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1097-0142%28197607%2938%3A1-273%3A%3AAID-CNCR2820380141-3.0.CO%3B2-8.pdf

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RADIATION-INDUCED XEROSTOMIA I N CANCER PATIENTS Effect on Sa1ivai.y and Sei-iLm Electrolytes SAM~JE L DDS, iMD, LEE R. BROWN,PHD, SANDRA DREIZEN, HANDLER, RS, A N D BARNETM. LEVY,DDS Saliva and s e r u m electrolyte concentrations were m o n i t o r e d in 30 patients given a co
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  RADIATION-INDUCED XEROSTOMIA IN CANCER PATIENTS Effect on Sa1ivai.y and Sei-iLm Electrolytes SAM~JEL REIZEN, DS, iMD, LEE R. BROWN, HD, SANDRA ANDLER, S, AND BARNET M. LEVY, DS Saliva and serum electrolyte concentrations were monitored in 30 patients given a course of xerostomia-producing cancer radiotherapy. The mean flow rate of stimulated whole saliva decreased 83.3 during a 6-week treatment period. The striking reduction in saliva output was accompanied by significant increases in saliva Na+, C1-, Cat+, Mg and Prot.- concentrations and by a decrease in saliva HCO; content. The xerostomic saliva was more concentrated and had a greater salinity than the pretreatment saliva in each instance. In contrast, none of the serum electrolytes measured was significantly altered by the subtotal salivary shutdown. ancer 38:273-278, 1976. IJMAN SALIVARY GLANDS IN THE PATH OF H tumor-suppressing ionizing radiation undergo progressive glandular atrophy, fi- brosis, and reduction in output beginning shortly after the initial exposiire and intensi- fying thereafter.5 Impaired production of sa- liva strips the teeth of an important natural defense against dental caries. The onset of xerostomia, from whatever cause, is followed invariably by the development of rampant dental caries unless stringent measures are taken to protect the Cross sectional and longitiitlirial studies of tlie influence of radiation-induced xerostomia on the human oral microbiota reveal that the reduction in salivation is paralleled by a shift to a highly cariogenic microflora at the expense of non- cariogenic organisms.lJJ Saliva protects the From the University of Texas Dental Science In- stitute, Houston, Texas 77025. Supported by Contract No. NIH-NIDR-71-2377 from the National Institute of Dental Research and by a grant from the Kimberly-Clark Foundation, Inc. Address for reprints: Samuel Dreizen, DDS, MD, University of Texas Dental Science Institute, Houston, TX 77025. The authors are grateful to Drs. Thomas E. Daly and Joe 1 . Drane, University of Texas M. D. Ander- son Hospital, for patient selection, to Dr. Dennis Johnston, M. D. Anderson Hospital, for statistical consultation, to Dr. H. M. Stiles of the National Institute of Dental Research, for administrative guid- ance and to Jacqueline Blackburn and Patricia Carter, for technical assistance. Received for publication July 9, 1975. teeth against caries by acting as a determinant of the oral microflora as well as ;I cleansing, diluting, mineralizing, and buffering agent. Normally, the salivary glands of man do not play a decisive part in regulating water and electrolyte balance since most of the salivary constituents are reabsorbed by the alimentary tract.13 The extent to wliicli radiation-iti- duced histologic changes in the salivary glands5 change tlie electrolyte composition of saliva has not been documented. To deter- mine whether a radiation-instigated drastic reduction in saliva output will materially alter saliva and serum electrolyte levels, a study of these parameters has been made in patients given radiotherapy for head or neck cii ricer. kfATERIAI S AND METHoI)S The study series was Lomposed of 30 pa- tients with radiosensitive malignancies of tlie lientl and/or neck treated at the LJniversity of Texas M. D. Anderson Hospital arid Tumor Institute in Houston. Subject selection was confined to patients who had not ieceived pre- vious cancer treatment, had a natural denti- tion in fair or good condition, were srlieduled to receive a minimum of 5,000 r,itls of ioniL- ing radiation at a level ok 1,000 rads a week and whose radiation fields included coverage of all major ralivary glands. The mem age ok the 21 men and nine women meeting these 273  274 CANCER 1(3‘76 PH LOW RATE ml /min) (ml 0.IN LACTIC ACID) ........ BUFFER CAPACITY VOl. 38 2 c 1 S 1 .c 0.s C \ \ \ \ \ .. ‘\ ............. ........... .>q ..... .....-. ------__ 7 5 7 0 FIG. 1. Effect of iadiation-in- duced xerostoinia on the mean pH, flow rate, and buffer ca- pacity of stimulated saliva from 30 patients with head or ncck cancer ’ 6 5 RAOlATl ON RADIATION WEEKS) criteria was 50.5 years with ii range of from 17 to 76 years. Nine had carcinoma of the tongue; eight, carcinoma of the nasopharynx; five, carcinoma of the tonsil; three, carcinoma of the floor of tlie mouth; two, carcinoma of tlie oropharynx; two, carcinoma of tlie soft palate; arid one malignant lymphoma of tlie upper neck. Samples of stimulated whole saliva gen- el-atetl by the cliewing of sterile rubber bands were obtained from each patient twice in tlie week before radiation antl once weekly during radiation. A venous blood specimen was tlrawri at each sampling period. The salivas were collected between 8:30 antl 10:30 a.m. in graduated glxs tubes containing a layer of par;iffiii oil. Collection periods were timed precisely with a stop watch for calculation of flow rates. Saliva in amounts adequate for andysis were obtained from a11 30 patients in radiation week 1; from 29, in weeks 2 arid 3; from 28, in weeks 4 and 5; ant1 from 20 in week 6. The pH of each saliva sample was nieasurecl with ;I Corning Model 12 Research pH Meter. Saliva Ijuffcr capacity W;IS tlcterniinecl in I-nil aliquots by tlie method ot Dreiren et al.“ Each saliva arid serum specimen was analyzed quantitatively for carbon dioxide, sodium, potassium, calcium, magnesium, inorganic pliosphoi us, chloride, and total protein. Car- bon dioxide was assessed in a Natelson MotoriLed Microgasometer Model 650 by the Natelson teclinic.’() Sodium and potassiuin were measured by flame photometry in a Coleman Model 21 Flame Photometer and calcium aiid magnesium by atomic absorption in Unicam SP 1900 Rtoniic Absorption Spec trophotometer. Chloride and total pro- tein were determined in a Beckman/Spinco Ultramicro Analytical System by the ultra- inicroada~~tations f the Schales and Schalesll and Kingsleyi procedures, respectively. Inor- ganic phosphorus W‘IS quantified by the micro- colorimeti ic method of Taussky and S11orr.l~ All T ‘iliics were con\ er tetl into milliequiva- lents per liter and means were calculated for each sampling point. lhe data were examined stati4cally by analysis of covariance1’ and by the “ ” test lor significant differences between the preradiation ine~iiis and the means at completion of atliotherapy.  No. 1 SALIVARY LECTROLYTES N RADIATION XEROSTOMIA Dreizen et al. 275 TABLE . Analysis of Covariance: Magnitude and Direction of Significant Slope Changes in Salivary Parameters During the DeveloDment of Xerostomia Slope change Salivary Overall* - magnitude Mean F component mean SD & directiont square: Ratio P Flow rate 0.635 + ,586 . 151 25.207 73.53 .003 Na+ 61.41 20.07 6.65 40797. 101.3 ,002 Ca++ 2.20 =k 1.06 ,218 44.278 39.64 008 Mg++ 0.811 ,487 ,121 13.137 55.34 ,006 CI- 40.45 16.53 3.51 12999, 47.56 .006 Proteiii- 0.770 0.436 0.084 7,4530 39.30 ,008 Overall mean from preradiation to 6000 rads (6 weeks). t Magnitude and direction: negative value indicates a decreasing slope. f Mean square = sum of squares since degrees of freedom equaled 1 in all instances. OI~SERVATIONS was a slight decrease in pH from a preradia- tion mean of 7.01 to a mean of 6.83 after 6 weeks of radiation. The average flow rate de- clined appreciably from 1.32 ml/min to 0.22 ml/min in the same period. The 83.3 reduc- The mean pH, flow rate, and buffer ca- pacity of stimulated whole saliva at each sampling period are graphed in Fig. 1. There TABLE . ComDarison of Saliva and Serum Values before and after Radiation Saliva Preradiation Postradiation Mean “t” Component mean SD mean SD diff. value P PH flow rate* buffer capacity’ Na+ mEq/L I< mEq/L Ca++ mEq/L Mg++ mEq/L Ci- mEq/L HPOa= mEq/L HC0,- mEq/L 1’rot.- mEq/L 7.01 1.32 0.63 38.42 21.40 1.51 0.37 24.68 7.32 19.80 0.48 0.37 1.33 0.31 14.01 3.92 1.07 0.29 18.43 2.40 8.71 0.27 6.83 0.22 0.35 78.27 21.96 2.80 0.99 45.03 6.15 7.95 1.01 0.45 0.24 0.13 27.47 8.72 1.42 0.57 17.63 2.62 3.33 0.63 0.18 1.10 0.28 39.85 0.56 1.29 0.62 20.35 1.17 11.85 0.53 1.15 3.64 1.76 7.66 0.38 3.72 5.56 4.09 1.66 3.25 5.15 > 05 <.001 > 05 <.001 >.05 < 001 < 001 < 001 > 05 < 01 < 001 Serum Prerndiation Postradiation Mean “t” Component mean SI) mean SD diff. value 1 Na+ mEq/L 136.42 12.13 137.82 12.25 1.40 0.40 > 05 K+ mEq/L 4.75 0.95 4.29 0.82 0.46 1.67 > 05 Ca++ mEq/L 5.05 0.37 5.02 0.52 0.03 0.62 > 05 Mg++ InEq/L 1.81 0.24 1.73 0.17 0.08 1.32 > 05 C1- mEq/’L 97.58 12.23 95.24 11.26 2.34 0.59 >.05 HPO4= mEq/L 2.27 0.64 2.43 0.65 0.16 0.87 > 05 Prot.- mEq/L 17.08 1.72 16.94 1.49 0.14 0.30 > 05 HCO,-mEq/L 27.04 1.95 28.16 1.85 1.12 0.43 > 05 SD = Standard deviation. “t” = Significance ratio. p = Probability level. Millimeter per minute. t Milliliters 0.1N lactic acid.  276 CANCER uly 1976 Vol. 38 9 7 Z 4 50 30 - 10 w4 € c 2 0 / / .............................. .................... =   I I PRE 12 3 4 5 6 FIG. 2. Effect of radiation-in- duced xerostomia on the mean saliva sodium, potassium, cal- cium, and magnesium levels of 30 patients with head or neck cancer. RADIATION RADIATION WEEKS) tion in flow rate was accompanied by a 44.4 reduction in buffering capacity. Although the reduction in flow rate was statistically impres- sive, those for pH and buffer capacity were not statistically significant (Tables 1 and 2). The weekly mean saliva electrolyte concen- trations are depicted in Figs. 2 and 3. Statis- tically significant changes in slope magnitude and direction during the development of xerostomia were evidenced by Na+, Cat+, Mg”, C1- and Prot.- (Table 1). As shown in Table 2, the mean increases of 39.85 mEq/L in Na’, 20.35 mEq/L in C1-, 1.29 rnEq/L in Ca++, .62 mEq/L in Mg”, and 0.53 mEq/L in Prot.- be- tween the initial and final measurements were all statistically meaningful (p < .001). The mean decrease of 11.85 mEq/L in HC0,- over the same period €ailed to reach the same level of significance (p < .Ol). The xerostomia-related changes in the sali- vary electrolyte levels occurred independent of concurrent alterations in serum electrolyte content. There were no significant changes in either slope magnitude and direction during radiotherapy or between the pretreatment and posttreatment means for any of the serum electrolytes tested (Table 2 . DISCUSSION The buffer capacity of saliva stems largely from bicarbonates with some contributions from phosphates and proteins.15 In 1878, Heidenhain6 noted that the salt content of saliva rises to a plateau as the flow rate in- creases in response to stimulation. This rela- tionship, termed Heidenhain’s law by Langley and Fletcher,s applies in general to hypotonic salivas. In man, Heidenhain’s law holds €or total salt, sodium, chloride, and bicarbonate and accounts for the greater neutralizing power of stimulated saliva over that of resting
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