend that an observer-based system (e.g., the Common Terminology Criteria for Adverse Events) be supplemented by a validated QOL measurement device (e.g., the XQ (xerostomia questionnaire) [7Eisbruch A. Kim K.M. Terrell J.E. et al.Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.Int J Radiat Oncol Biol Phys. 2001; 50: 695-704Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar]) and/or salivary measurements (e.g., whole mouth-stimulated measurements).
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