Total hypophysectomy for advanced breast cancer

Clin. Radiol. (1968) 19, 426-432

TOTAL

HYPOPHYSECTOMY

FOR ADVANCED

BREAST

CANCER

G E O R G E EDELSTYN, COLIN G L E A D H I L L and A R N O L D LYONS

From the Northern Ireland Radiotherapy Centre, Montgomery House, Purdysburn, Belfast and the Department of Neurological Surgery, Royal Victoria Hospital, Belfast, Northern Ireland

One person in 5 dies from cancer and in woman about 1 in 4 arises in the breast; hence 1 woman in 20 will develop breast cancer. In Northern Ireland with a population of 1.5 million there are 300 new cases every year; 200 of these may eventually require palliative therapy. Unlike many other cancers recognition that cure is impossible does not always mean early death possibly postponed a little by cytotoxic drugs or other unpleasant procedures. Worthwhile prolongation of life can sometimes be obtained by the alteration of the endocrine milieu by a number of simple measures such as oophorectomy or the administration of androgens, oestrogens, progesterones or corticosteroids alone or in combination. These measures may be the limit of therapeutic endeavour, but sometimes hypophysectomy should be considered.

HYPOPHYSECTOMY THIS can be a valuable measure in the management of advanced breast cancer, bringing some patients sustained and worthwhile improvement, though never cure. But at its worst it may add further discomfort to an already severe burden, and only protract by a few months a miserable existence. There are at least 2 explanations for these contrasting possibilities. Firstly, subtotal removal of the hypophysis. This common autopsy finding is generally disregarded on the assumption that small surviving fragments of gland are incapable of function. This is irrational because: 1. Surviving gland fragments receive their blood supply through the capsule and are independent of the pituitary stalk. (Connolly and Connell, 1958; Daniel et al. 1958). 2. Following hypophysectomy downgrowth of the pituitary stalk can occur and may link up with any surviving glandular tissue. (Harris and Johnston, 1950; De Groot, 1952; Le Beau, 1960; Le Beau and Foncin, 1960; Schurr, 1932). 3. Such surviving tissue can regenerate. (Harris and Johnston, 1950; Smith, 1932). 4. Removal of 75 ~ of a rat's or dog's pituitary does not interfere with endocrine function and as little as 10 ~ can stimulate the adrenals. (Ganong and Hume, 1956). 5. This resumed function occurs even if the link up between stalk and gland is prevented by an interposed foreign body. (Van Buren and Bergenstal,

1960; Ehni and Eckles, 1959; Dugger et al., 1958). In fact hormone secretion can occur in animals when the anterior pituitary is transplanted to the eye (Zuckerman, 1954). There is no evidence that such resumed hormone production is less effective in sustaining cancer than that from the intact gland. Hence there can be no justification for a procedure which is less than complete. To deal with this problem a n operation using surgery for the bulk of the gland and intrasellar radiation with Yttrium 90 has been designed. (Edelstyn et al., 1958; Edelstyn et al., 1964; Edelstyn et aL, 1965). METHOD 10 mcs. of yttrium 90 is mixed in wax at Harwell, and flown to Belfast. For radiation protection further preparation is performed behind 2 cms. of perspex (Fig. 1). The wax is rolled between perspex spatulae to produce a thin cylinder which is inserted into a metal syringe, Slight pressure on the plunger with the barrel end against a spatula fixes the wax in position. It is then placed in a sterile case for transport to theatre where the operation is under way. Through a right frontal approach a complete removal of the gland is attempted. The syringe is then placed in the fossa and the wax extruded and packed tightly, using a spatula to bring it into firm contact with any residual gland. A piece of temporal muscle is laid on top of the wax to protect the optic nerves and chiasma from radiation. The radiation dose on the wails of the fossa is about 150,000r and is similar in the centre of a 5 mm. 426

TOTAL

HYPOPHYSECTOMY

FOR

ADVANCED

BREAST

427

CANCER

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FIG. 1B

FIG. 1A Perspex b o x in which all m a n i p u l a t i o n of yttrium is performed.

Instruments used in p r e p a r a t i o n of y t t r i u m for operation.

FIG. 1D Rolling the y t t r i u m - w a x pellet to f o r m a cylinder. FIG. 1 c Y t t r i u m - w a x pellet on arrival being e m p t i e d from container.

transit

]FIG l e A, L o a d i n g the prepared yttrium-wax cylinder into B, fixing the wax in place.

FIG. 1e syringe.

Insertion of the l o a d e d syringe into carrier for t r a n s p o r t i n g to operating theatre.

nodule of gland. The optic nerves receive about 4,000r whilst 1 cm. deep in bone the dose is negligible. Figure 2 illustrates a satisfactory implant.

The initial 76 cases treated whilst the yttrium method was being developed had either method on a chance basis whilst the last 96 constituted a clinical trial. Originally these groups were presented separately but as their results were similar they have been considered together here. Major Complications.--Ocular complications have either been instantaneous due to operative trauma or more commonly appeared 8-10 days

CASE M A T E R I A L Hypophysectomy had been performed in 172 patients up to January, 1965. Surgery alone was used in 70 and 102 had surgery plus yttrium 90.

428

CLINICAL

RADIOLOGY

FIG. 2 The implantation has satisfactorily filled the fossa (anteroposterior and lateral radiographs).

FIG 3 An unsatisfactory implant, the wax lying in the cavernous tissue.

FIG. 4 Another example of an unsatisfactory implant. In this case the wax is partly extruding from the fossa.

later when radiation was responsible. There were 2 forms. Firstly (Figure 3) surgical perforation of the fossa wall allowed the wax to enter the cavernous sinus and damage the 3rd cranial nerve. Secondly (Figure 4) damage to 1 or both optic nerves could result from a faulty insertion of wax into the fossa and has varied from a unilateral hemianopia to total loss of sight. Really serious damage occurred in 8 of 102 patients receiving yttrium (8 %) and in 2 out of 70 surgical cases (3 %). Definition of Terms and Results.--Any death within 1 month of operation was ascribed there-to. To qualify as a remission there had to be objective evidence of improvement lasting at least 3 months. Shorter remissions and purely subjective responses were classified as failures. Operative mortality initially was high but has fallen sharply with only 2 deaths amongst the last 50 yttrium patients (Table D,

TABLE 1 RESULTS OBTAINEDBY HYPOPHYSECTOMY Method employed Total Operative deaths Assessable Remissions Survival (months)

Surgery 70

12 07 %)

58 14 (24%) 24

Yttrium 102 10 (10%) 92 53 (57 %) 30

Statistical analysis. X 2 = 14.80, P. 0.001

The yttrium group had 57% remissions, much superior to the surgical group and in addition these patients had a longer average survival time, some being controlled for 5 years and one for 8 years after operation. Survival amongst failures was 4 months in both groups. Autopsy Studies on the Pituitary F o s s a . - - P o s t m o r t e m histological examination of the pituitary

TOTAL

HYPOPHYSECTOMY

FOR

fossa is the only sure method of assessing whether residual gland is present. A number of sections were examined and the results classified as with or without residual gland. Only 30 ~ of the surgical group had no demonstrable tissue wtlilst the figure for the yttrium patients was 7 7 ~ . Remissions occurred in 22 ~o of subtotal and in 48 ~ of total operations suggesting a relationship between the completeness of operation and its outcome. To summarise the evidence :--(1) Total hypophysectomy is more often associated with remission than subtotal hypophyscctomy. (2) Yttrium wax is more likely to produce total hypophysectomy. (3) Yttrium wax produces more frequent and longer lasting remissions. SELECTION OF PATIENTS F O R O P E R A T I O N The operation cart only be of value in hormone dependent cases and the second reason for failure is the lack of any method of forecasting which cancers come into this category. To overcome this problem a search was made for clinical details common to patients responding to operation and not possessed by the failures. Only the Yttrium group (92 patients) has been analysed because the poor response in the surgery alone series will lead to a number of potential responders being added to the group of inevitable failures with obvious disadvantages. First investigated was the behaviour pattern of the growth. Recurrent breast cancer may develop in 3 distinct ways (Table 2). TABLE 2 SITE OF METASTASES AND RESPONSE TO OPERATION Site of disease 1. Local (i) 2. Blood-borne metastases (a) Osseous (ii) (b) Visceral (iii)

ADVANCED

BREAST

429

CANCER

Osseous.~All patients with bony deposits provided there is no detectable hepatic or cerebral involvement. Limited pulmonary involvement does not exclude patients from this group. 74~ responded. Visceral.--Any patient with pulmonary, hepatic, or cerebral deposits with or without bony involvement with the one exception mentioned above. 14 ~ responded. The pattern of disease recurrence therefore had a considerable influence on the incidence of response. The second factor examined was the rate of tumour progression as estimated by the time intervM between the detection of the primary growth and the appearance of metastases. TABLE 3 THE TIME INTERVAL BETWEEN PRIMARY TUMOUR AND RECOGNITION OF METASTASES AND RESPONSE TO OPERATION Time (months)

Patient total

Remission

0-24 25 +

24 45

18 (43 ~ ) 30 (65 ~ )

X = 4'06105 P 0"02 (In 5 patients this time was uncertain.)

Two conditions have been considered: Firstly, rapidly progressive disease with the interval less than 2 years and secondly, a more slowly progressive variant with the period in excess of this time. The latter group did best with Hypophysectomy (Table 3). TABLE 4 AGE OF PATIENT AND RESPONSE TO OPERATION

Patient t o t a l

Remission

Age

Patient t o t a l

16

6 (37~)

61 15

45 (74 ~ ) 2 (14 %)

40 or less 41-50 51-60 61 +

18 39 26 9

4 29 14 6

Total

92

53 (57 ~ )

X ~ (i v i i ) = 5 ' 9 2 , 0"02 P 0"01 X ~ (i v i i i ) = 1 "27, 0'3 P 0"2 X z (ii v i + iii) = 1 7 ' 4 5 , P. 0'001

(1) Local Disease.--This grows extensively in the breast, on the chest wall, and in regional nodes. It lacks the ability for blood borne metastasis. In this group 37 ~ responded to hypophysectomy. (2) Blood-borne Metastasis.--This group may be associated with local recurrence but does possess the ability to spread through the blood stream. There are 2 subgroups.

Remission (22yo) (74 ~o) (58 ~ ) (66 ~ )

X (Under 40's v. over 40's) = 0.74, 0.01 P 0.001

In Table 4, age at operation has been considered. Patients under 40 years had the least chance of benefit. Once past this age the likelihood of response improved, though there was little difference between any of the subsequent decades. Most patients had preliminary hormone therapy (Table 5). A response to androgens or oophorectomy or alternatively failure to respond to oestro-

430

CLINICAL

RADIOLOGY

patients will therefore have the benefit of 2 remissions instead of one. The total length of such consecutive remissions is another matter. Ideally all these factors should be combined together to give the best guide but the limited number of patients makes the subgroups too small. The factors were, however, considered in pairs (Table 5) taking the metastatic pattern as a fundamental characteristic of the growth and combining the 3 other 'subsidiary' alternatives with it. This produced 3 sets of groupings. In the first both factors were favourable i.e. bone plus A, C or E, and this produced remission rates between 93 and 80 per cent. The second grouping was of a favourable and art unfavourable factor i.e. bone plus B, D or F, or alternatively soft tissue with G, I or K. This produced remission rates between 66 and 35 per cent. The last grouping with both factors unfavourable, i.e. soft tissue plus H, J or L, produced between 22 and 0 per cent responses. All 4 factors may be taken into account if they are considered merely as favourable or unfavourable prognostic points (Table 7).

gens indicated a good response to hypophysectomy. The converse reduced the likelihood of benefit. Patients who received no hormone therapy showed a reasonable response rate. This conceivably argues for preliminary hormone administration, as some TABLE 5 OUTCOME ON PREVIOUS HORMONE THERAPY AND RESPONSE TO OPERATION

Hormone therapy outcome Measure

Response

Androgens and/or oophorectomy

Failure

Ocstrogens

Remission

Hypophysectomy " Numbe------'~ response

Remission (i)

17 (85 per cen0

(ii)

Failure

117 (42 per cen0 0

-5T-4

None

9 (60 per cent; 15 (62 per cent)

i

x 2 (iv. ii) = 8.15, 0.01 > P > 0.001 Seven patients had both androgens and oestrogens and are entered under both headings.

TABLE 6 PROGNOSTIC FACTORS IN PAIRS AND RESPONSE TO OPERATION

Factors

Statistical analysit Total

Fundamental Bone

Bone

Bone

Soft tissue

Soft tissue

Soft tissue

Subsidiary

Number responding

A. Previous androgen remission

14

13 (93 per cent)

B. Previous androgen failure

22

13 (60 per cent)

C. Over 40

51

41 (80 per cent)

D. Under 40

10

4 (40 per cent)

E. Slow progression

29

24 (83 per cent)

F. Rapid progression

28

17 (60 per cent)

G. Previous androgen remission

6

4 (66 per cent)

H. Previous androgen failure

18

4 (22 per cent)

I.

Over 40

23

8 (35 per cent)

J.

Under 40

K. Slow progression

8

0 (0 per cent)

16

6 (36 per cen0

x2

p

5.30

0.05 > P > 0.02

5-12

0.05 > P >

2 "42

0.2> P>

0.1

3 '09

0./ > P >

0.05

2.15

0.2> P>

2.34 , L. Rapid progression

1 (7 per cent)

Soft tissue includes both local and visceral recurrences.

0.2> P>

0.02

0.1

0.1

TOTAL

HYPOPHYSECTOMY

FOR ADVANCED

TABLE 7 COMBINATIONS OF PROGNOSTIC FACTORS AND RESPONSE TO OPERATION Factors

Responses

Favourable

Unfavourable

Total in group

No.

Per cent

All (3 or 4)

None

22

20

90

BREAST

431

CANCER

drug combined with testosterone proprionate to increase marrow tolerance. Thiotepa was given as 15 mgm. intramuscularly initially followed on alternate days by 30 mgm. to a total of 285 mgm. This total was subsequently reduced to 165 mgm. TABLE 8 RESULTS

3

None

1

23

16

70

1 or2

28

15

53

2or3

13

1

7

All (3 or 4)

5

0

0

In some patients only 3 factors were available for analysis. One patient with only 2 factors available has not been included,

When all factors were favourable the response rate was 90 per cent. One unfavourable reduced this to 70%, two unfavourable to 53%, three unfavourable to 7 % and with no favourable factors 0% responded. POST-OPERATIVE M A I N T E N A N C E THERAPY This is not a major disadvantage but on 2 occasions operation has been withheld because the patient was unreliable. The regime is simple, provided that long familiarity does not produce carelessness. As one hopes for remissions to be measured in years this point has to be repeatedly stressed. Cortisone.--We usually give 25 mg. twice daily. With stress or illness the dose must be doubled or trebled and injected if there is vomiting. An Addisonian crisis can be rapidly fatal and vigorous therapy is essential. Thyroid Replacement.--Hypothyroidism develops slowly over many weeks and some thyroid function may continue in the absence of the pituitary. Usually 0,3 mg. thyroxine daily suffices. Pitressin.--Some patients never need any Pitressin; others require variable quantities for a long or a short time, either immediately after operation or after a latent period of up to a fortnight. Requiremeats usually lessen by about 3 months and rarely continue for more than 9 months. Usually 1.5 ml. of Pitressin Tannate in Oil twice weekly is sufficient and in mild cases Vasopressin Lysine nasal spray suffices; fluid retention must not be produced. H Y P O P H Y S E C T O M Y OR C H E M O T H E R A P Y Thiotepa.--Lyons and Edelstyn (1962, 1965) reported on 72 patients (Table 8) treated with this

Incidence and duration of remissions Number of cases in series Treatment deaths (i.e. less than 1 month survival) Objective remissions (3 months minimum duration) Mean response time in remission Mean survival time in responders Mean survival time in non-responders

72

8 (11%) 24 (32 ~ ) 8 months 16.4 months 6.4 months

There were 8 fatalities (11 ~o). Amongst the survivors 24 had objective remissions (37 %). The mean duration of response was 8 months with a total survival of 16.4 months, compared with 6-4 months amongst those failing to benefit. An attempt was made to predict which patients were most likely to respond using criteria as for hypophysectomy. The results were similar. Good findings were slowly evolving disease with deposits in bone and a previous response to androgens or to hypophysectomy. Thiotepa therefore benefits those patients who would respond to hypophysectomy but less effectively, and if treatment with thiotepa could be made safer it might be of value. The drug is not of value when the prediction for hypophysectomy is unfavourable. Unfortunately, and oddly, it is of little value in this group. This is shown by 5 of 8 hypophysectomy responders subsequently responding to thiotepa whilst only 2 of 8 operative failures did well with the drug. Cydophosphamide.--Locally advanced cancer is unlikely to respond to hypophysectomy or thiotepa. One such case who failed to respond to durabolin, oophorectomy, thiotepa and hypophysectomy was as a last measure given cyclophosphamide 100 mgm. per day. After 3 months, improvement was noted and this continued for a further year. Fifty-eight patients have since been treated with cyclophosphamide without fatality. Usually 100150 mgm. daily was given orally with monthly blood counts. (Edelstyn, 1965). Of these, 48 % have responded; with local disease only, 57 % have benefited; twice as many as osseous cases (Table 9). However, the results obtained in bony disease are not comparable as some case selection has occurred. With the good results

CLINICAL RADIOLOGY

432

obtained in Belfast by h y p o p h y s e c t o m y , only those t oo ill for o p er at i o n or w h o refused it, h a d cyclophosphamide. Th e m o r e slowty progressive cases TABLE 9 RESPONSE TO CYCLOPHOSPHAMIDE BY SITE OF DISEASE

Site Local Visceral Bony

Total

Response

33 4 21

19 (57 ~) 3 (75 ~) 6 (28 %)

again did better as did the y o u n g patients. Previous responders to h y p o p h y s e c t o m y did p o o r l y w i t h the d r u g whilst failures did rather better (Table 10). TABLE10 CYCLOPHOSPItAMIDE AND PREVIOUS HYPOPHYSECTOMY

Hypophysectomy result Result with cyclophosphamide

Response

Response

Failure

5 0

8 3

CONCLUSIONS It is co n cl u d ed that preliminary t h e r a p y for a d v a n c e d breast cancer should consist o f h o r m o n e a d m i n i s t r a t i o n a n d o o p h o r e c t o m y . N o t only m ay these p r o d u c e remission but they also help in decisions on the future m a n a g e m e n t o f the patient. The next step is consideration o f h y p o p h y s e c to m y. Careful selection is essential a n d the o p e r a t i o n should be total. F o r local disease c y c l o p h o s p h a mide is preferred to h y p o p h y s e c to m y , a n d T k i o t e p a should rarely be used in a d v a n c e d breast cancer.

Aeknowledgements.--I am most grateful to Mr. A. R. Taylor and Mr. D. S. Gordon of the Department of Neurological Surgery, Royal Victoria Hospital, Belfast, who performed a number of operations. I am also indebted to my colleagues at the Northern Ireland Radiotherapy Centre and especially to Dr. G. A. Lyach for their co-operation and advice over the past few years. The illustrations are by Mr. George Smyth, Medical Artist, R.V.H. to whom I express my thanks and I am also very grateful to Mrs. Malcolm and Mrs. Convey for typing. Figures 1-6 and certain tables are by kind permission of the publishers of the British Journal of Surgery.

REFERENCES CONNOLLY, C. t~ CONNELL,A. M. S. (1958). Brit. 3". Surg., 46, 118. DANIEL,P. M., PRITCHARD,M. M., • SCHURR,P. H. (1958). Lancet, i, 1101. DEGROOT,J. (1952). M.D. Thesis, Amsterdam. DUGGER, D. S., VAN WYKE, J. J., & NEWSOME,J. F. (1958). Amer. Surg., 24, 603. EDELSTYN,G. A. (1965). Lancet, i, 237. EDELSTYN,G. A., GLEADHILL,C. A., LYONS,A. R., RODGERS, H. W., TAYLOR, A. R., & WELBOURN, R. B. (1958). Lancet, i, 462. EDELSTVN, G. A., GLEADmLL, C. A., LYONS, A. R. (1964). British J. of Surg., 51, 1, Jan. 1964 p. 32. EDELSTYN,G. A., GLEADHILL,G. A., & LYONS,A. R. (1965). British J. of Surg., 52, 953. EHNI, G. & ECKLES,N. E. (1959). J. Neurosurg., 16, 628. GANONG, W. F. & HUME,D. M. (1956). Endocrinology, 59, 293. HARRIS, G. W. & JOHNSTON,R. T. (1950). Nature, Lon., 165, 819. LE BEAU, J. (1960). Neuro-chirurgie, 6, 128. LE BEAU,J. & FONCIN,J. (1960). Actapsychiat., Kbh., 35, 13. LYONS, A. R. & EDELSTYN,G. A. (1962). Brit. Med. J., ii, 1280. LYONS, A. R. & EDELSTYN, G. A. (1965). Brit. J, Cancer, XIX, 490. SCHURR,P. (1960). J. Neurol. Neurosurg. Psychiat., 23, 82. SMITH,P. E. (1932). Anat. Rec., 52, 191. VANBUREN,J. M. & BERGENSTAL,D. M. (1960). Cancer, 12, 155. ZUCKERMAN,S. (1954). Lancet, i, 789.

BOOK REVIEW Frontiers of Radiation Therapy and Oncology. Volume 2. Electron Beam Therapy. Pp. viii + 267, with 185 illustrations. Basel and New York: S. Karger. 1968. The Betatron is now in widespread use for radiotherapy in both Europe and North America, scarcely at all in Britain. This may be partly caused by lack of a suitable British-made unit but partly also to the belief that it is better to use a megavoltage X-ray generator, especially the linear accelerator. This publication is the proceedings of a Symposium held in 1966 in San Francisco, and gives one an opportunity to review progress in electron beam therapy. Papers were given not only from the foremost American centres, but also from Villejuif, St. Bartholomew's Hospital,

London, Hong-Kong, Lubeck and Bern. There are very good physical papers on the historical background and on many very important physical aspects, on radio-biology and on dosimetry. Clinical topics include the treatment of mycosis fungoides, and of tumours of the breast, vulva, bladder and pharynx. If electron beam therapy has advantages they must be related to the distribution of the absorption in depth rather than to any radiobiological factor. Many of the papers give useful clinical results and isodose plans used in treatment. These will be of considerable interest and value to those of us who will soon have available electron beams from the newer linear accelerators. This book is very well produced and is highly recommended to anyone interested in electron therapy. K. E. HALNAN