Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.

[1]  A. Kuten,et al.  Oral side effects of head and neck irradiation: correlation between clinical manifestations and laboratory data. , 1986, International journal of radiation oncology, biology, physics.

[2]  M. Goitein,et al.  Fitting of normal tissue tolerance data to an analytic function. , 1991, International journal of radiation oncology, biology, physics.

[3]  W. B. Wescott,et al.  Some factors influencing salivary function when treating with radiotherapy. , 1981, International journal of radiation oncology, biology, physics.

[4]  M. Martel,et al.  Preservation of parotid function after external beam irradiation in head and neck cancer patients: a feasibility study using 3-dimensional treatment planning. , 1993, International journal of radiation oncology, biology, physics.

[5]  W. B. Wescott,et al.  Alterations in whole saliva flow rate induced by fractionated radiotherapy. , 1978, AJR. American journal of roentgenology.

[6]  G J Kutcher,et al.  Probability of radiation-induced complications in normal tissues with parallel architecture under conditions of uniform whole or partial organ irradiation. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[7]  T E Schultheiss,et al.  Inter-tumor heterogeneity and radiation dose-control curves. , 1987, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[8]  P. McCullagh,et al.  Generalized Linear Models , 1992 .

[9]  D. Cox,et al.  Analysis of Binary Data (2nd ed.). , 1990 .

[10]  Ipsilateral parotid sparing study in head and neck cancer patients who receive radiation therapy: results after 1 year. , 1996, Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics.

[11]  W. B. Wescott,et al.  Effect of Radiotherapy on Whole Saliva Flow , 1977, Journal of dental research.

[12]  M. Martel,et al.  Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing. , 1998, International journal of radiation oncology, biology, physics.

[13]  P. McCullagh,et al.  Generalized Linear Models , 1984 .

[14]  B. J. Baum,et al.  Basic Biological Sciences Unstimulated and Stimulated Parotid Salivary Flow Rate in Individuals of Different Ages , 1984, Journal of dental research.

[15]  M. Martel,et al.  Parotid gland sparing in patients undergoing bilateral head and neck irradiation: techniques and early results. , 1996, International journal of radiation oncology, biology, physics.

[16]  R. Henriksson,et al.  Parotid saliva composition during and after irradiation of head and neck cancer. , 1994, European journal of cancer. Part B, Oral oncology.

[17]  P. Fox,et al.  Major salivary gland function in patients with radiation-induced xerostomia: flow rates and sialochemistry. , 1993, International journal of radiation oncology, biology, physics.

[18]  S. Dische,et al.  The early changes in salivary gland function during and after radiotherapy given for head and neck cancer. , 1994, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[19]  R. Henriksson,et al.  Parotid gland function during and following radiotherapy of malignancies in the head and neck. A consecutive study of salivary flow and patient discomfort. , 1992, European journal of cancer.

[20]  R K Ten Haken,et al.  Use of Veff and iso-NTCP in the implementation of dose escalation protocols. , 1993, International journal of radiation oncology, biology, physics.

[21]  J. Lyman Complication Probability as Assessed from Dose-Volume Histograms , 1985 .

[22]  D L McShan,et al.  A computer-controlled conformal radiotherapy system. I: Overview. , 1995, International journal of radiation oncology, biology, physics.

[23]  P. McCullagh,et al.  Generalized Linear Models, 2nd Edn. , 1990 .

[24]  K. Ang,et al.  Target cell and mode of radiation injury in rhesus salivary glands. , 1986, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[25]  A. Vissink,et al.  Contrasting dose-rate effects of gamma-irradiation on rat salivary gland function. , 1992, International journal of radiation biology.

[26]  S. Zeger,et al.  Longitudinal data analysis using generalized linear models , 1986 .

[27]  B. Levy,et al.  Radiation‐induced xerostomia in cancer patients. Effect on salivary and serum electrolytes , 1976, Cancer.

[28]  R. Chappell,et al.  Fitting bent lines to data, with applications to allometry. , 1989, Journal of theoretical biology.

[29]  P. Jakobsson,et al.  Effect of fractionated radiotherapy on salivary gland function , 1972, Cancer.

[30]  M. Marunick,et al.  The effect of head and neck cancer treatment on whole salivary flow , 1991, Journal of surgical oncology.

[31]  P. Vilja,et al.  Changes in the protein composition of whole saliva during radiotherapy in patients with oral or pharyngeal cancer. , 1986, Oral surgery, oral medicine, and oral pathology.

[32]  B. Baum,et al.  How Much Saliva is Enough , 1991 .

[33]  C. Burman,et al.  Calculation of complication probability factors for non-uniform normal tissue irradiation: the effective volume method. , 1989, International journal of radiation oncology, biology, physics.

[34]  G J Kutcher,et al.  Analysis of clinical complication data for radiation hepatitis using a parallel architecture model. , 1995, International journal of radiation oncology, biology, physics.

[35]  B. Levy,et al.  Radiation‐induced xerostomia in cancer patients. Effect on salivary and serum electrolytes , 1976, Cancer.

[36]  Steve Webb Three-Dimensional Radiation-Therapy Treatment Planning , 1993 .

[37]  H. Withers,et al.  Treatment volume and tissue tolerance. , 1988, International journal of radiation oncology, biology, physics.

[38]  R K Ten Haken,et al.  Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. , 1998, International journal of radiation oncology, biology, physics.

[39]  J. Cooper,et al.  Late effects of radiation therapy in the head and neck region. , 1995, International journal of radiation oncology, biology, physics.

[40]  Marc L. Kessler,et al.  The use of 3-D dose volume analysis to predict radiation hepatitis. , 1991 .

[41]  David R. Cox The analysis of binary data , 1970 .

[42]  R. T. Ten Haken,et al.  Expanding the use and effectiveness of dose-volume histograms for 3-D treatment planning. I: Integration of 3-D dose-display. , 1994, International journal of radiation oncology, biology, physics.

[43]  A. Niemierko,et al.  Modeling of normal tissue response to radiation: the critical volume model. , 1993, International journal of radiation oncology, biology, physics.

[44]  J. Marks,et al.  The effects of radiation of parotid salivary function. , 1981, International journal of radiation oncology, biology, physics.

[45]  M. Goitein,et al.  Tolerance of normal tissue to therapeutic irradiation. , 1991, International journal of radiation oncology, biology, physics.

[46]  H. Sandler,et al.  Optimization and clinical use of multisegment intensity-modulated radiation therapy for high-dose conformal therapy. , 1999, Seminars in radiation oncology.

[47]  B. J. Baum,et al.  Clinical Science , 1981 .