Radiation-induced changes in gustatory function comparison of effects of neutron and photon irradiation

In!. J. Radiation Oncology Biol. @ Pergamon Press Ltd., 1979.

Phys., Vol. 5, pp. 521-528 Printed in the U.S.A.

??Brief Communication

RADIATION-INDUCED COMPARISON

CHANGES

IN GUSTATORY

OF EFFECTS OF NEUTRON

FUNCTION

AND PHOTON IRRADIATION?

KENNETH L. MOSSMAN, Ph.D.,* JUDITH D. CHENCHARICK, M.S..Pi ALAN C. SCHEER, M.D.,” W. PAUL WALKER, M.D.,” ROBERT D. ORNITZ, M.D.,?? CHARLES C. ROGERS, M.D.H and ROBERT I. HENKIN, M.D., Ph.D.55 Division of Radiological Sciences, Sensory Disorders.

Department of Radiology and The Center for Molecular Nutrition Georgetown University Medical Center, Washington, DC 20007. U.S.A.

and

Changes in gustatory function were measured in 51 patients with various forms of cancer who received radiation to the head and neck region. Forty patients (group I) were treated with conventional photon radiation (e.g. 66Gy/7 weeks), and 11 patients (group II) were treated with cyclotron produced fast neutrons (e.g. 22 Gy/7 weeks). Taste acuity was measured for four taste qualities (salt, sweet, sour and bitter) by a forced choice-three stimulus drop technique which measured detection and recognition thresholds and by a forced scaling technique which measured taste intensity responsiveness. Subjective complaints of anorexia, dysgeusia, taste loss and xerostomia were also recorded. Patients were studied before, during and up to two months after therapy. Prior to therapy, detection and recognition thresholds, intensity responsiveness and the frequency of subjective complaints in patients from groups I and II were statisticallyequivalent. During and up to 2 months after therapy, taste impairment and frequency of subjective complaints increased significantly in neutron and photon treated patients, but were statistically equivalent. Results of this study indicate that gustatory tissue response, as measured by taste detection and recognition and intensity responsiveness, and the frequency of subjective complaints related to taste are statistically equivalent in patients before, during, or up to 2 months after they were given either neutron or photon radiation for tumors of the head and neck. Continued study of these patients will be necessary to determine the relation between acute and late gustatory tissue response in neutron patients are compared to photon patients.

Taste detection and recognition thresholds, Taste intensity responses, Head and neck cancer. Neutron therapy, Photon therapy.

INTRODUCTION

ventional low linear energy transfer (LET) radiations, neutrons have a reduced dependence on the presence of intracellular oxygen’.7.7 and on the variation in cellular radiosensitivity through the cell cycle.‘.’ In addition, the amount of recovery from sub-lethal radiation damage seen between fractionated doses of neutrons is much less than is observed between fractions of X-rays or y-rays.‘.4

Fast neutrons will be advantageous in the treatment of cancer only if serious damage to normal tissues can be avoided and if. compared to conventional photon treatment, fast neutrons can produce a greater effect on the tumor for an equal amount of damage to normal tissue. The rationale for using fast neutrons in the treatment of cancer is that, compared to contThis investigation was supported by Grant Nos. CA 17465 and CA 18865 awarded by the National Cancer Institute, Department of Health, Education and Welfare. SDirector, Division of Radiological Sciences, Department of Radiology and Assistant Professor of Radiology. DDivision of Radiological Sciences, Department of Radiology and the Center for Molecular Nutrition and Sensory Disorders. “Director, Division of Radiation Therapy, Department of Radiology and Associate Professor of Radiology. “Radiotherapist, Department of Radiology, District of Columbia General Hospital, Washington, DC 20002, U.S.A. Middle Atlantic Neutron t+Principal Investigator.

Therapy Association and Associate Research Professor, Department of Radiology, The George Washington University Medical Center, Washington, DC 20037, U.S.A. S$Director, Division of Radiation Oncology and Biophysics, Department of Radiology and Professor of Radiology, The George Washington University Medical Center, Washington, DC 20037. U.S.A. PPDirector of the Center for Molecular Nutrition and Sensory Disorders and Associate Professor of Pediatrics and Neurology. Reprint requests to: Kenneth L. Mossman. Ph.D. Accepted for publication 13 October 1978. 521

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522

The assessment of normal tissue response is an important aspect in the determination of the usefulness of fast neutrons in radiotherapy. It is only when the criterion of equivalence of normal tissue damage is met that a valid comparison can be made of the efficacy of neutrons and conventional photons in achieving local tumor control. Previously, we have demonstrated that radiation therapy is associated with specific changes in taste acuity that can be measured by sensitive psychophysical tests.” These tests, measuring taste detection and recognition as well as taste intensity responsiveness, can be used as a quantitative method for determining the effects of radiation on gustatory tissue.‘” The present study was designed to compare gustatory function in patients who received radiation treatment for tumors of the head and neck with either mCo y-rays or cyclotron-produced fast neutrons. METHODS

measurements

been tics of this beam have described previously. 10,‘7.2S22Treatment techniques employed were similar to those used with conventional radiation beams. Ten patients received curative doses of radiotherapy ranging from 20.2 Gy-23.2 Gy in 7-8 weeks.t Most patients received 22.4 Gy/28-32 fractions/7-8 weeks. This treatment regimen was thought to be equivalent to megavoltage X-ray or hoCo y-ray treatment of 70 Gy/35 fractions/7 weeks.” Another patient was given 12.5 Gy in 4 weeks and then left MANTA for electron beam therapy elsewhere. This patient was studied before and during the 4 weeks of neutron therapy only. All head and neck cancer patients who came for radiotherapy at GUMC. DCGH, or MANTA were approached to enter the study, but only 51 agreed to participate. All patients were treated between 1976 and 1978. Patients were studied before, during, and after radiation treatment, when possible.

AND MATERIALS

Patients Two groups of patients were evaluated in this study (Table 1). Patients in group I (32 men, 8 women) came to the radiotherapy service at Georgetown University Medical Center (GUMC) or the District of Columbia General Hospital (DCGH), Washington, DC, for radiation treatment of tumors of the head and neck. The sites of the primaries, shown in Table 1, indicate that 90% (36/40) were squamous cell carcinomas; the rest were anaplastic carcinomas or lymphomas. Thirty six patients with epithelial cancers received curative doses of radiation-typically 66 Gy/35-40 fractions/7-8 weeks. Three patients were treated preoperatively and were given 30-40Gy/15-20 fractions/3-4 weeks prior to surgery but were included in the study until surgery was performed. One patient with lymphoma of the tonsil was given 45 Gy in 7 weeks. This last patient was not included in the study after his treatment began because of the marked difference in the daily fraction size used compared to that used in the other 39 patients. All patients were treated with 6oCo y-rays using conventional treatment techniques. Patients in group II (8 men, 3 women) came to The Middle Atlantic Neutron Therapy Association (MANTA) in Washington, DC, for treatment of tumors of the head and neck (Table 1). The sites of the primaries in these patients, shown in Table 1, indicate that 8 patients had squamous cell carcinomas, 3 had adenocarcinomas. All patients were treated with fast neutrons (mean energy, 15 MeV) produced by the collision of cyclotronproduced 35 MeV deuterons on a thick beryllium target.” The physical and radiobiological characteristDose

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at MANTA

include

neutron

Subjective responses Each patient was required to indicate the presence of any subjective awareness of loss of taste, the presence of dysgeusia (unpleasant taste sensations),” xerostomia or anorexia by means of standard forms. Measurement of taste acuity Detection and recognition thresholds for representatives of each of four taste qualities (salt, sweet, sour and bitter) were measured using a forced-choice three stimulus drop technique previously described in detail.8,‘4.‘5.‘” The lowest concentration of solute which the subject consistently distinguished as simply different from water was called detection threshold. The lowest concentration of solute which the patient consistently recognized correctly specifically as salty, sweet, sour or bitter was called recognition threshold. Additional information about taste acuity was obtained by using the forced scaling test previously described in detail.8,‘5.‘x RESULTS The frequency of xerostomia, taste loss, dysgeusia, and anorexia in groups I and II patients prior to and during therapy are shown in Table 1. Comparison of these frequencies of subjective complaints before therapy indicate no significant differences between photon and neutron groups (x2 contingency test, p > 0.05) for any of the four complaint categories. In group I, after radiation treatments had begun, a significant increase in the frequency of complaints was observed for each category (x2 contingency test, p ~0.01). In group II, after treatment had begun, a significant increase in the frequencies was observed

plus gamma component

of the radiation

beam.

Radiation-induced

changes in gustatory function 0 K. L. MOSSMAN et al.

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for all categories except anorexia (x2 contingency test, p (0.05). Comparison of the frequencies of subjective complaints recorded after therapy began indicate no significant differences between groups I and II (x2 contingency test, p > 0.05) for any of the four categories (Table 1). Detection and recognition thresholds for patients in groups I and II before, during, and after therapy appear in Figs. 1 and 2, respectively. Individual threshold measurements were transformed to a scale in whch each tastant concentration was designated as a single bottle unit (BU) with the lowest concentration of tastant for each taste quality assigned BU 1.14t Using this transformation, the range of threshold values obtained in normal volunteers is l-4 BU for each taste quality.‘2*‘s This procedure was used to obtain means and standard errors of thresholds (as shown in Figs. 1 and 2) thus facilitating statistical comparison between neutron and photon treated patients. In both patient groups, before radiation detection thresholds were within or slightly above normal limits for all taste qualities except bitter: recognition

thresholds sour with

were

elevated

for

all

taste

qualities

the most severely affected (Figs. 1 and 2). In group I, 25 of 26 patients studied (96%) and in group II, 7 of 7 patients studied (100%) had abnormal detection and/or recognition thresholds for at least one taste quality. Comparison of detection and recognition thresholds prior to treatment indicate that there were no significant differences between patient groups for any of the four taste qualities (Student’s t-test, p > 0.10). Statistical analysis of thresholds using mM/l instead of BU also show no significant differences. Table 2 compares the patterns of taste impairment observed in neutron and photon patients (Figs. 1 and 2). The pattern of taste impairment may be analyzed into four phases: (1) the time for taste impairment (elevated detection and/or recognition thresholds) first to appear; (2) the highest level of impairment; (3) the time at which this level of impairment occurs; and (4) recovery, the time at which threshold values return to or towards pre-treatment values. Decreased taste acuity first occurred after two weeks of treatment in both patient groups for NaCI,

12 10 8 6 * .%

4

s e E

2

$

12 10 8 6 4 2 Pre

1

2

3

4

5

6

1

8

F,F2

Prel

2

3

4

5

6

1

Weeks

Fig. 1. Mean detection and recognition thresholds for NaCI, sucrose, HCl, and. urea^ (in BU; see text for explanation) in photon patients (group I) before, during, and one and two months atter radiation. 0, mean recognition thresholds in BU; 0, mean detection thresholds, in BU. Error bars represent one standard error of the mean. The shaded areas are the range of values obtained in normal volunteers.‘2V’4*‘s Numbers in boxes above data points for NaCl indicate number of patients. These same numbers apply to corresponding points for sucrose, HCl and urea.

I’NaCl concentrations, mM/I (BU): 6(l), 12(2), 30(3), 60(4), 90(5), l50(6), 300(7), 500(g), 800(9), lOOO(lO), 3000(1l), saturated (12). Sucrose concentrations, mM/l (BU): 6(l), l2(2), 30(3), 60(4), 90(5), 150(6), 300(7), 500(8), 800(9), lOOO(lO), saturated (I I). HCI concentrations, mM/l (BU):

0.5(l), O&2), 3(3), WI), l5(5), 30(6), 60(7), 90(8), 150(9), 300(10), 500(11). Urea concentrations, mM/I (BU): 60(l), 90(2), 120(3), 150(4), 300(5), 500(6), 800(7), 1000(8), 2000(9), 5000(10), 8300( 11).

Radiation-induced

Table 2. Comparison

NaCl Time to initiation of impairment (weeks) severe imMost pairment (BU) Time to most severe impairment (weeks) Recovery (weeks)

525

changes in gustatory function 0 K. L. MOSSMAN et al.

of taste impairment

in neutron

and photon patients

Photont HCl Sucrose

Urea

NaCl

Neutron$ HCl Sucose

Urea

2120

212

414

212

212

212

213

212

7.7/10.8

6.8/10.9

6.8/10.9

8.6110.3

8.019.8

9.319.3

8.519.8

10.3/10.3

517

415

618

813

413

814

F, tt/N.O.

tData taken from Fig. 1. SData taken from Fig. 2. QNumerator of fraction refers threshold. ‘Bottle units. ‘IF*,2 months after treatment. WF,, 1 month after treatment. N.O., Recovery not observed.

FJF,

to detection

5/F2”

417

8/N.O.

FJN.0

threshold;

,N.O./N.O. N.O./N.O.

denominator

of fraction

N.0./7

N.O.IN.0.

refers

to recognition

Sucrose

NaCl

12 10 8

8 6

12 10 8 6

Weeks

Fig. 2. Mean detection

and recognition thresholds for NaCl, sucrose, HCl and urea, in BU, in neutron patients (group II) before, during and one month after radiation. 0, mean recognition thresholds, in BU; 0, mean detection thresholds, in BU.

sucrose and urea. For HCI, impairment was seen first at 4 weeks for detection and recognition thresholds in group I patients, and at 2 and 3 weeks for detection and recognition thresholds, respectively, in group II patients. The severity of impairment was similar in the two groups for NaCl, HCl and urea but was higher in the neutron group for sucrose. The time at which the most severe impairment occurred varied in the neutron and photon groups but was most similar for NaCl (detection and recognition thresholds) and HCI (detection thresholds). Recovery of detection thresholds was not observed for any taste quality in the group II patients but was

observed after treatment for NaCI, sucrose, and urea and in the last week of treatment for HCI in the group I patients (Table 2). For recognition thresholds no recovery was observed for either NaCl or urea in either patient group but was observed after therapy for sucrose in the photon group and after 7 weeks of treatment for HCl in the neutron group. In general, the patterns of impairment were most similar for NaCl and least similar for sucrose in the two groups. Comparison of detection and recognition thresholds for all taste. qualities indicated that there were no significant differences (Student’s t-test, p > 0.05) between patient groups at any time during the

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NaCl 100 -

100

80 -

80

60 -

60

40 -

40

100 80 60

60

40

40 20

1000

~

,,-

0

s

Concentration

(mM/L)

Fig. 3. Mean forced scaling responses for NaCl, sucrose, HCl and urea in photon patients (group I) before and during radiation. 0, mean forced scaling responses in patients prior to therapy in %; 0, mean forced scaling responses in patients after 2 weeks of radiation treatment; triangles, mean forced scaling responses in patients after 5 weeks of radiation. Error bars represent 1 standard error of the mean. -, mean forced scaling responses observed in normal volunteers.‘5 Numbers in boxes at the end of the curve for NaCl indicate number of patients studied. These same numbers also apply to corresponding curves for sucrose, HCl, and urea.

100

100

80

80

60

60

40

40

: 5

20

20

8

0

as P

04 s m

100

100

80

80

60

60

40

40

20

20

0

10

100

1000

s

Concentration

10

100

1,000

10,000

0

(mM/L)

Fig. 4. Mean forced scaling responses for NaCl, sucrose, HCl and urea in neutron patients (group II) before and during radiation. 0, mean forced scaling responses in patients prior to therapy; 0, mean forced scaling responses in patients after 2 weeks of radiation treatment; A, mean forced scaling responses in patients after 5 weeks of radiation.

course of therapy or after therapy. Statistical analysis of thesholds using mM/l instead of BU also shows no significant differences. Forced scaling data for patients in groups I and II appear in Figs. 3 and 4 respectively. In each figure,

the solid curve for each taste quality represents the mean forced scaling responses observed in normal volunteers.” The mean forced scaling values for alltaste qualities in both patient groups, except NaCl in group II patients, were significantly below scaling

Radiation-induced

changes in gustatory function 0 K. L. MOSSMANet al.

values obtained in normal volunteers: the differences were most apparent at the highest tastant concentrations. Scaling for NaCl in neutron patients prior to therapy was similar to that observed in normal volunteers. After 2 weeks of treatment, scaling for tastants became progressively impaired for all taste qualities in both groups. Comparison of scaling values, at each time period, at all tastant concentrations was not significantly different (Student’s ttest, p > 0.05) between patient groups, for any taste quality tested. DISCUSSION Results of this study indicate that gustatory tissue response, (as measured by taste detection and recognition intensity responsiveness, and the and frequency of subjective complaints related to taste) are statistically equivalent in patients before or after they are given either neutron radiation or photon radiation for tumors of the head and neck. The object of the radiotherapy was similar in both patient groups. In group 1. 36/40 patients (90%) received a complete course of curative radiotherapy of 66Gy/35-40 fractions/7-8 weeks. In group 11 patients, lo/l1 (91%) received a complete course of curative therapy, i.e. 22.4 Gy/28-32 fractions/7-8 weeks. Seventy five per cent (30/40) of patients in group 1 and 82% (9/l 1) of patients in group 11 had radiation treatments to part or all of the oral cavity (Table I). However, the 10 patients in group 1 and the 2 patients in group 11 who did not have oral cavity irradiation did receive radiation treatments to the laryngopharyngeal area which, like the tongue and palate, is also responsive to salt, sweet, sour and bitter stimuli.‘3 Impairment of taste detection and recognition thresholds and impairment of ability of patients to estimate taste intensities was observed 2 weeks after radiation therapy began in both patient groups. For taste thresholds, the bitter and salt qualities showed the earliest and greatest impairment and the sweet quality the least; scaling impairment was most severe for the bitter taste quality and least for sour (Figs. 1 and 2, Table 1). Similar observations of severity of impairment in the bitter taste quality following radiotherapy have been noted previously.2.‘8 The preservation of the sweet taste quality may be related to the observation that the greatest number of taste buds in the oral cavity are devoted to the perception of sweet taste.” The time and degree of recovery of taste acuity after therapy is of clinical importance. Of the 7 photon patients available for study at least one month after therapy, every one had detection or recognition thresholds for one or more taste qualities at least 1 BU above the pre-treatment value. In the neutron

527

treated group, this was observed in 2 of the 3 patients available for study one month after completion of therapy. The present results also indicate that a measurable taste impairment was present prior to therapy, in both groups. Ninety six per cent of group 1 patients and 100% of group 11 patients had abnormal taste acuity for one or more taste qualities prior to initiation of therapy. In our previous study, impairment of taste acuity prior to radiation was measured in 95% of the patients. Impairments in estimation of taste intensity was also present before therapy in each group (Figs. 3 and 4). Dewy?’ also noted decreased taste acuity in cancer patients prior to chemotherapy: these taste impairments were observed in patients with tumors in various sites including the head and neck. Subjectively, prior to radiation treatments, 88% (23/26) of group 1 patients and 100% (7/7) of group 11 patients were unaware of any impairment of taste. As we have noted previously,‘* present results indicate there is little correlation between complaints of taste impairment and measurement of decreased taste acuity prior to radiotherapy in either group. The reason for this discrepancy is not clear; however, these results suggest that gradual changes in taste acuity may not be readily perceived by the patient. During and after radiotherapy, subjective complaints of taste impairment increased. Seventy seven per cent (23/30) of group 1 patients and 73% (S/II) of group 11 patients had subjective complaints of taste impairment after therapy had begun. Measurements of decreased taste acuity were made in each of these patients and subjective complaints of taste loss and measured decreased taste acuity occurred at about the same time. These results suggest that rapid changes in taste acuity may be perceived readily by the patient. When quantitative methods are used to measure taste acuity in patients with head and neck cancer who are treated with either neutrons or photons, an equivalent amount of acute damage to gustatory tissue is produced. Since this damage is equivalent, a neutron relative biological effectiveness (RBE) for this tissue, at the total radiation doses used, can be defined and is about 3 (66 Gy/22.4 Gy). Although the acute effects produced by these two radiation modalities were similar, we can speculate that the late changes in gustatory function, occurring months or years after treatment is terminated, may be different. Severe late effects of neutrons have been reported in other tissues not preceded by excessive acute injury and tended to occur at an earlier time than was expected with conventional photon irradiation.” Continued study of our patients will be necessary to determine the relation between acute and late gustatory tissue response in neutron patients as compared

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to patients given conventional radiation. The ultimate demonstration of the superiority of fast neutrons will depend not only on an improved local tumor control

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rate but also on an acceptable level of acute and late normal tissue injury as compared to conventional radiation treatment.

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G., Van Kersen, G.: Survival of cultured human cells after irradiation with fast neutrons of different energies in hypoxia and oxygenated conditions. Znt. J. Radiat. Biol. 13: 559-572, 1968. 4. Broerse, J., Roelse, H.: Survival of intestinal crypt cells after fractionated exposure to X-rays and 15 meV neutrons. Int. J. Radiat. Biol. 20: 391-395, 1971. 5. DeWys, W.: Abnormalities of taste as a remote effect of a neoplasm. Ann. N.Y. Acad. Sci. 230: 427434, 1974. 6. DeWys, W., Walters,

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13. Henkin, R., Graziadei, P., Bradley, D.: The molecular basis of taste and its disorders. Ann. Intern. Med. 71: 791-821, 1969. 14. Henkin, R., Schechter, P., Friedewald, W., Demets, D., Raff, M.: A double blind study of the effects of zinc sulfate on taste and smell dysfunction. Am. J. Med. Sci. 272: 285-299, 1976. 15. Henkin, R., Schechter, P., Hoye, R., Mattern, C.: Idiopathic hypogeusia with dysgeusia, hyposmia, and dysosmia: A new syndrome. J. Am. Med. Assoc. 217: 434-440, 1971. 16. Henkin, R., Talal, N., Larson, A., Mattern, C.: Abnormalities of taste and smell in SjGgren’s syndrome. Ann. Intern. Med. 76: 375-383, 1972. 17. Montour, J., Wilson, J., Rogers, C., Theus, R., Attix, F.: Biological characteristics of a high energy neutron beam for radiation therapy. Cancer 34: 54-64, 1974. 18. Mossman, K., Henkin, R.: Radiation-induced changes in taste acuity in cancer patients. Inc. J. Radiat. Oncol. Biof. Phys. 4: 663-670, 1978. 19. Ornitz, R., Bradley, E., Mossman, K., Fender, F., Schell, M., Rogers, C.: Clinical observations of early and late tissue injury in patients receiving fast neutron irradiation. Submitted to Znt. J. Radiat. Oncol. Biol. Phys. 1978. 20. Rogers, C.: The middle Atlantic neutron therapy trial. In Radiation Research Biomedical, Chemical, and Physical Perspectives, ed. by Nygaard, O.F., Adler, H.I., Sinclair, W.K. New York, Academic Press, 197S, pp. 1092-I 105. 21. Theus, R., Bondelid, R., Attix, F., August, L., Shapiro, P., Surratt, R., Rogers, C.: Physical characteristics of the NRL fast neutron beam for radiation therapy. Cancer 34: 17-32, 1974. 22. Todd, P., Schroy, C., Attix,

F.. Theus, R.: Spatial distribution of human cell survival in a neutron beam designed for therapy. Cancer 34: 33-38, 1974.