stereotactic treatment of acromegaly

J. Neurol. Neurosurg. Psychiat., 1969, 32, 48-59

Stereotactic treatment of acromegaly'LOUIS W. CONWAY, FEARGHUS T. O'FOGHLUDHA, AND

WILLIAM F. COLLINS

From the Department of Neurological Surgery, University of California, Davis, School of Medicine; theDepartment of Radiology, Medical College of Virginia; and the Division of Neurological Surgery, Yale

University School of Medicine, U.S.A.

The normal anterior pituitary is resistant to radiation.Tissue effects vary with the characteristics of theradiation source, time over which the radiation isdelivered, and the interval between treatment andhistological study. Nevertheless, over 20,000 r arerequired for significant necrosis (Kelly, Feldsted,Brown, Ortega, Bierman, Lowbeer, and Shimkin,1951; Nickson, 1957; Plunkett, 1957; Lawrence,Tobias, and Born, 1958) and between 70,000 r and190,000 r for complete destruction of either thehuman or primate gland (Rasmussen, Harper, andKennedy, 1953; Greening, 1957; Notter, 1959).The optic chiasm, hypothalmus, and other

neuronal structures adjacent to the pituitary arerelatively more sensitive (Rasmussen et al., 1953).Although the report of Crompton and Layton (1961)of a case of fatal necrosis of these structures follow-ing 4,500 r over four weeks must be unusual,histological changes are characteristically found inthe neuronal structures of the parasellar regionafter 6,400 r to 15,000 r of external gamma radiationto this area (Kelly et al., 1951; Nickson, 1957;Crompton and Layton, 1961).Growth hormone producing adenomas of the

pituitary are more radiosensitive than the normalgland. They also appear to be often more radio-sensitive than the surrounding neuronal structures.The margin of safety is, however, slight.Although metabolic and endocrine studies of

acromegalic patients following conventional dosesof radiation by conventional sources have beendisappointing (Beck, Schalch, Parker, Kipnis, andDaughaday, 1965; Greenwood, Stewart, Forrest,and Wood, 1965; Kozak, Vagnucci, Lauler, andThorn, 1966; Drucker, Segal, Verde, and Christy,1967; Roth, Glick, Cuatrecasas, and Hollander,1967), Linfoot and Greenwood (1965) have treatedacromegalic patients with up to 9,000 r of radiationto the sella with the proton beam and have reporteddelayed but significant decreases in plasma growth'This study was supported in part by NIH Grant #08281. The patientswere hospitalized on the Clinical Research Center, Medical Collegeof Virginia, Grant #NIH 1 FR065 (General Clinical ResearchCenters).

48

hormone level. This paper describes our experiencewith interstitial implantation of single or multiplepoint sources of yttrium90 in the treatment ofacromegaly. Using an optimal dose of interstitialradiation, we anticipated that there would be adifferential effect on the growth hormone producingadenoma of acromegaly with sparing of the normalpituitary remnant. In view of the above data, wedecided that no portion of the adenoma shouldreceive less than 9,000 r; no portion of the pituitaryremnant, more than 20,000 r; and no significantvolume of nervous tissue, more than 6,000 r.

In addition, several cases underwent cryogenicdestruction of their gland, for reasons to be describedbelow.

MATERIAL

As listed in Table I, 11 patients with acromegaly withdocumented intrasellar tumours without suprasellarextension have been treated with stereotactic surgery.Each of these was found to have elevated serum growthhormone levels, not suppressible to zero by an oralglucose load, thus confirming the diagnosis of acromegaly(Earll, Sparks, and Forsham, 1967). Eight of these casesreceived implantation of interstitial sources of yttrium90and three cases underwent central cryogenic destructionof their tumour. Of the eight cases treated with yttrium90,four were males and four females. Their ages rangedfrom 18 to 56. Of the three patients treated withcryosurgery, two were males, and one was a female. Sixof the 11 patients had had one or more courses ofprevious radiation two and a half to seven and a halfyears previously.For reasons to be described below, those patients

with severe erosion of the floor of the sella were selectedfor cryogenic surgery. Review of Table I indicates, asmight be expected, that those cases with erosion of thefloor of the sella were among the larger tumours in theseries. There were, however, equally large tumours inthe yttrium90 treated group.

METHOD

In order to estimate the number, distribution, andstrength of the yttrium90 sources to satisfy the criteria

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Stereotactic treatnment of acromegaly

TABLE 1SUMMARY OF CASES

Previous x-ray therapy Post-op. (mth.)

Patient Tumour dose Yr. previous Size of tumour Modality, Dose Pituitary function2 Pre-op.3 2 8 12 18 24(r) (mm)

I E.L.G. 16 x 17 x 20 Y90 9,000 Gr. horm. (mpg/mi.) 115 50 18 25 20 232 r

0-8 mc

7 14 x I I x 18 yLo1 r

1-3 mc

10 x 10 x 16 Y90I r

0 45 mc

4 G.C. 3,50053 2,500d 1,500

4,000

2017144

19 x 23 x 22 Y904 r

1-28 mc

2.j 17 x 12 x 16 Y902 r

0-42 mc

13 15 x I0 x 20 Y90I r

1-3 mc

2j 23 x 21 x 16 Y904 r

0-84 mc

21 x 13 x 17 Y904 r

1-96 mc

20x 19 x21 Cold

22 x 18 x 21 Cold

18 x 19 x 23 Cold

r Gon.Thyr.Adr. cor.Post. pit.

8,000 Gr. horm. (myg/ml.)60,000 Gon.

r Thyr.Adr. cor.Post. pit.

10,000 Gr. horm. (mvog/ml.)r Gon.

Thyr.Adr. cor.Post. pit.

10,000 Gr. horm. (mrg/ml.)r Gon.


10,000 Gr. horm. (mjsg/mI.)r Gon.


12,000 Gr. horm. (mug/ml.)r Gon.


12,000 Gr. horm. (mpg/ml.)r Gon.


15,000 Gr. horm. (m,Mg/ml.)r Gon.


-180°C Gr. horm. (m,g/ml.)6 min Gon.x 1 Thyr.

Adr. cor.Post. pit.

- 180°C Gr. horm. (m,ug/ml.)15 min Gon.x I Thyr.

Adr. cor.Post. pit.

- 180°C Gr. horm. (mAg/ml.)5 min Gon.x 2 Thyr.

Adr. cor.Post. pit.

N N N NN N N NN N N NN N N N

32 23 6N N NN N NN N NL 0 0

36 3 5 3N N N NN N N NN N N NN N N N

111 41 5N N NL L NL N NN L N

23 9 3N N NN N NL N NN N N

17 5 5 6N N N NL N N NN N N NL L N N

25 10 16L N NN N NL N NN N N

145 3 2 20 L N NN N N NL L L LN N N N

130 41 40 42N N N N

L L N NL L N N

34 2 2 1N N N NN L L LN 0 L LN 0 L N

60 6 6N N NN N NL N NL N N

56

49

6,3002 J.S.42

3 G.S.51

N NN NN NN N

5 M.L.39

6 H.S.46y

7 R.G.30

3,500

4,000

4,475

8 A.K.18

9 S.A.59

3NNNN

2 2N NN NN NN N

31N

NN

2NLLN

6,000

10 J.B.51

11 E.L.54

'The mc are the sum of all rods used-each rod being of equal strength.'Gr. horm. = growth hormone. Gon. = gonadotropin. Thyr. = thyroid. Adr. cor. = adrenal cortex. Post. pit. = posterior pituitary.3N = normal, L = low, 0 = no detectable function.



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Louis W. Conway, Fearghus T. O'Foghludha, and William F. Collins

of having no portion of the adenoma receive less than9,000 r and no portion of the normal pituitary remnantmore than 20,000 r, the assumption was made that thepituitary remnant would always be subcapsular inlocation. Personal experience, at craniotomy, wouldindicate that the pituitary remnant is usually situatedposteriorly and superiorly, and this has been theexperience of others (Ray, 1968).

Figure 1 is a semilog. plot of the radiation dosebroadside to a 2 x 3 mm yttrium90 rod of 0-21 mc anda similar rod of 1-3 mc-the lowest and highest activitiesused in this study. Dose is plotted against distance inmillimetres. These values were calculated by the methodof the Jones Survey (Jones, Mallard, and Elmanharawy,1963) and the most recent available figures of Elman-harawy (1965) using the figure of 342,000 r/mc (totaldecay) at 1 mm broadside to the rod. The fall off inradiation dosage is steep, and approximately 3 mm fromthe surface of the 0-21 mc source and 5 2 mm from thesurface from the 1-3 mc source, the radiation dose isapproximately 12,000 r. This dose would seem ideal.Again referring to Fig. 1, 2 mm beyond the structurereceiving this ideal radiation dose, tissue would receive

100-

50-

40-

30-

20-

0

atoa6.

10 -

5.

12,000 rodsot 3 m.m.

1.3 mc-y90

0.21 mc-y9o

I 2 3 4 5 6 7 8(m.m)

FIG. 1. A semilog. plot of the radiation broadside to a

2 x 3 mm yttrium90 rod 0-21 mc, a similar rod 1-3 mc as

labelled, calculated by the method of the Jones Survey andthe most recent figures of Elmanharawy.

less than 4,000 r, a level well tolerated by the surroundingstructures. Furthermore, thle decrement continues to berapid, and the total volume of neural tissue receiving tradiation is small.

Figure 2 includes AP and lateral radiographs of a sella,21 x 13 x 17 mm, containing four yttrium90 rods,0 49 mc each. Above the radiographs is a diagram ofthe isodose curve in one plane around these rods. Theradiation dose in the cross-fire between the rods isexceedingly high. If the rods are placed more than 5 mmapart, however, the effect of one rod system on the regionlateral to its neighbour is negligible.Thus, by appropriate positioning of single or multiple

sources of yttrium90 in the sella turcica, a relativelyuniform and critical level of radiation source can beadministered to the border of the tumour mass withoutexcessive radiation to the pituitary remnant. FuLrthermore,little radiation will be received by a significant volumeof neuronal tissue.

In order to space the radiation sources to give areasonably uniform dose of radiation to the peripheryof the tumour, a reliable estimate of the size and shapeof the tumour was needed.

PLAIN RADIOGRAPHS Radiographs and laminograms ofthe sella turcica were obtained and the width, height, andlength of the sella were determined as described byDiChiro and Nelson (1962) and corrected for magnifica-tion.

PNEUMOENCEPHALOGRAPHY In several cases, a completepneumoencephalogram was performed several daysbefore surgery. In general, just before stereotacticsurgery, the patient was placed in a sitting position andair was introduced into the suprasellar region via alumbar spinal needle. The suprasellar air shadow wasused to make appropriate corrections in rod placementsif the superior border of the tumour was not in theanticipated position.

ARTERIOGRAPHY Before or during surgery, each patientunderwent bilateral carotid arteriography. Lateraldisplacement of the carotid siphon was taken intoaccount in estimating the lateral margins of the tumour.

RETROGRADE CAVERNOUS ANGIOGRAPHY In each case, thepatient underwent retrograde cavemous angiography asdescribed by Hanafee, Rosen, Weidner, and Wilson(1965), thus demonstrating another structure presumablyimmediately lateral to the sella contents.As a first approximation, the width of the floor of

the sella was considered as the width of the tumour.In no case was it necessary to revise this estimate bymore than 4 mm. In nine cases in which the lateral viewof the carotid siphon crossed squarely over the centralportion of the sella turcica (Fig. 3), the medial borderof the carotid artery and the medial border of thecavernous sinus were the same distance from the midline.In two cases, the carotid siphon was opened anddisplaced anteriorly, presumably by tumour mass. Inthese instances, the cavernous sinus was lateral to themedial border of the carotid artery, as seen on x-rayexamination.

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FIG. 2. (Below) Lateral and AP radiographs of the final placement of the interstitial radiation inA.K, received 15,000 r at the gland margin. There is a single Forrest screw each side of the midline.Each screw is tipped with two 0 49 mc yttrium90 rods spaced by a 2 mm plastic blank. (Above) Adiagram of the isodose curve in one plane around these rods. The radiation dose in the crossfire betweenthe rods is exceedingly high. If the rods are placed more than 5 mm apart, however, as they are inthis case, the effect ofone rod on the region lateral to its neighbour is negligible.

FIG. 3. Lateral and AP views of a carotid angiograph of R.G. Note that the carotid siphon passes squarely over thecentre of the enlarged sella turcica in the lateral view. In such cases cavernous sinus angiography shows the mnedial borderof the cavernous sinus and the medial border of the carotid siphon to be the sanie distance from the midline and bothpresumably reflect the lateral extension of the tumour.



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In all cases, yttrium90 sources or the cryogenic probewere introduced via the transnasal route using theRand-Wells stereotactic apparatus, as previously de-scribed (Rand, Dashe, Paglia, Conway, and Solomon,1964).

Previous experience (unpublished data) has shownthat yttrium90 sources placed freely in tissue will migratein the direction of gravity. The use of free yttrium90sources, therefore, would mitigate against carefulcalculation of tumour size and accurate placement ofthe sources. The yttrium90 rods were accordingly fixedby a modification of the screw described by Forrest,Blair, Peebles Brown, Stewart, Sandison, Harrington,Valentine, and Carter (1959).' This is a stainless screw,tipped with a nylon sheath of varying lengths. Yttrium90rods can be placed within the sheath and plastic blanksplaced between the rods for positive fixation and spacingof the radiation sources. At the top of Fig. 4 is photo-graphed a Forrest screw tipped with an 8 mm nylonsheath containing two 3 mm yttrium rods spaced by a2 mm plastic blank. Beneath this is a second Forrestscrew tipped with a 3 mm sheath containing a singleyttrium rod. Below these are the disassembled components.In the cases under discussion, a single midline screw wasused or two screws, one each side of the midline, con-taining one or more rods. As listed in Table I, one tofour rods were used with a total dose of 0-8 to 2 mc.

In order to place these screws in the sella, guides andscrewdrivers designed by Forrest were used.' These arereadily adaptable to the Rand-Wells stereotactic guide,by placing a suitable bushing in the probe carrier.The patients were placed in the stereotactic headrest

and, under x-ray control, the screws were fixed in thefloor of the sella turcica, with the nylon sheaths extendingthrough the tumour mass. This method of fixationproved adequate in cases in which the sella floor wasnot severely eroded. In cases in which the floor of thesella turcica was demineralized and thinned, the tumourswere treated stereotactically, using a cryoprobe, 4 76 mmin diameter.2 The number of lesions and time of freezingare summarized in Table I. In each case, the freezingtemperature was -180°C. One or two centrally placedcryogenic lesions were used. The success of such lesionshas been previously published, along with the develop-ment and rationale for this technique (Rand et al., 1964).Lateral to the sella contents is the rapidly flowing bloodcontained in the cavernous sinus and carotid arteries.Superiorly, spinal fluid is circulating in the supra-chiasmatic and prepontine cysterns. 'TOese body fluids,being at body temperature, are warW,nr elative to thetissue being frozen. Thus, these structures act as a heatsink and might well protect the subcapsular tissueadjacent to these structures from cold damage. Acentrally placed lesion might well not affect the moreperipheral portion of the sella contents, at least laterally,superiorly, and posteriorly; and thus preserve the pituitaryremnant.

In order to protect the surrounding neuronal structuresfrom excessive cold, the cryogenic surgical procedures'Obtained from the London Splint Company, Ltd., 50-52 NewCavendish Street, London W. 1, England.2Linde CE-2A Cryosurgery Unit.

FIG. 4. Shown from above down are: a Forrest screwtipped by a nylon sheath I cm long and containing two3 mm yttrium rods spaced by a 2 mm plastic blank, aForrest screw tipped with a 4 mm sheath containing a3 mm yttrium rod, a I cm nylon sheath, a 3 mm x 2 mmyttrium rod, a 2 mm x 2 mm plastic blank, and a2 mm x 2 mm yttrium rod.

were performed under local anaesthesia with the patientawake. Visual fields, visual acuity, and extraocularmo'yements were tested continuously during the activefreezing of the probe tip, as previously described (Randet al., 1964). Yttrium90 implantations were performedunder general anaesthesia. Before introduction of thedestructive medium, a biopsy needle was stereotacticallyintroduced into the sella turcica, and a biopsy confirmingan edosinophilic adenoma was obtained in each case.Each patient was admitted to the hospital for extensivemetabolic and endocrine evaluation before the aboveprocedures, and subsequently, two months post-operatively and then at intervals, usually of six months.

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Stereotactic treatment of acromegaly

To date, the patients have been followed for fromeight months to 24 months since operation. Studies haveincluded:

GONADOTROPINS Two 24-hour urine samples wereanalysed for gonadotropins by the method of Bradbury,Brown, and Brown (1949)1 Two 24-hour urine sampleswere collected for 1 7-ketosteroids (Drekter, Heisler,Scism, Stern, Pearson, and McGavack, 1952). In females,a vaginal smear was evaluated for oestrogen effect(Young, Bulbrook, and Greenwood, 1957).

THYROID FUNCTION Studies included I'31 uptake forthree, five, and 24-hour reading, protein bound iodine,'T4 by column,1 and serum cholesterol.'

ADRENOCORTICAL FUNCTION Urine 1 7-hydroxycortico-steroids were determined after methopyropone stimulationas described by Liddle, Estep, Kendall, Carter, Williams,and Townes (1959). Plasma 17-hydroxycorticosteroidswere measured by the method of Nelson and Samuels(1952) and the diurnal variation was determined on twoseparate occasions as was the plasma 17-hydroxycortico-steroids response to 25 u. intravenous ACTH describedby Christy, Wallace, and Jailer (1955). Plasma17-hydroxycorticosteroids were determined before andafter stress stimulation with insulin induced hypo-glycaemia (Landon, Wynn, and James, 1963).

INTEGRITY OF VASOPRESSIN SECRETION This was evaluatedby determining blood and urine osmolarities after12 hours of water deprivation (Dashe, Cramm, Crist,Habener, and Solomon, 1963).

SERUM GROWTH HORMONE This was measured byradioimmunoassay (Schalch and Parker, 1964). Fastingsamples were obtained on hospitalized patients early inthe morning. A Coumand needle was placed in theantibrachial vein, and subsequently the patient was keptat complete bedrest for at least 30 minutes before twosamples were drawn, 15 minutes apart. These duplicatesamples were obtained on three separate occasions,during each admission. Each sample was analysed induplicate.

RESULTS

Figure 5 charts the mean fasting resting growthhormone level of each patient, pre-operatively, andperiodically post-operatively, for up to 24 months.The total variation is indicated. The eight casestreated with interstitial yttrium90 are arranged inorder of increasing dose of radiation at the glandmargin, with the exception of the second case. Inthis case, a single central rod of 1-3 mc was implanted2 mm higher than desired. Thus, the calculated doseat the superior border of the gland was. 60,000 r

whereas the inferior border received but 8,000 r.

All cryogenic lesions were made at - 180°C. The

'Bio-Science Laboratories, Van Nuys, California, U.S.A.

minutes of freezing for each lesion and the numberof lesions are indicated.To the right, the bar labelled 'normal' indicates

the average and variation of resting fasting growthhormone as determined in our laboratory on 157non-acromegalic subjects. These subjects hadcarcinoma of the breast, carcinoma of the prostate,and lumbar disc disease. Patients with intracranialdisease, overt diabetes mellitus, or other knownendocrine disorders were excluded. These values areconsistent with normal values reported by others(Unger, Eisentraut, Madison, and Siperstein, 1965).

Table I summarizes these same 11 cases, includingdetails of previous conventional radiation, the sizeof their tumours, and the therapeutic modalityemployed. The right side of Table I summarizes thepre-operative and post-operative endocrine studieson these patients. The average plasma growth hor-mone levels in m,ug/ml., as charted in Fig. 5,are listed horizontally. Beneath the growth hormonelevels, the gonadotropin, thyroid, adrenal cortex,and posterior pituitary functions are summarized.The results of the tests, described under Method,are synthesized as being N (normal), L (low), andO (no detectable function).

Table II summarizes this data for the yttrium90treated cases pre-operatively and at the time of theirlast follow-up evaluation, eight to 24 months aftersurgery. Results are grouped as 'normal' or'abnormal'. Abnormal in respect to growth hormoneindicates excessively high plasma levels, whereasabnormal in respect to other pituitary functionsindicates subnormal baseline levels or subnormalresponse to the provocative tests listed above.Of the eight cases undergoing yttrium90 implanta-

tion and receiving 9,000 r to 15,000 r to the entiregland margin, all eight had excessively high growthhormone levels pre-operatively and two of these(Case 1 and Case 7) continue to have elevated,although diminished, fasting growth hormone levels.Case 1 received the lowest dose of radiation in the

TABLE ILTREATED CASES OF ACROMEGALY. YTTRIUM9" IMPLANTS

(EIGHT CASES)

Last follow-upPre-operative (8-24 months)

Pituitary function abnormal' cases (no.) abnormal' cases (no.)

Growth hormone 8 2Gonadotropin 2 0Thyroid 2 0Adrenal cortex 4 0Posterior pituitary 2 1'

"'Abnormal' indicates excessively high growth hormone level orinsufficiency of the other pituitary functions listed.20n replacement therapy.

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FASTING GROWTH HORMONE IN TREATED ACROMEGALY

2 8 121824 2 8 2 a12 18 2 8 2 8 2 8 12 289,000 r 8,000 to 10,000 r 10,000 r 10,000 r 12,000 r 12,000 rE.LG. 60,000 r G.S. G.C. M.L. H.S. R.G.

J.S.

0 BEFORE OPERATION

2 8 12 18 24 NORMAL15,000 r

A.K.

AFTER YTTRIUM - 90 IMPLANTATIONED AFTER CRYOSURGERY

2 8 1218 24 2 8 121824 2 8 NORMAL

S.A.-6mInXI J.B.-15mImXI E.L-5mInX2

FIG. 5. The pre-operative and serial post-operative growth hormone levels of each patient. The average of each set ofdeterminations and the total variation of these determinations is depicted. The cases treated with yttrium90 interstitialradiation are arranged in the top row in order ofascending dose of radiation at the gland margin, with the exception ofCase 2, whose eccentric placement led to a variable dose at the gland margin. Below are the growth hormone levels ofthe three cases treated with stereotactic cryosurgery. The time in minutes is listed followed by the number of lesions.All lesions were made with the 4-76 mm cryoprobe supplied with the Linde CE-2A apparatus. The time in each case isthe time at which the probe was being actively cooled at minus 180°C.

series, 9,000 r to the gland margin. She had asignificant drop in growth hormone level from115 m,ug/ml. to approximately 20 m,ug/ml., overthe first eight months, but subsequently has beenfollowed for a total of 24 months post-operativelywithout further decrease in her growth hormonelevel. Case 7 received 12,000 r to the tumour margin,a level which has been highly successful in otherpatients, but, eight months post-operatively, hasfailed to show complete ablation of excess growthhormone.

Pre-operatively, several of the yttrium90 treatedgroup had deficiencies in one or more other pituitaryfunctions. As seen in Table I, there was a progressiveimprovement in other pituitary functions over amatter of months, up to 18 months. At this time,eight to 24 months post-operatively, all patients

have had a return of other pituitary functions tonormal with the exception of Case 2 (J.S.) who,presumably due to excessively high placement of theyttrium90 rod, has developed overt diabetes insipidus.Pre-operatively she was unable to concentrate herurine after an overnight fast. Post-operatively sherequired Pitressin which she continues to take,although the severity of her diabetes insipiduscontinues to lessen.

Three cases underwent cryogenic therapy. Asseen in Table I, all three tumours were of approxi-mately the same volume. Cases 9 and 10 werespherical and Case 11 oval with the greatest diametercorresponding to the width of the sella turcica. Forthis reason, Case 11 received two cryogenic lesions,centred 4 mm each side of the midline, whereasCases 9 and 10 were treated with single midline

150 -

.i o00 -

50 -

ISO -

_ 100-ob

SO -

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Stereotactic treatment ofacromegaly

lesions of six to 15 minutes, respectively. Of thethree cases, only one continues to have an elevatedgrowth hormone level, although this dropped from130 to levels of between 31 and 42 mug/ml. Thisresult followed a single midline lesion at -1800for six minutes. By contrast, Case 10 received asingle midline lesion for 15 minutes and had completeablation of growth hormone but developed severeanterior and posterior pituitary insufficiency, which,although it has improved over 24 months, continues.He initially required cortisone and Pitressin replace-ment and continues to require the former. Thepatient tolerated mild hypothyroidism for one yearwithout improvement and subsequently was givenoral replacement. By contrast, Case 11 hadsatisfactory ablation of gowth hormone withpreservation of other pituitary functions. In fact,pre-operatively, there were deficiencies in adrenalcortex and posterior pituitary functions whichreverted to normal within two months of treatment.

Table III summarizes the endocrine status of thethree cases treated with cryosurgery, pre-operativelyand at the time of their last follow-up eight to24 months after treatment. As previously stated,one of the three growth hormone levels remainedabove normal. Pre-operatively, two cases haddeficiencies in adrenal cortex and posterior pituitaryfunction. The last post-operative evaluation revealedone instance of thyroid deficiency and one instanceof adrenal cortex deficiency, both requiring replace-ment therapy. Analysis of the details in Table Ireveals that the minor abnormalities pre-operativelyhad reverted to normal and that the two severeabnormalities, requiring replacement therapy, occur-red in Case 10, who had normal pituitary functionpre-operatively. These results indicate that it ispossible to ablate growth hormone producingadenomas with cryosurgery. Furthermore, it ispossible to do this with preservation of the pituitaryremnant and, on occasion, improvement in functionof the remaining pituitary. In contrast to the

TABLE IIITREATED CASES OF ACROMEGALY. CRYOSURGERY (THREE

CASES)

Last .follow-upPre-operative (8-24 months)

Pituitary function abnormnall cases (no.) abnormal' cases (no.)

Growth hormone 3 1Gonadotropin 0 0Thyroid 0 12Adrenal cortex 2 12Posterior pituitary 2 0

"Abnormal' indicates excessively high growth hormone level orinsufficiency of the other pituitary functions listed.'On replacement therapy.

radiation treated group, however, it is difficult topredict parameters that will lead to this optimaltherapeutic result. A review of tumour sizes and theparameters of destruction indicate that minordifferences in technique produce major differencesin results.

CLINICAL CHANGES Pre-operative symptoms in-cluded weakness, increased sweating, headaches,and arthralgia in all cases. With the exception ofCases 4 and 7, both last evaluated eight monthsafter treatment, all cases had complete relief ofsymptoms. Case 4 continues to have arthralgia,which is attributed to his far-advanced acromegaly,and severe joint deformities. Case 7 continues tohave headache and arthralgia, which is attributed toincomplete growth hormone ablation. Nevertheless,all other cases, even with incomplete ablation, havehad a gratifying clinical response. In most cases witha progressive drop in growth hormone level,symptomatic relief has characteristically precededthe maximum therapeutic effect, as measured by fallin growth hormone.

Reversal of acromegalic features is variable. Softtissue changes around the eyes and nose and markedsoft tissue absorption in the hands and feet with aconcomitant decrease in glove and shoe sizeoccurred in all cases. Younger patients and thosewith a shorter history of clinically evident diseaseresponded more favourably. Serial radiographs ofthe face, hands, and feet have failed to showdecrease in the distinctive changes of acromegaly orin the size of the bones to date. Decrease in the sizeof the sella turcica, however, has been the rule inmost cases observed for over one year. In one case,Case 10, pneumoencephalography was performed18 months after surgery and outlined a considerabledecrease in the volume of the intrasellar contents.

Table IV summarizes the diabetic status of thecases pre-operatively, and at the time of their lastevaluation, eight to 24 months after surgery. Theblood sugar was elevated in nine of the 11 casespre-operatively. Six of these returned to normal.The glucose tolerance test (100 g glucose orally) wasabnormal in 11 cases pre-operatively and four ofthese have returned to normal. Two of the patients

TABLE IVTHE 'DIABETIC STATUS' OF THE PATIENTS UNDER STUDY

( 1 CASES)

Clinical status Pre-operative Post-operative

Elevated F.B.S. 9 3Abnormal G.T.T. 11 7On treatment for diabetes 2 0

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required therapy for diabetes mellitus pre-operatively.G.S. took an oral hypoglycaemic agent and E.L.took 60 u. NPH insulin daily. Both had successfulablation of excess growth hormone. Post-operativelyneither required their therapy for diabetes; G.S.now has a normal fasting blood sugar and a slightlyabnormal glucose tolerance curve; E.L. has aborderline to elevated fasting blood sugar and amoderately elevated glucose tolerance curve. Onepatient (J.B.) had a bilateral carpal tunnel syndromepre-operatively and another (G.C.) had a severeperipheral neuritis. The former did not improve for18 months but responded to local surgery at thewrist. The latter has not improved during eightmonths of follow-up examination.

COMPLICATIONS Table V lists the potential compli-cations and their incidence, transient and permanent,in the cases under discussion. There was noincidence of rhinorrhoea, bacterial meningitis,or optic nerve damage. There were two cases oftransient cranial nerve palsy, a sixth nerve in oneyttrium90 implant and a third nerve in onecryogenic operation. Both of these were delayedfor several days and lasted a matter of weeks. Thedelayed onset and transient character of the deficitssuggests that they were secondary to swelling ofthe tumour, post-operatively. One cryogenic casedeveloped permanent anterior pituitary insufficiency.Evaluation ofposterior pituitary function two monthsafter surgery revealed, in two cases, inadequacy ofurinary concentration after 12 hours of waterdeprivation. A third case had clinically evidentdiabetes insipidus. The former two cases proved tobe transient, and a third case continues to requirePitressin snuff, eight months after surgery.

TABLE VINCIDENCE OF COMPLICATIONS

Transient Permanent

Rhinorrhoea 0 0Bacterial meningitis 0 0Optic nerve damage 0 0Paresis III, IV, or VI 2 0Pituitary insufficiency

anterior 0 1posterior 2 1

Epistaxis 1Appendicitis 1

Transnasal operative manipulation was accom-panied in all cases by minor degrees of nasalhaemorrhage. In one case this was significant.Case 1 (E.L.G.) returned two weeks after theyttrium90 implantation with brisk nasal bleeding.

Radiographs of the skull revealed a change inposition of one of the yttrium90 screws. She receiveda unit of blood while in the emergency room. Inretrospect, this was probably not necessary.One patient developed appendicitis and peritonitis

one week post-operatively. He was not on steroidtherapy at this time and the associated disease waspresumably coincidental.

DISCUSSION

As recently as 1961, Sheline, Goldberg, andFeldman, referring to external beam conventionalradiation of the sella in acromegaly stated, 'subse-quently, its value was proved and it remains theprocedure of choice except in patients with largetumors ... [requiring] ... immediate decompression'.

Recent experience with objective criteria, includingcalcium, phosphorus, hydroxyproline, and carbo-hydrate metabolism, and biopsy of the costochondraljunction justifies doubt as to the effectiveness of thislevel of radiation (Kozak et al., 1966). Since thedevelopment of a reliable radioimmunoassay forgrowth hormone, several authors have investigatedthe effect of conventional external beam radiationon the plasma growth hormone levels in acromegaly(Beck et al., 1965; Greenwood et al., 1965; Rothet al., 1967) and have failed to demonstrate aconsistent or significant drop in the majority oftheir subjects.

Table I lists the previous conventional radiationtherapy received by six of the 11 cases under study.They are not distinguished by either lower fastinggrowth hormone levels or greater susceptibility tosubsequent interstitial radiation or cryosurgery.Indeed, the only case that did not respond satis-factorily to the interstitial application of 12,000 rat the gland margin (Case 7) received 4,475 r ofexternal gamma radiation from a cobalt source,two and a half years previously.Two cases (Case 5 and Case 7) were first seen

before their radiation therapy. Fasting restinggrowth hormone levels were determined at thattime. They were subsequently followed serially, atsix month intervals, for over two years. There wasno drop in growth hormone levels. This has alsobeen our experience in a larger group of cases whohave, as yet, not undergone stereotactic treatment.On occasion, neurovascular damage (Peck and

McGovern, 1966; Darmody, Thomas, and Gurdjian,1967), sarcomas of the brain (Goldberg, Sheline, andMalamud, 1963; Waltz and Brownell, 1966), andcarcinoma of the perinasal sinuses (Sheline et al.,1961) have resulted from conventional therapy. Ingeneral, these cases have had as a single course, ormore commonly as multiple courses, more than the

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recommended dose of radiation, often over ashorter treatment period than is probably optimalin preventing complication. The report of Cromptonand Layton (1961) on delayed fatal radionecrosis ofthe brain, including hypothalamus, in two cases,one receiving 4,500 r over four weeks and the other,6,250 r over six weeks, reveals the potential althoughuncommon hazard of this form of therapy. Compli-cations of conventional radiation therapy, althoughdramatic, must be rare. Nevertheless, we wouldconsider interstitial radiation a superior form oftherapy. It is possible to deliver a higher andcontrolled dose of radiation to the tumour and avoidsignificant radiation to the surrounding centralnervous system.

Stereotactic interstitial radiation has been reportedby others with variable success. Molinatti, Camanni,Massara, Olivetti, Pizzini, and Giuliani (1962),using free yttrium90 pellets, reported clinicalbenefits and improvement in carbohydrate andcalcium metabolism in 16 cases, only one of whomrequired replacement therapy for adrenal insuf-ficiency. Two females had the return of menstruationand one male, return of potency. Growth hormonewas not measured. One case had cerebrospinal fluidrhinorrhoea and paresis of the left oculomotor nerve,and one case had a temporary sixth nerve palsy andanother transistory hemianopsia. Three cases hadpersistent polyuria. Total dose of radiation ad-ministered was 14 8 to 42 mc, or seven to 100 timesthe dose received in our series.

Hartog, Doyle, Fraser, and Joplin (1965) studied22 patients receiving free interstitial implants ofAu'98, Y90, or both. The early cases were judged tohave received 10,000 r at the tumour margin andthis was later increased to an estimated 100,000 r.Nine of the patients had a second pituitary implant.Results, based on clinical findings and carbohydratemetabolism, were considered satisfactory in 13 ofthe 22 cases. Nine cases required replacementtherapy due to pituitary insufficiency. One patientdeveloped permanent diabetes insipidus. Growthhormone was not evaluated. A total of 39 implanta-tions were performed in 28 patients (including sixthat were not fully evaluated post-operatively).Complications included eight cases of abscesswithin the sella turcica, four cases of cerebrospinalfluid rhinorrhoea, two cases of visual impairment,and one death.Greenwood et al. (1965) report eight acromegalic

subjects studied before and after Au198 or Y90implantation of free seeds into the sella turcica,with a follow-up of several years in five patients.Their dose ranged from 6 to 70 mc in the yttrium90treated group with an estimated dose to thediaphragma sellae of 6 to 20,000 r. They considered

several of the patients to have vague clinicalimprovement but, measuring growth hormone, wereunable to establish a clear-cut beneficial effect aftertheir technique of therapy and concluded the doseof radiation used was inadequate to cause thesymptoms of acromegaly to regress.

McCullagh, Feldstein, Tweed, and Dohn (1965)using the Forrest technique to fix yttrium90 sourcesin the pituitary tumour of two acromegalic patients,report clinical improvement. Gelinas, McCullagh,and Dohn (1966), reporting from the same institu-tion, describe a single case treated in a similarmanner in which a slightly elevated fasting growthhormone level was reduced to normal. Kaufman,Pearson, Shealy, Chernak, Samaan, and Storaasli(1966) report the effects of interstitial radiation withfixed sources of yttrium90 in nine cases of acrome-galy. They used the Forrest technique of insertingthe yttrium90 tipped screws, which is more or lessfreehand under fluoroscopic control. Little effortwas apparently expended in outlining the size andshape of the tumour. We would consider the doseof radiation used to be high, 2 8 to 36 mc. All ninecases had a drop in growth hormone levels but thethree with the lowest growth hormone levelsdeveloped pituitary insufficiency. One case wasjudged to have had a remission in his acromegalywith retention of other pituitary functions. Complica-tions were not mentioned.

Reviewing the above data in light of ourexperience, we conclude that lack of success inmany of these cases was related to an unevendistribution of the radiation dose. Thus, even whensources over 200 times the strength of the sourcesused in this study were employed, a significantportion of the patients failed to have a clinicalresponse. This would indicate that, either due toimplantation technique or to migration of the source,significant portions of the tumour failed to receiveadequate radiation. We also conclude that thesehigher doses of radiation are inadvisable, particularlyif the source is allowed to migrate, for they canproduce an unacceptable incidence of damage tosurrounding neural structures and the pituitaryremnant, and a high incidence of cerebrospinalfluid fistulae with attendant cerebrospinal fluidrhinorrhoea and intrasellar and intracranial in-fection.

Clinical improvement in a single case ofacromegaly following cryogenic destruction of theadenoma was first reported in 1964 by Rand et al.Bleasel and Lazarus (1965) reported cryosurgery offour cases of acromegaly with one death. Clinicalimprovement occurred in the other cases. Wilson,Winternitz, Bertan, and Sizemore (1966) reported asingle case with clinical improvement. We had the

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opportunity to perform pre-operative and post-operative growth hormone levels on this patient inour laboratory. Pre-operative levels of 49 to150 m,ug/ml. fell to less than 2 m,tg/ml. Wilsonreports that this patient developed decreasedpituitary function, however, and required cortisonereplacement.More recently, Dashe, Solomon, Rand, Frasier,

Brown, and Spears (1966), reporting on six casesundergoing cryosurgery by a technique slightlydifferent from that used in the present study,describe marked clinical improvement and partialor complete ablation of excess growth hormonelevels in the peripheral blood. Two patients requiredreplacement therapy, and only one had the optimalclinical result of complete ablation of excess growthhormone without pituitary insufficiency.Adams, Seymour, Earll, Tuck, Sparks, and

Forsham (1968) report the treatment of 16 acrome-galics. Multiple cryogenic lesions were placed in thesella turcica of these patients, using a smaller probethan that used in this study. Growth hormone wasdetermined in 14 cases. The majority had a decreasein growth hormone levels. Ten of these consistentlyhad growth hormone within normal limits for upto one year. Post-operatively, however, five casesrequired thyroid and three cortisone replacement,who did not require this before treatment. Four ofsix males developed decreased libido. These resultsare similar to our smaller series of acromegalicstreated with cryosurgery and confirm the usefulnessof this form of therapy in ablating the excess growthhormone of acromegaly, but further emphasize thedifficulty in predicting the critical level of cryo-destruction needed for differential ablation of thepituitary adenoma with sparing of normal pituitaryfunctions.

It is of concern that with either form of therapyadenoma cells may remain viable, multiply, andlead to recurrence of the tumour. To date, clinical,radiological, and endocrine studies have failed toreveal recrudescence, regardless of the method oftherapy or the completeness of ablation.

SUMMARY

The trans-sphenoidal stereotactic treatment of11 cases of acromegaly with growth hormoneproducing intrasellar tumours and proven elevatedresting, fasting, growth hormone levels is presented.These were treated either with fixed sources ofyttrium90 or cryosurgery. The rationale for choice oftreatment, technique used, and endocrine and clinicalresults are reported. It is concluded that interstitialfixed source radiation with yttrium90 is an effectivemeans of decreasing growth hormone levels and

arresting the clinical signs and symptoms ofacromegaly, without adversely affecting otherpituitary functions. At times, other pituitaryfunctions are improved. With the authors' technique,dosage of radiation 1/7 to 1/200 of conventionaldosage is effective. Cryosurgery is an effectivemeans of attacking tumours in which it istechnically difficult to fix point sources of radiation.The critical parameters of cooling required todestroy the adenoma and preserve the normalpituitary remnant, however, are less predictable anddifferential pituitary preservation has been less welldemonstrated.

The authors wish to acknowledge the help of numerousphysicians on the staff of the Medical College of Virginiaand the community of Richmond who helped with theevaluation and follow-up of these patients. The authorswould also particularly like to thank Dr. William H.Daughaday and Dr. Robert D. Utiger for their generousadvice and assistance in techniques of radioimmunoassay.The growth hormone used in this study was generouslysupplied by the National Pituitary Agency and thepurified standard growth hormone was generouslysupplied by A. E. Wilhelmi, Ph.D., through the NationalPituitary Agency.

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