036&3016/79/111981-06$02.00/O
Int. J. Radiation Oncology Biol. Phys.,, Vol. 5, pp. 1981-3986 @ Pergamon Press Ltd., 1979. Printed m the U.S.A.
??Original Contribution
REVIEW OF 154 PATIENTS
CHARLES
J.
ERLICHMAN,
WILLIAM
W.
WITH NON-FUNCTIONING TUMORS
MEAKIN,
JOHN
M.D., M.D.,
SIMPSON,
MD.,
PITUITARY
F.R.C.P.(C),T and
F.R.C.P.(C)t
F.R.C.P.(C)S
University of Toronto, Princess Margaret Hospital, Toronto, Ontario A retrospective
review was carried out on the charts of 154 patients with pituitary tumors that were not associated with Cushing’s Disease or acromegaly. Patients were divided into three treatment groups: (1) surgery + post-operative radiation (S+R); (2) radiotherapy (R); and (3) surgery followed by radiation at the time of recurrence (S). Pretreatment evaluation revealed that patients in (S+R) had significantly larger tumors than patients in (R). However, there was no difference in the endocrinological status of patients prior to therapy in all treatment groups. The results of treatment were similar in the (S+R) and (R) treatment groups. This suggests that patients with small pituitary tumors may be treated successfully with radiation alone. Analysis of the recurrences revealed several reasons for failure of initial therapy, chiefly very large or locally aggressive tumors. Patients had recurrences up to 15 years after initial therapy. Therefore, follow-up of these patients should continue over a long period of time. Complications of each form of therapy were evaluated. Only one case of vascular occlusion was felt to be radiation-related. Long term steroid replacement therapy also was associated with complications. These included avascular necrosis of the femoral heads, gram negative sepsis and Addisonian crisis. The role of surgery as a single modality could not be assessed.
Pituitary tumors,
Chromophobe
adenoma,
Radiotherapy,
Pituitary tumors comprise between 6 and 10% of all intracranial neoplasms. However, their clinical importance outweighs their incidence. Because of their location, they can often lead to devastating visual loss. Their ability to elaborate hormones or destroy normal pituitary tissue may cause specific clinical syndromes. Those tumors classically referred to as chromophobe adenomas comprise 85% of pituitary neoplasms. These tumors are usually treated by surgery, radiation or a combination of the two. Surgery was first used by Horsley in 1889 but was refined by Gushing.” Between 1913 and 1932 Cushing operated on 338 patients with pituitary tumors, via a transfrontal or transphenoidal approach. External radiation was used initially by B&l&e in 1909 in a case of giantism.4 The patient experienced relief from headache and visual loss, and was alive and well 13 years later. Local applications of radium were tried but
Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, M4X lK9.
tDepartment of Medicine *Department of Radiation Oncology to: Dr. W. J. Simpson,
radiotherapy.
soon abandoned because of high morbidity and mortality. Thus, both radiation and surgery were shown to benefit patients with pituitary tumors. In 1939, Henderson9 reviewed Cushing’s series of 338 patients with pituitary tumors, and reported that post-operative radiotherapy reduced the incidence of recurrence. The five year recurrence-free rate was 32.8% with transphenoidal surgery alone, but increased to 65.3% if the surgery was followed by radiation; it was 57.5% in patients who were treated with transfrontal surgery alone but increased to 87.1% when post-operative radiation was given. This was a surprising result because the radiation therapy consisted of only 500 rad given in two treatments. Subsequently, other authors4,‘“,14 have advocated either combination therapy or a trial of radiation alone in selected patients. We undertook a retrospective review of patients with non-functioning pituitary tumors who were treated at the Princess Margaret Hospital between 1958 and 1972 inclusive. Our purpose was to assess
INTRODUCTION
Reprint requests
Surgery and post-operative
Department
Accepted for publication
of 1981
20 August 1979.
1982
RadiationOncology 0 Biology 0 Physics
the role of each modality in the treatment of these tumors, the results of therapy, and the complications of treatment and hormonal replacement.
November-December 1979, Vol. 5, No. 11 and No. 12
Age and
sex dlstrlbutlon
according
to therapy
I
30 28 26 2422-
METHODS AND MATERIALS
We reviewed the records of all patients with pituitary tumors who were referred to the Princess Margaret Hospital between 1958 and 1972. Excluding patients with acromegaly or Cushing’s Disease, there were 154 patients for this analysis. Since the Princess Margaret Hospital is a non-surgical referral institution, the patients were selected by the referring surgeon or physician for possible irradiation. Furthermore, the surgery was carried out at other hospitals by a number of surgeons using various techniques. The patients were divided into three therapeutic groups: 1) S+R: surgery + post-operative radiation (114 patients). Post-operative radiotherapy was administered several weeks to several months after surgery, as part of the planned initial therapy. 2) R: radiotherapy only (25 patients). 3) S: surgery initially, followed by radiation at the time of tumor recurrence (15 patients). Histological confirmation was obtained in all patients in the S+R and S groups and in four in the R group (2 pre-treatment biopsies and 2 at surgery for recurrence). The tumors were reported to be chromophobe adenomas in 105 patients, eosinophilic in 4 patients, mixed in 19 patients, and in 3 patients the tissue was insufficient to make an accurate histologic diagnosis. In 2 patients aggressive local spread led to a diagnosis of pituitary carcinoma. No biopsy was carried out in 21 patients. The age and sex distribution at the time of registration at Princess Margaret Hospital is presented in Figure 1. The mean age was similar in S+R, R and S groups-44.2, 43.7, 42.1 years respectively. S+R had a male:female ratio of 1.5:1, R-1:1.8, S-1:1. There was no apparent explanation for the difference between S+R and R. Testing of statistical significance was done by the corrected Chi square method. Disease-free intervals were calculated on an actuarial basis using Kaplan-Meier curves. Clinical findings Headache, visual disturbances, loss of libido and amenorrhea were the only symptoms that were analyzed since their presence or absence was usually recorded (Table 1). There was no difference in the incidence of headache, loss of libido or amenorrhea between S+R and R. However, the visual disturbances were significantly more common in S+R than
10-19
20-29
30-39
40-49
50- 59
60-69
70-79
1. Distribution by age and sex of patients in the treatment groups.
Fig.
Table 1. Symptoms
No. patients evaluable Headache Visual disturbance Loss of libido or amenorrhea
at presentation
S + R*
R*
S*
113t 48 85
2.5 14 4
15 6 12
38
10
5
tone patient’s records contained no statement regarding initial symptoms. *S+R = surgery + post-operative radiation; R = radiotherapy only; S = surgery followed by radiation at time of tumor recurrence.
in R suggesting that the S+R patients had larger tumors (p 98: 149-153, 1971. 9. Henderson, W.R.: The pituitary adenomata: A followup study of the surgical results in 338 cases (Dr. Harvey Cushing’s series). Br. J. Surg. 26: 811-921, 1939. 10. Horrax, G., Smedal, M.I., Trump, J.G., Granke, R.C.. Wright, K.A.: Present-day treatment of pituitary adenomas: Surgery versus x-ray therapy. N. Engl. J. Med. 252: 524-526, 1955. 11. Horvath, E., Kovac, K.: Ultrastructural classification of pituitary adenomas. Can. J. Neural. Sri. 3: 921. 1976. 12. Kramer, S.: The value of radiation therapy for pituit-
1986
Radiation Oncology 0 Biology 0 Physics
ary and parapituitary tumors. Can. Med. Assoc. J. 99: 1120-l 127, 1968. 13. Perry-Keene, D.A., Conneliy, J.F., Young, R.A., Wettenhall, H.N.B., Martin, F.I.R.: Hypothalamic hypopituitarism following external radiotherapy for tumors distant from the adenohypophysis. Clin. Endocrinol. 5: 373-380, 1976. 14. Pistenma, D.A., Goffinet, D.R., Bagshaw, M.A., Hanbery, J.W., Eltringham, J.R.: Treatment of chromophobe adenomas with megavoltage irradiation. Cancer 35: 15741582, 1975. 15. Ray, B.S., Patterson, Jr., R.H.: Surgical experience with chromophobe adenomas of the pituitary gland. J. Neurosurg. 34: 726-729, 1971. 16. Samaan, N.A., Bakdash, M.M., Caderao, J.B., Cangir, A., Jesse, R.H. Jr., Ballantyne, A.J.: Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin. Ann. Intern. Med.
November-December 1979, Vol. 5, No. 11 and No. 12
83: 771-777, 1975. 17. Shale& S.M., Beardwell, C.G., Pearson, D., MorrisJones, P.H.: The effect of varying doses of cerebral irradiation on growth hormone production in childhood. Clin. Endocrinol. 5: 287-290, 1976. 18. Sheline, G. E.: Treatment of nonfunctioning Am. J. chromophobe adenomas of the pituitary. Roentgenol. 120: 553-561, 1974. 19. Sheline, G.E.: Untreated and recurrent chromophobe 112: adenomas of the pituitary. Am. J. Roentgenol. 768-773, 1971. 20. Sheline, G.E., Boldrey, E.B., Phillips, T.L.: Chromophobe adenomas of the pituitary gland. Am. J. Roentgenol. 92: 160-173, 1964. 21. Svien, H.J., Colby, M.Y., Jr.,: Treatment for Springfield, Illinois. C.C. Chromophobe Adenoma, Thomas. 1967, pp. 41-55.
Int. J. Radiation Oncology Biol. Phys.,, Vol. 5, pp. 1981-3986 @ Pergamon Press Ltd., 1979. Printed m the U.S.A.
??Original Contribution
REVIEW OF 154 PATIENTS
CHARLES
J.
ERLICHMAN,
WILLIAM
W.
WITH NON-FUNCTIONING TUMORS
MEAKIN,
JOHN
M.D., M.D.,
SIMPSON,
MD.,
PITUITARY
F.R.C.P.(C),T and
F.R.C.P.(C)t
F.R.C.P.(C)S
University of Toronto, Princess Margaret Hospital, Toronto, Ontario A retrospective
review was carried out on the charts of 154 patients with pituitary tumors that were not associated with Cushing’s Disease or acromegaly. Patients were divided into three treatment groups: (1) surgery + post-operative radiation (S+R); (2) radiotherapy (R); and (3) surgery followed by radiation at the time of recurrence (S). Pretreatment evaluation revealed that patients in (S+R) had significantly larger tumors than patients in (R). However, there was no difference in the endocrinological status of patients prior to therapy in all treatment groups. The results of treatment were similar in the (S+R) and (R) treatment groups. This suggests that patients with small pituitary tumors may be treated successfully with radiation alone. Analysis of the recurrences revealed several reasons for failure of initial therapy, chiefly very large or locally aggressive tumors. Patients had recurrences up to 15 years after initial therapy. Therefore, follow-up of these patients should continue over a long period of time. Complications of each form of therapy were evaluated. Only one case of vascular occlusion was felt to be radiation-related. Long term steroid replacement therapy also was associated with complications. These included avascular necrosis of the femoral heads, gram negative sepsis and Addisonian crisis. The role of surgery as a single modality could not be assessed.
Pituitary tumors,
Chromophobe
adenoma,
Radiotherapy,
Pituitary tumors comprise between 6 and 10% of all intracranial neoplasms. However, their clinical importance outweighs their incidence. Because of their location, they can often lead to devastating visual loss. Their ability to elaborate hormones or destroy normal pituitary tissue may cause specific clinical syndromes. Those tumors classically referred to as chromophobe adenomas comprise 85% of pituitary neoplasms. These tumors are usually treated by surgery, radiation or a combination of the two. Surgery was first used by Horsley in 1889 but was refined by Gushing.” Between 1913 and 1932 Cushing operated on 338 patients with pituitary tumors, via a transfrontal or transphenoidal approach. External radiation was used initially by B&l&e in 1909 in a case of giantism.4 The patient experienced relief from headache and visual loss, and was alive and well 13 years later. Local applications of radium were tried but
Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, M4X lK9.
tDepartment of Medicine *Department of Radiation Oncology to: Dr. W. J. Simpson,
radiotherapy.
soon abandoned because of high morbidity and mortality. Thus, both radiation and surgery were shown to benefit patients with pituitary tumors. In 1939, Henderson9 reviewed Cushing’s series of 338 patients with pituitary tumors, and reported that post-operative radiotherapy reduced the incidence of recurrence. The five year recurrence-free rate was 32.8% with transphenoidal surgery alone, but increased to 65.3% if the surgery was followed by radiation; it was 57.5% in patients who were treated with transfrontal surgery alone but increased to 87.1% when post-operative radiation was given. This was a surprising result because the radiation therapy consisted of only 500 rad given in two treatments. Subsequently, other authors4,‘“,14 have advocated either combination therapy or a trial of radiation alone in selected patients. We undertook a retrospective review of patients with non-functioning pituitary tumors who were treated at the Princess Margaret Hospital between 1958 and 1972 inclusive. Our purpose was to assess
INTRODUCTION
Reprint requests
Surgery and post-operative
Department
Accepted for publication
of 1981
20 August 1979.
1982
RadiationOncology 0 Biology 0 Physics
the role of each modality in the treatment of these tumors, the results of therapy, and the complications of treatment and hormonal replacement.
November-December 1979, Vol. 5, No. 11 and No. 12
Age and
sex dlstrlbutlon
according
to therapy
I
30 28 26 2422-
METHODS AND MATERIALS
We reviewed the records of all patients with pituitary tumors who were referred to the Princess Margaret Hospital between 1958 and 1972. Excluding patients with acromegaly or Cushing’s Disease, there were 154 patients for this analysis. Since the Princess Margaret Hospital is a non-surgical referral institution, the patients were selected by the referring surgeon or physician for possible irradiation. Furthermore, the surgery was carried out at other hospitals by a number of surgeons using various techniques. The patients were divided into three therapeutic groups: 1) S+R: surgery + post-operative radiation (114 patients). Post-operative radiotherapy was administered several weeks to several months after surgery, as part of the planned initial therapy. 2) R: radiotherapy only (25 patients). 3) S: surgery initially, followed by radiation at the time of tumor recurrence (15 patients). Histological confirmation was obtained in all patients in the S+R and S groups and in four in the R group (2 pre-treatment biopsies and 2 at surgery for recurrence). The tumors were reported to be chromophobe adenomas in 105 patients, eosinophilic in 4 patients, mixed in 19 patients, and in 3 patients the tissue was insufficient to make an accurate histologic diagnosis. In 2 patients aggressive local spread led to a diagnosis of pituitary carcinoma. No biopsy was carried out in 21 patients. The age and sex distribution at the time of registration at Princess Margaret Hospital is presented in Figure 1. The mean age was similar in S+R, R and S groups-44.2, 43.7, 42.1 years respectively. S+R had a male:female ratio of 1.5:1, R-1:1.8, S-1:1. There was no apparent explanation for the difference between S+R and R. Testing of statistical significance was done by the corrected Chi square method. Disease-free intervals were calculated on an actuarial basis using Kaplan-Meier curves. Clinical findings Headache, visual disturbances, loss of libido and amenorrhea were the only symptoms that were analyzed since their presence or absence was usually recorded (Table 1). There was no difference in the incidence of headache, loss of libido or amenorrhea between S+R and R. However, the visual disturbances were significantly more common in S+R than
10-19
20-29
30-39
40-49
50- 59
60-69
70-79
1. Distribution by age and sex of patients in the treatment groups.
Fig.
Table 1. Symptoms
No. patients evaluable Headache Visual disturbance Loss of libido or amenorrhea
at presentation
S + R*
R*
S*
113t 48 85
2.5 14 4
15 6 12
38
10
5
tone patient’s records contained no statement regarding initial symptoms. *S+R = surgery + post-operative radiation; R = radiotherapy only; S = surgery followed by radiation at time of tumor recurrence.
in R suggesting that the S+R patients had larger tumors (p 98: 149-153, 1971. 9. Henderson, W.R.: The pituitary adenomata: A followup study of the surgical results in 338 cases (Dr. Harvey Cushing’s series). Br. J. Surg. 26: 811-921, 1939. 10. Horrax, G., Smedal, M.I., Trump, J.G., Granke, R.C.. Wright, K.A.: Present-day treatment of pituitary adenomas: Surgery versus x-ray therapy. N. Engl. J. Med. 252: 524-526, 1955. 11. Horvath, E., Kovac, K.: Ultrastructural classification of pituitary adenomas. Can. J. Neural. Sri. 3: 921. 1976. 12. Kramer, S.: The value of radiation therapy for pituit-
1986
Radiation Oncology 0 Biology 0 Physics
ary and parapituitary tumors. Can. Med. Assoc. J. 99: 1120-l 127, 1968. 13. Perry-Keene, D.A., Conneliy, J.F., Young, R.A., Wettenhall, H.N.B., Martin, F.I.R.: Hypothalamic hypopituitarism following external radiotherapy for tumors distant from the adenohypophysis. Clin. Endocrinol. 5: 373-380, 1976. 14. Pistenma, D.A., Goffinet, D.R., Bagshaw, M.A., Hanbery, J.W., Eltringham, J.R.: Treatment of chromophobe adenomas with megavoltage irradiation. Cancer 35: 15741582, 1975. 15. Ray, B.S., Patterson, Jr., R.H.: Surgical experience with chromophobe adenomas of the pituitary gland. J. Neurosurg. 34: 726-729, 1971. 16. Samaan, N.A., Bakdash, M.M., Caderao, J.B., Cangir, A., Jesse, R.H. Jr., Ballantyne, A.J.: Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin. Ann. Intern. Med.
November-December 1979, Vol. 5, No. 11 and No. 12
83: 771-777, 1975. 17. Shale& S.M., Beardwell, C.G., Pearson, D., MorrisJones, P.H.: The effect of varying doses of cerebral irradiation on growth hormone production in childhood. Clin. Endocrinol. 5: 287-290, 1976. 18. Sheline, G. E.: Treatment of nonfunctioning Am. J. chromophobe adenomas of the pituitary. Roentgenol. 120: 553-561, 1974. 19. Sheline, G.E.: Untreated and recurrent chromophobe 112: adenomas of the pituitary. Am. J. Roentgenol. 768-773, 1971. 20. Sheline, G.E., Boldrey, E.B., Phillips, T.L.: Chromophobe adenomas of the pituitary gland. Am. J. Roentgenol. 92: 160-173, 1964. 21. Svien, H.J., Colby, M.Y., Jr.,: Treatment for Springfield, Illinois. C.C. Chromophobe Adenoma, Thomas. 1967, pp. 41-55.
