THYROIDVolume 4, Number 1, 1994Mary Ann Liebert, Inc., Publishers

Influence of Diagnostic Radioiodines on the Uptake of AblativeDose of Iodine-131

HEE-MYUNG PARK,1 ORRIN W. PERKINS,1 JAMES W. EDMONDSON,2 RICHARD B. SCHNUTE,2 andAMITA MANATUNGA3

ABSTRACT

The uptakes of thyroablative doses of I31I by postoperative thyroid remnants and/or thyroid carcinoma métastasesfollowing diagnostic surveys with 131I or 123I were retrospectively compared by visual inspection. Only those patientswith a diagnostic scan demonstrating functioning tissue, remnant, and/or metastasis, following thyroidectomy fordifferentiated thyroid carcinoma, were evaluated. The 131I survey group (n = 26) had received a diagnostic dose of 3to 10 mCi of ,3,I. The I23I group (« = 14) had received the usual diagnostic dose of 300 u.Ci of I23I. The age, sex, andtumor type in the two groups were not statistically different. The uptake of the ensuing thyroablative dose of 131Iappeared, by visual inspection, to be impaired in 20 of 26 patients in the 131I group and in none of the 14 patients in the123I group (p < 0.00003). In the 13,I group there was suggestion of a dose-response, that is, the higher theadministered activity of 13II for the diagnostic scan, the more reduced was the subsequent apparent uptake of thethyroablative dose (p = 0.0007). Thyroid remnants or cervical lymph node métastases appeared to be affected more

frequently than were the distant (pulmonary or skeletal) métastases (p = 0.004). This study suggests that iodineuptake function may be suppressed by the absorbed radiation from the 3 to 10 mCi "diagnostic" scanning dose of 131I.In this regard, 123I may be a better initial diagnostic agent to be used prior to radioablation therapy.

INTRODUCTION

IN USUAL RADIOTRACER IMAGING STUDIES the higher thescanning dose, the better the image quality. It is true also in

postoperative thyroid cancer metastasis surveys that the higherthe dose of l3lI the better the lesions are demonstrated. Inpostthyroidectomy patients, a 400% increase in sensitivity indetecting functioning thyroid tissue with a 10-mCi dose relativeto a 2-mCi dose has been reported ( 1 ). Even higher (therapeutic)doses of l31I, in the range of50-150 mCi, can reveal functioningtissue which is not detected with 0.2-5 mCi of 13II (2-4). At ourinstitution we had chosen a high diagnostic dose (3-10 mCi) tominimize the chance of missing métastases in patients who maybenefit from l3lI therapy.

Scintigraphic images using ,23I are generally superior to thoseusing 13II due to the physical characteristics of the l23I photons.The high cost of 123I, however, makes it impractical to use inmultimillicurie quantities. Accordingly, l3lI has been usedwhenever a large amount of radioiodine is needed as in the

detection of functioning thyroid remnant/metastasis in patientswith differentiated thyroid carcinomas. However, the absorbedradiation dose from I, a ß emitter, is significantly higher thanthat from 123I, a pure y emitter. There have been previousreports of a potential adverse effect of such high diagnosticdoses ofl3lI (5-8). To investigate the possibility of a detrimentaleffect from the use of diagnostic l3lI the following study was

performed. The uptake patterns of thyroablative doses of l3lI intwo groups of patients were retrospectively compared by visualinspection of survey images. One group had received l3lI whilethe comparison group had received 123I for their diagnostic scan

prior to thyroablation therapy.

MATERIALS AND METHODS

The records of all patients who had received l3lI therapy fordifferentiated thyroid carcinoma at our institution from 1980through 1992 were retrospectively reviewed. Patients who

Divisions of 'Nuclear Medicine, 2Endocrinology, and 3Biostatistics, Indiana University, Indianapolis, Indiana 46202.

49

50 PARK ET AL.

received only a diagnostic survey scan and did not have a scan

following the therapeutic administration of 131I were excludedfrom the study. The study group consisted of 26 patients whohad received 3-10 mCi of l31I for diagnostic metastasis surveyscans prior to thyroablation/carcinoma ablation therapy and 14other patients who had received 123I asthe diagnostic scanningagent. Because we began using l23Tàs the exclusive initialdiagnostic scanning agent after we noticed the stunning phe-nomenon described in this paper, patients in the 13'I group werethose treated before 1990 and those in the 123I group were thosetreated subsequently. All 40 patients had had a total or near totalthyroidectomy for well-differentiated thyroid carcinoma. Diag-nostic scans were obtained after withholding thyroxine for 6weeks and triiodothyronine for 2 weeks. The serum thyroid-stimulating hormone level was usually above 30 |xIU per mLand frequently greater than 100 u.IU per mL. All received 131Iablation therapy in the range of 100-200 mCi following a

positive diagnostic radioiodine scan. Each subject showed atleast one focus of functioning thyroid remnant or metastasis.

1311 diagnostic scan group (n = 26): The mean age of thepatients was 50.3 years (range 17-83). There were 19 femalesand 7 males. Twenty patients had papillary carcinoma and sixhad follicular carcinoma. In this group, 18 patients received a 10mCi scanning dose, three patients received a 5 mCi scanningdose, and five patients received a 3 mCi scanning dose. Thedose simply depended upon which of three staff nuclear physi-cians was performing the study. Diagnostic scans of the neckand chest were obtained 48-72 h after the dose. Images wereobtained with a 20% window centered at the 364 keV photo-peak , a medium energy parallel hole collimator designed for '311scanning, and a 15 min acquisition time.

123I diagnostic scan group (n = 14): The mean age of thepatients was 50.0 years (range 16-87). There were 11 femalesand 3 males. Ten patients had papillary carcinoma and four hadfollicular carcinoma. All in this group received 300 u.Ci of 123Ias the diagnostic scanning agent. Diagnostic scans were ob-tained 24 h after the dose. Images were obtained with a 20%window centered at the 159 keV photopeak, a low energyparallel hole collimator, and a 15 min acquisition time.

13II therapy dose scan: Usually within a few hours but alwayswithin days ofapositive diagnostic scan, either with 131I or 123I, thepatient was orally administered 100-200 mCi of l3lI. Afterreceiving the ablation therapy, all patients had scans of the neck,chest, and other parts of the body when the residual l3lI activitydropped below the 30 mCi level. Usually, this occurred 24—48 hsafter the therapy. These were called "therapy scans." The diagnos-tic survey scans and corresponding therapy scans were visuallycompared. Quantitative comparison was not made as quantitativedata were not available for the therapy scans. When the diagnosticscan showed avid radioiodine uptake in a lesion but apparently lessuptake in the therapy scan, the thyroid tissue was consideredimpaired in its function, or "stunned" by the diagnostic radioio-dine. Due to the nonquantitative nature of the analysis, subtledifferences in apparent uptake were ignored. Only very visuallyobvious differences in lesion conspicuity between the diagnosisand therapy scans were recorded as positive. Proportions betweengroups were compared by using chi-square and Fisher's exact tests.Logistic regression analysis was used to investigate the relationshipbetween the administered activity of radioiodine and the occur-rence of apparent impaired function.

RESULTS

Of the 26 patients in the ,3'I group, 20 (77%) showedscintigraphic patterns of apparent decreased uptake in theresidual thyroid tissue or in the metastasis on the therapy scans,whereas none (0%) of the 14 patients in the 123I group showedsuch a phenomenon (p = 0.0004). Illustrative cases are shownas Figures 1 through 4. Within the l3lI group, two of the fivewho received 3 mCi, two of the three who received 5 mCi, and16 of the 18 given 10 mCi showed evidence of apparentlyimpaired function. In the 123I group there was a total of 16positive foci in the neck (including residual thyroid, tumor, or

local lymph node métastases) and 4 foci of distant metastasis. Inthe l3lI group there were 24 foci in the neck with 15 (63%)showing the stunning phenomenon and 11 distant métastaseswith 1 (9%) showing stunning. Logistic regression analysisshowed that there is a significant positive relationship between

FIG. 1. (A) A 37-year-old female with papillary carcinoma had amodified radical neck dissection 6 weeks previously. A diagnosticsurvey scan of the neck obtained 24 h after 300 u.Ci of l23Idemonstrates several areas of functioning thyroid remnants. (B) Atherapy-dose scan was obtained 48 h after an ablative dose of 101mCi of l3lI. The scan shows avid uptake of the therapy dose in thesame thyroid remnants. This was typical of patients that hadreceived l23I diagnostic surveys. The faint star-burst artifact is dueto the high concentration of l3lI in the small areas causing septalpenetration.

INFLUENCE OF DIAGNOSTIC RADIOIODINE 51

:&.

* '*

mäiJfv*W--

- .

s^::'v;

BFIG. 2. (A) A 22-year-old female with papillary carcinoma withcervical metastasis had a diagnostic scan using 10 mCi of l3lI. The72 h scan of the neck and chest shows avid uptake in the multiplemetastatic foci in the neck (arrows). The uptake in the lesions isgreater than that in the parotid glands. The activity in the left lowerportion represents normal gastric fundus. (B) A therapy-dose scanobtained 48 h after 200 mCi of l31I shows that the métastases(arrows) took up much less of the therapy dose than of the diagnosticdose. This suggests that their function may have been impaired bythe irradiation from the diagnostic l31I. This phenomenon has notbeen observed when l23I was used for the diagnostic scan.

BFIG. 3. (A) A 37-year-old female with papillary carcinoma had atotal thyroidectomy and received 106mCiof l3lI 1 year previously.A survey scan obtained 48 h after 10 mCi of 13II shows uptake bythe pyramidal lobe and two small foci in the thyroid bed. (B) Atherapy-dose scan was obtained 48 hrs after 100 mCi of l31I. Thereis much less uptake in the lesions when compared with the surveyscan.

52 PARK ET AL.

the probability of the occurrence of the phenomenon and theactivity of the diagnostic l3lI administered (p = 0.0007) (Fig.5). In other words, the higher the administered activity of 13II,the greater the chance of apparent impairment of function of thethyroid tissue. When the location of the functioning thyroidtissue was analyzed, 15 of the 24 cervical lesions (thyroidremnants and regional lymph nodes) and 1 of the 11 distantmétastases (pulmonary and skeletal) showed apparently im-paired function. This was significant (p = 0.004). Seventeen ofthe 20 patients with papillary carcinoma and 3 of 6 patients withfollicular carcinoma showed the same phenomenon, which wasnot statistically different (p = 0.112).

DISCUSSION

m:

There have been few anecdotal reports on the adverse influ-ence of the diagnostic scanning dose of radioiodine 13II on thesubsequent radioablation ofthe thyroid remnant or metastasis inthyroid cancer patients. Rawson et al. made the observation that"noncancericidal" doses of l3lI can impair the ability of thethyroid tumors to take up a therapeutic dose of radioiodine (5).Jeevanram et al. used an exposure rate meter to measurebaseline uptake and subsequent thyroid remnant uptake afteradministering 3.7-18.5 MBq (100 u.Ci to 5 mCi) of 13,I tothyroid carcinoma patients (6). Estimated radiation dose to theremnants ranged from 4.46 to 79.3 Gy (446 to 7930 rads), withevidence of a dose response relationship. That is, the greater theestimated radiation dose from the initial administration ofradioiodine, the more reduced was the subsequent uptake.Initial doses above 35 Gy (3500 rads) were associated with an

average 75% reduction in subsequent uptake by the thyroidremnant. We have also reported preliminary data demonstratingapparent decreased uptake following a diagnostic administra-tion of l3lI (7). Since the report, we have used l23I exclusively as

the initial scanning agent postoperatively.Compared with the usual administered activity (300 uCi) of

1231,10 mCi of '3 ' I may deliver approximately 3,300 times more

?^*jsr* :*

B

FIG. 4. (A) A 17-year-old female with papillary carcinoma had atotal thyroidectomy 4 weeks previously. A survey scan of the neckobtained 72 h after 5.2 mCi of l3lI demonstrates a large activemetastasis superior and to the left of the thyroid cartilage (V) and atleast 3 other foci on the right side of the neck showing much lessuptake. Two of these right-sided lesions may be thyroid remnants.(X) indicates the suprastemal notch. (B) A therapy scan obtained 24h after 110 mCi of 13'I demonstrates marked reduction in uptake byall of the lesions. The most obvious change is seen in the left upperlesion, which was the most active on the survey scan, suggestingthat the effect is radiation dose related.

% with Reduced Uptake'100

1-123 0.3 mCi 1-131 3 mQ 1-131 5 mQ 1-131 10 mQDiagnostic Radioiodines

*% ol thvrapy scans showmg reduced upufc»

FIG. 5. Frequency of "stunned" thyroid after diagnostic radio-iodines. The percent of patients with scintigraphic appearance ofreduced uptake of therapeutic 13II increases with higher diagnosticdoses of ,3,I.

INFLUENCE OF DIAGNOSTIC RADIOIODINE 53

radiation dose to the thyroid tissue. Although our study was notquantitative, a rough estimate of radiation dose can be made.Assuming a 6 day effective half-life in normal thyroid tissue (orremnant) the dose to the thyroid has been calculated to be 91 radsper u.Ci retained per gram of tissue (8). Assuming a 3 dayeffective half-life in métastases [as measured by Maxon et al.(9)] the dose to a metastasis would be 46 rads per u.Ci retainedper gram. Thus, one gram of tissue concentrating 1% of a 10mCi l3lI administration would receive a dose of 9100 rads if a

thyroid remnant, or 4600 rads if a metastasis. The uptakefunction will, most likely, decrease as the accumulated radiationdose increases. This is supported by the findings ofJeevanram etal. (6), already mentioned. This is also supported by the findingin our study that the higher the administered activity for thediagnostic scan, the more reduced was the subsequent apparentuptake of the therapeutic dose (p = 0.0007). However a precisedose-response relationship could not be determined in our studyas tissue masses, biological half-life of the radioiodine, andquantitative uptakes were not known. Thyroid remnants orcervical lymph node métastases showed apparent functionalimpairment more frequently than the distant (pulmonary or

skeletal) métastases (p = 0.004). This may be due to the distantmétastases being less active in iodide trapping or having a

shorter effective iodine half-life during the diagnostic study,thus receiving a lower radiation dose prior to the therapeuticadministration. A smaller mass of functioning tissue at a

metastatic site would also contribute to a lower radiation dose tothe metastasis.

It is unlikely that too much background activity or shortenedbiological half-life after 13II therapy was responsible for thereduced uptake phenomenon observed in our study, since no one

in the l23I group who received the same therapy dose demon-strated this finding. Technical factors associated with imaginghigh activities of l3lI, e.g., pulse pile up, dead time losses, andexcessive scatter, may have decreased conspicuity of foci on thetherapy scans. To gain an appreciation of the extent of this effectwe did the experiment shown in Figure 6. However, again thiswould not account for the observed differences between the 13IIand l23I groups.

We feel that l23I is the preferable initial scanning agent fordifferentiated thyroid cancer patients postthyroidectomy. I23Ibeing a 7 emitter may not impair the cellular function as much,and would allow the maximum uptake of the subsequent therapydose. One disadvantage of an initial l23I scanning is a logisticalone. Since the usual dose is only 300 p.Ci, the sensitivity will belower than that of a 10 mCi l3lI scan. Also, the short physicalhalf-life of 123I requires earlier scanning than with I. Thismakes ' 23I less sensitive for lesions with delayed uptake kinetics(10). Thus, a negative 123I scan would require a repeat studywith l3lI. Additionally, the short physical half-life of l23I doesnot allow accurate calculation of quantitative dosimetry if onewished to make such a calculation prior to therapy (11). Also,some important questions remain unanswered: If a lesion isvisualized by a high-dose l3lI scanning would it be beneficial towait for the cells to recover from "stunning" before l31I therapy?If so, what would be an optimal time period? We are not awareof any data available in the literature to answer these questions.We observed a patient whose thyroid remained nearly nonfunc-tioning 2 weeks after a 10 mCi "diagnostic" administration of

1-131 200 mCi

0.13 mCi

FIG.6. To assess the effect of technical factors in reducing lesionconspicuity on the therapy scans, the above image was acquired.The patient was the patient shown in Figure 2 who had received 200mCi of l3lI 48 h previously. The therapy scan (Fig. 2b) showed nofoci of uptake. The above image was obtained with a syringecontaining 0.13 mCi of l3'I in 1 mL of saline (corresponding to a

1-g "lesion" with 0.06% uptake) placed anteriorly on the patient'sneck. This image suggests that a real lesion of this size with just0.06% uptake would be conspicuous on a therapy scan (of course,with conspicuity lessening with depth of the focus within thepatient).

I3II (12). In another patient the thyroid was nonfunctioningwhen rescanned 7 months after a 10 mCi "diagnostic" adminis-tration. In this case, the "diagnostic" dose was probably thera-peutic in effect. These observations made us raise questionsabout the practice of using fractionated doses of radioiodine,i.e., 30 mCi weekly for 2 to 3 times, for ablation (13). The effectof the second or the third administration, if they were givenwhen the thyroid function was impaired by the first administra-tion, may have been minimal.

We would like to propose a two-level diagnostic scheme:First, a low-level survey using l23I for patients who are more

likely to have functioning tissue and to receive l31I ablationtherapy, i.e., those who are having a first postthyroidectomysurvey, or those with palpable cervical masses. Second, a

high-level survey using 10 mCi of l31I for the ,23I surveynegative cases, for better determination of ablation (1), and forthe follow-up of the patients who have had a successful thyroidablation.

54

LIMITATION OF THE STUDY

(l)Thiswasnota prospective study. The '3 ' I group data wereobtained by the review of existing data and included imagesfrom different y cameras. (2) The optimal time delay of 48—72hs (4) for diagnostic scanning for l31I, and the 24 h delay for l23Iscanning were different. This was unavoidable because of themuch shorter (13 h) half life of 123I. The time delays fordiagnostic scans and therapy scans were not precisely matchedin all patients. This was because the therapy scans were obtainedwhen the body retention dropped below the 30 mCi level, whichvaried in time with each patient. (3) We compared the relativeuptake scintigraphically without quantitative data. However, itshould be recognized that absolute quantification of therapy-dose (100-200 mCi) uptake is very difficult using commonlyavailable thyroid uptake systems.

CONCLUSION

Our study suggested that the degree of uptake of therapeutic1311 by the thyroid remnant or metastasis is different between thegroup of patients who received an l3,I diagnostic scan and thosewho received an l23I diagnostic scan prior to therapy. The use ofl3lI in the 3-10 mCi dose range as a diagnostic scanning agentappeared to have stunned the thyroid and reduced the iodinetrapping function. Such doses, given 48-72 hs or longer beforeradioiodine therapy may inadvertently prevent the maximumpossible uptake of an ablative dose by the thyroid remnantand/or metastatic thyroid cancer. Therefore, we feel that forinitial evaluation after total thyroidectomy l23I is the preferreddiagnostic agent to demonstrate the functioning thyroid tissue.A high dose l3lI scan is indicated if the 123I study fails to showfunctioning thyroid tissue, and for better determination ofablation.

Further studies seem warranted to evaluate the long-termeffect of large scanning doses of 13II in the management ofpatients with differentiated thyroid cancers.

ACKNOWLEDGMENTS

The authors thank Pat Booher for assistance in the datamanagement and in the preparation of the manuscript. Presentedin part at the 65th American Thyroid Association meeting,Boston, MA, September 1991.

PARK ET AL.

REFERENCES

1. Waxman A, Ramanna N, Chapman D, et al. 1981 The significance of1-131 scan dose in patients with thyroid cancer: Determination ofablation: Concise Communication. J Nucl Med 22: 861-865.

2. Nemec J, Rohling S, Zamrazil V, Pohunkova D 1979 Comparison ofthe distribution of diagnostic and thyroablative 1-131 in the evaluationof differentiated thyroid cancers. J Nucí Med 20: 92-97.

3. Pacini F, Francesco L, Formica N, et al. 1987 Therapeutic doses ofiodine-131 reveal undiagnosed métastases in thyroid cancer patientswith detectable serum thyroglobulin levels. J Nucl Med 28:1888-1891.

4. Coakley AJ, Page CJ, Croft D Letters to the Editor: Scanning dose anddetection of thyroid métastases. J Nucl Med 21: 803-804.

5. Rawson RW, Rail JE, Peacock W 1951 Limitations in the treatment ofcancer of the thyroid with radioactive iodine. J Clin Endocrinol 11:1128.

6. Jeevanram RK, Shah DH, Sharma SM, Ganatra RD 1986 Influence ofinitial large dose on subsequent uptake of therapeutic radioiodine inthyroid cancer patients. Nucl Med Biol 13: 277-279.

7. Park HM 1991 Potential adverse effect of high survey dose of 1-131administered prior to I-131 therapy in the management of differentiatedthyroid cancers. In: Schmidt H, VanDerSchoot JB (eds) NuclearMedicine: The State of the Art of Nuclear Medicine in Europe.Schattauer, pp 340-342.

8. Maxon HR, Thomas SR, Saenger EL, BuncherCR, Kereiakes JG 1977Ionizing irradiation and the induction of clinically significant disease inthe human thyroid gland. Am J Med 63: 967-978.

9. Maxon HR et al. 1983 Relation between effective radiation dose andoutcome of radioiodine therapy for thyroid cancer. N EngI J Med 309:937-941.

10. Briele B et al. 1990 Erhöht sensitvitat der ganzkorperzintigraphie mitJ-131 fur den nachweis jodspeichernder metatasen durch spatereaufnahme-zeitpunkte. Nuklearmedizin 29: 264-268.

11. MaxonHRetal. 1993 High activity 1-123 for the diagnostic evaluationof patients with thyroid cancer. J Nucl Med 34: 42P.

12. Park HM 1992 Stunned thyroid after high-dose 1-131 scanning. J ClinNucl Med 17: 501-502.

13. Arad E, Flannery K, Wilson G, O'Mara R 1990 Fractionated doses ofradioiodine for ablation of postsurgical thyroid tissue remnants. J ClinNucl Med 15: 676-677.

Address reprint requests to:Hee-Myung Park, M.D.

Nuclear MedicineIndiana University Hospital

University Blvd., Room 0663Indianapolis, IN 46202-5250

550 N.