Ini .I Radmron Oncology &,I/ Phr\ Vol. Printed I” the U.S.A. All rights reserved.
20. pp.
655-660 Copyright
0360-3016191 $3.00 + .OO 0 I99 Pergamon Press plc
I
??Original Contribution
EXTERNAL IRRADIATION OF GROWTH HORMONE PRODUCING PITUITARY ADENOMAS: PROLACTIN AS A MARKER OF HYPOTHALAMIC AND PITUITARY EFFECTS EVA AF TRAMPE,
M.D.,*
G~RAN
LUNDELL,
AND SIGBRITT
WERNER
M.D.,*
INGMAR
LAX,
PH.D.+
M.D.’
Karolinska Hospital, S- 104 0 I Stockholm, Sweden Fifty-six patients with acromegaly were treated with external irradiation, 50 Gy, after unsuccessful pituitary surgery. A 50% reduction of pre-irradiation growth hormone levels was obtained in 51/56 patients. This level was reached after 26 + 14 months in 33 patients with prolactin levels < 25 pg/l at diagnosis, after 21 + 17 months in 18 patients with prolactin 2 25 pg/l, and after 20 f 21 months in 12 patients with prolactin > 40 Mg/l at diagnosis. A further 50% decrease of growth hormone levels was obtained in 40/51 patients 42 f 22 months after radiotherapy, indicating that in clearly responsive patients, the growth hormone depression after radiotherapy follows a first order reaction. Four patients did not reach a 50% reduction of growth hormone levels 48-80 months after radiotherapy. During 10 years of follow-up, the growth hormone depression tended to be more pronounced in patients with mixed secretion of growth hormone and prolactin. The reduction of growth hormone levels was not correlated with the irradiated volume or the cumulative radiation effect. Within the first year, prolactin increased within the normal range in normoprolactinemic patients and remained so during follow-up. In hyperprolactinemic patients, prolactin decreased successively but to a lesser extent than growth hormone. Pituitary insufficiencies increased over time and three patients developed GH-insufficiency. Hypothalamic damage as indicated by prolactin changes was a regular phenomenon after radiotherapy. Radiotherapy,
Acromegaly,
Growth hormone, Prolactin, IGF-1.
INTRODUCTION In a previous study (18) we showed that external photon irradiation, given to a total dose of 50 Gy over approximately 5 weeks with a three-field technique and a daily dose of 1.8 Gy, was efficient in lowering growth hormone (GH) and insulin-like growth factor 1 (IGF- 1) in patients with acromegaly. The GH levels were reduced in a timedependent manner regardless of the pre-irradiation GH levels, tumor volume, irradiated volume, and the suprasellar part of the irradiated volume. Seven patients with concomitant hyperprolactinemia responded with a more pronounced GH reduction after 2 years than 18 patients with acromegaly and normoprolactinemia. Prolactin (PRL) secretion as illustrated by PRL concentrations in serum tended to increase after radiotherapy in patients initially normoprolactinemic but decreased in patients who had shown concomitant hyperprolactinemia at diagnosis.
* Department of General Oncology, Radiumhemmet. + Department of Hospital Physics. * Department of Endocrinology. Reprint requests to: Eva af Trampe, M.D. Acknowledgements-We thank Kerstin Florell, Christina
The aim of the present study was to characterize further these changes of the two lactogenic hormones in a larger number of patients with special regard to possible hypothalamic damage as a function of time and to the risk of developing ACTH, TSH, gonadotropin as well as GH insufficiency after radiotherapy. The latter has hitherto not been reported in patients with acromegaly who have been treated with pituitary irradiation.
METHODS
AND
MATERIALS
The study concerns patients with acromegaly who were primarily treated by transsphenoidal pituitary microsurgery. External radiotherapy was given because of postoperatively remaining pathological GH secretion and clinical activity of the disease; the patients lacked normal diurnal GH secretion and GH was depressed by I-dopa and increased after the injection of TRH intravenously.
Bremer, and Katarina Breitholtz for expert help in preparing figures, tables, and manuscript. This work was supported Swedish Medical Research Council (no 19x-06865). Accepted for publication 12 October 1990.
by the
656
I. J. Radiation Oncology 0 Biology 0 Physics
The diagnosis of GH producing pituitary adenomas was based on light microscopy and immunohistochemical staining. At the Karolinska Hospital, 60 patients received standardized radiotherapy on this indication between 1972-1986. Four of these patients had been given bromocriptine before (0.8-6 years) and during radiotherapy. These patients were excluded from analysis, as it was impossible to evaluate the radiation effect properly. The mean age of the evaluated 56 patients (23 males) was 43.9 years, median age 43.1 years, and range 19-70 years. The mean time between primary pituitary surgery and radiotherapy was 2.1 years (0.2- 16 years). The size of the sellar and pituitary volumes and erosive features of the sellae were estimated according to plain X ray and computed tomography. The volume was normal with no bone erosions in four patients, moderately enlarged with no bone erosions in 38 patients, and severely enlarged. all showing of bone destructions. in 14 patients. The treatment technique was described in detail previously (18). In short, high energy photons (4 MV to 3 patients, 6 MV to 50 patients, and 2 I MV to 3 patients) were administered with a three-held technique, using bilateral temporal and a single frontal portals. The daily mean target dose was 1.8 Gy given Monday through Friday and the total tumor dose was planned to 50 Gy. To increase the precision of the treatment, the patients were treated in individual plastic masks. The biological effect of the radiation therapy was calculated according to the CRE-value (Cumulative Radiation Effect) (12). The irradiated volume was defined as the volume confined within the intersection of the geometric borders of the beams. During follow-up four patients have died, 49-63 years old. due to acute lymphoblastic leukemia, subarachnoidal haemorrhage, cardiac insufficiency. and heavy drug abuse with suspected cardiac insufficiency. Growth hormone in plasma was analyzed according to a radioimmunoassay with double antibody technique with a detection limit of 0.2 pg/l and interassay and intraassay variation of 9% and 3%, respectively (1). Prolactin in serum was analyzed by a commercial radioimmunoassay* with a detection limit of 1.6 pg/l. IGF- 1 was analyzed by a commercial radioimmunoassay.+ At annual follow-ups. triiodothyronine, thyroxine, luteinizing hormone (LH). follicle stimulating hormone (FSH). serum/urinary cortisol, testosterone in males, and estradiol in females were analyzed with commercial radioimmunoassays. When there was uncertainty about the cortisol insufficiency, this diagnosis was confirmed by ACTH infusion tests or metyrapone tests. In patients whose GH had been undetectable for at least 2 years and whose IGF- 1 levels were below the normal range, the GH reserve was tested by 1-dopa,
* Farmos ’ Nichols USA.
Diagnostica. P.O. Box 425 Turku, Finland. Institute Diagnostics, San Juan, Capistrano,
CA,
April IO9I. Volume 20. Number 4
500 mg given orally after which growth hormone secretion was measured up to 2 hours. Undetectable basal levels without an increment after l-dopa leading to the occurrence of detectable GH was taken as an indication of GH insufficiency. The other prerequisite for the diagnosis of GH insufficiency was a diurnal GH profile with non-detectable GH at 06, 08. 12, 16, 20, 22. and 02 hours. During radiation therapy, haemoglobin, leucocyte, and platelet counts were checked regularly. For the statistical analyses unpaired T-tests between groups were used.
RESULTS The 56 patients received 50.1 ? 0.1 Gy (mean + SEM). The average length of treatment was 47 days. The cumulative radiation effect was 14.8 * 0.05 Geu. The irradiated volume was 66.2 + 5.7 cm3 (mean + SEM). During the period of treatment 3 patients noted nausea, 9 patients headache, and 14 patients fatigue. The most longstanding side-effect, nausea, disappeared within 2 months after termination of radiotherapy. Visual field defects, present in 15 patients before surgery, persisted in I2 patients after surgery, disappeared in 7 patients after radiotherapy, improved in 2 patients, and were unaltered in 3 patients. After the two interventions no persistent visual field defects have occurred up to the latest follow-up of the 56 patients. Furthermore, there has been no evidence of deterioration of visual acuity. The numerical values on which the changes of GH and PRL are calculated are shown in Tables 1 and 2. Each patient is not included with a GH or PRL value every year. The average GH concentrations in plasma decreased in a regular manner as a function of time, 0- 12 years (Fig. 1). In 5 l/56 patients a 50% reduction of GH levels was obtained. 24 + 13 months (mean * SD.) (range 6-80 months) after radiotherapy with a further decrease, reached by 40/5 I patients, 42 ? 22 months after radiotherapy. The reduction was obtained regardless of preirradiation GH levels, volume, or invasiveness of the adenoma. No patient was completely unresponsive to radiotherapy with regard to GH reduction. The patient who responded least to treatment showed a percentual reduction of preirradiation GH levels (30 pg/l) of lo%, 17%, 30%. 2. 3, and 5 years, respectively, after radiotherapy. Three other patients had not reached 50% GH reduction 48, 48. and 80 months after irradiation. Mean PRL levels for the total material were increased I year after radiotherapy, and the levels remained increased with no significant tendency to increase further as a function of time (Fig. 1). The changes in GH and
Radiotherapy for acromegaly 0 E. AF TRAMPE et al. Table 1. Growth
hormone
levels, fig/l, in plasma in 56 patients with acromegaly who underwent microsurgery and external photon radiotherapy, total dose 50 Gy Minimum
S.D.
554
76.4 34.2 26.4
19.4 18.2 10.2
143.9 135.0 76.6
648 433 438 33 355 21 19 164 136 72 70 65
21.7 18.0 15.0 4.5 14.3 3.8 3.4 13.7 21.5 8.5 25.5 18.2
12.7 10.6 9.7 1.2 9.5 1.0 1.0 9.5 19.0 6.4 15.9 15.6
90.6 67.7 65.4 6.7 58.0 4.8 4.4 39.3 50.5 21.2 31.9 31.2
Median
Preop Postop Pre-irr. Post-irr. 1 2 3 4 5 6 7 8 9 IO II 12
55 55 56
41 7.9 7.6
1.3 0.9 0.9
1000 1000
51 41 45 30 37 23 20 I7 7 II 4 4
4.8 3.0 2.0 2.7 2.3 2.3 2.3 1.7 2.3 1.2 15.6 2.6
0.3
20. pp.
655-660 Copyright
0360-3016191 $3.00 + .OO 0 I99 Pergamon Press plc
I
??Original Contribution
EXTERNAL IRRADIATION OF GROWTH HORMONE PRODUCING PITUITARY ADENOMAS: PROLACTIN AS A MARKER OF HYPOTHALAMIC AND PITUITARY EFFECTS EVA AF TRAMPE,
M.D.,*
G~RAN
LUNDELL,
AND SIGBRITT
WERNER
M.D.,*
INGMAR
LAX,
PH.D.+
M.D.’
Karolinska Hospital, S- 104 0 I Stockholm, Sweden Fifty-six patients with acromegaly were treated with external irradiation, 50 Gy, after unsuccessful pituitary surgery. A 50% reduction of pre-irradiation growth hormone levels was obtained in 51/56 patients. This level was reached after 26 + 14 months in 33 patients with prolactin levels < 25 pg/l at diagnosis, after 21 + 17 months in 18 patients with prolactin 2 25 pg/l, and after 20 f 21 months in 12 patients with prolactin > 40 Mg/l at diagnosis. A further 50% decrease of growth hormone levels was obtained in 40/51 patients 42 f 22 months after radiotherapy, indicating that in clearly responsive patients, the growth hormone depression after radiotherapy follows a first order reaction. Four patients did not reach a 50% reduction of growth hormone levels 48-80 months after radiotherapy. During 10 years of follow-up, the growth hormone depression tended to be more pronounced in patients with mixed secretion of growth hormone and prolactin. The reduction of growth hormone levels was not correlated with the irradiated volume or the cumulative radiation effect. Within the first year, prolactin increased within the normal range in normoprolactinemic patients and remained so during follow-up. In hyperprolactinemic patients, prolactin decreased successively but to a lesser extent than growth hormone. Pituitary insufficiencies increased over time and three patients developed GH-insufficiency. Hypothalamic damage as indicated by prolactin changes was a regular phenomenon after radiotherapy. Radiotherapy,
Acromegaly,
Growth hormone, Prolactin, IGF-1.
INTRODUCTION In a previous study (18) we showed that external photon irradiation, given to a total dose of 50 Gy over approximately 5 weeks with a three-field technique and a daily dose of 1.8 Gy, was efficient in lowering growth hormone (GH) and insulin-like growth factor 1 (IGF- 1) in patients with acromegaly. The GH levels were reduced in a timedependent manner regardless of the pre-irradiation GH levels, tumor volume, irradiated volume, and the suprasellar part of the irradiated volume. Seven patients with concomitant hyperprolactinemia responded with a more pronounced GH reduction after 2 years than 18 patients with acromegaly and normoprolactinemia. Prolactin (PRL) secretion as illustrated by PRL concentrations in serum tended to increase after radiotherapy in patients initially normoprolactinemic but decreased in patients who had shown concomitant hyperprolactinemia at diagnosis.
* Department of General Oncology, Radiumhemmet. + Department of Hospital Physics. * Department of Endocrinology. Reprint requests to: Eva af Trampe, M.D. Acknowledgements-We thank Kerstin Florell, Christina
The aim of the present study was to characterize further these changes of the two lactogenic hormones in a larger number of patients with special regard to possible hypothalamic damage as a function of time and to the risk of developing ACTH, TSH, gonadotropin as well as GH insufficiency after radiotherapy. The latter has hitherto not been reported in patients with acromegaly who have been treated with pituitary irradiation.
METHODS
AND
MATERIALS
The study concerns patients with acromegaly who were primarily treated by transsphenoidal pituitary microsurgery. External radiotherapy was given because of postoperatively remaining pathological GH secretion and clinical activity of the disease; the patients lacked normal diurnal GH secretion and GH was depressed by I-dopa and increased after the injection of TRH intravenously.
Bremer, and Katarina Breitholtz for expert help in preparing figures, tables, and manuscript. This work was supported Swedish Medical Research Council (no 19x-06865). Accepted for publication 12 October 1990.
by the
656
I. J. Radiation Oncology 0 Biology 0 Physics
The diagnosis of GH producing pituitary adenomas was based on light microscopy and immunohistochemical staining. At the Karolinska Hospital, 60 patients received standardized radiotherapy on this indication between 1972-1986. Four of these patients had been given bromocriptine before (0.8-6 years) and during radiotherapy. These patients were excluded from analysis, as it was impossible to evaluate the radiation effect properly. The mean age of the evaluated 56 patients (23 males) was 43.9 years, median age 43.1 years, and range 19-70 years. The mean time between primary pituitary surgery and radiotherapy was 2.1 years (0.2- 16 years). The size of the sellar and pituitary volumes and erosive features of the sellae were estimated according to plain X ray and computed tomography. The volume was normal with no bone erosions in four patients, moderately enlarged with no bone erosions in 38 patients, and severely enlarged. all showing of bone destructions. in 14 patients. The treatment technique was described in detail previously (18). In short, high energy photons (4 MV to 3 patients, 6 MV to 50 patients, and 2 I MV to 3 patients) were administered with a three-held technique, using bilateral temporal and a single frontal portals. The daily mean target dose was 1.8 Gy given Monday through Friday and the total tumor dose was planned to 50 Gy. To increase the precision of the treatment, the patients were treated in individual plastic masks. The biological effect of the radiation therapy was calculated according to the CRE-value (Cumulative Radiation Effect) (12). The irradiated volume was defined as the volume confined within the intersection of the geometric borders of the beams. During follow-up four patients have died, 49-63 years old. due to acute lymphoblastic leukemia, subarachnoidal haemorrhage, cardiac insufficiency. and heavy drug abuse with suspected cardiac insufficiency. Growth hormone in plasma was analyzed according to a radioimmunoassay with double antibody technique with a detection limit of 0.2 pg/l and interassay and intraassay variation of 9% and 3%, respectively (1). Prolactin in serum was analyzed by a commercial radioimmunoassay* with a detection limit of 1.6 pg/l. IGF- 1 was analyzed by a commercial radioimmunoassay.+ At annual follow-ups. triiodothyronine, thyroxine, luteinizing hormone (LH). follicle stimulating hormone (FSH). serum/urinary cortisol, testosterone in males, and estradiol in females were analyzed with commercial radioimmunoassays. When there was uncertainty about the cortisol insufficiency, this diagnosis was confirmed by ACTH infusion tests or metyrapone tests. In patients whose GH had been undetectable for at least 2 years and whose IGF- 1 levels were below the normal range, the GH reserve was tested by 1-dopa,
* Farmos ’ Nichols USA.
Diagnostica. P.O. Box 425 Turku, Finland. Institute Diagnostics, San Juan, Capistrano,
CA,
April IO9I. Volume 20. Number 4
500 mg given orally after which growth hormone secretion was measured up to 2 hours. Undetectable basal levels without an increment after l-dopa leading to the occurrence of detectable GH was taken as an indication of GH insufficiency. The other prerequisite for the diagnosis of GH insufficiency was a diurnal GH profile with non-detectable GH at 06, 08. 12, 16, 20, 22. and 02 hours. During radiation therapy, haemoglobin, leucocyte, and platelet counts were checked regularly. For the statistical analyses unpaired T-tests between groups were used.
RESULTS The 56 patients received 50.1 ? 0.1 Gy (mean + SEM). The average length of treatment was 47 days. The cumulative radiation effect was 14.8 * 0.05 Geu. The irradiated volume was 66.2 + 5.7 cm3 (mean + SEM). During the period of treatment 3 patients noted nausea, 9 patients headache, and 14 patients fatigue. The most longstanding side-effect, nausea, disappeared within 2 months after termination of radiotherapy. Visual field defects, present in 15 patients before surgery, persisted in I2 patients after surgery, disappeared in 7 patients after radiotherapy, improved in 2 patients, and were unaltered in 3 patients. After the two interventions no persistent visual field defects have occurred up to the latest follow-up of the 56 patients. Furthermore, there has been no evidence of deterioration of visual acuity. The numerical values on which the changes of GH and PRL are calculated are shown in Tables 1 and 2. Each patient is not included with a GH or PRL value every year. The average GH concentrations in plasma decreased in a regular manner as a function of time, 0- 12 years (Fig. 1). In 5 l/56 patients a 50% reduction of GH levels was obtained. 24 + 13 months (mean * SD.) (range 6-80 months) after radiotherapy with a further decrease, reached by 40/5 I patients, 42 ? 22 months after radiotherapy. The reduction was obtained regardless of preirradiation GH levels, volume, or invasiveness of the adenoma. No patient was completely unresponsive to radiotherapy with regard to GH reduction. The patient who responded least to treatment showed a percentual reduction of preirradiation GH levels (30 pg/l) of lo%, 17%, 30%. 2. 3, and 5 years, respectively, after radiotherapy. Three other patients had not reached 50% GH reduction 48, 48. and 80 months after irradiation. Mean PRL levels for the total material were increased I year after radiotherapy, and the levels remained increased with no significant tendency to increase further as a function of time (Fig. 1). The changes in GH and
Radiotherapy for acromegaly 0 E. AF TRAMPE et al. Table 1. Growth
hormone
levels, fig/l, in plasma in 56 patients with acromegaly who underwent microsurgery and external photon radiotherapy, total dose 50 Gy Minimum
S.D.
554
76.4 34.2 26.4
19.4 18.2 10.2
143.9 135.0 76.6
648 433 438 33 355 21 19 164 136 72 70 65
21.7 18.0 15.0 4.5 14.3 3.8 3.4 13.7 21.5 8.5 25.5 18.2
12.7 10.6 9.7 1.2 9.5 1.0 1.0 9.5 19.0 6.4 15.9 15.6
90.6 67.7 65.4 6.7 58.0 4.8 4.4 39.3 50.5 21.2 31.9 31.2
Median
Preop Postop Pre-irr. Post-irr. 1 2 3 4 5 6 7 8 9 IO II 12
55 55 56
41 7.9 7.6
1.3 0.9 0.9
1000 1000
51 41 45 30 37 23 20 I7 7 II 4 4
4.8 3.0 2.0 2.7 2.3 2.3 2.3 1.7 2.3 1.2 15.6 2.6
0.3
