|Year : 2016 | Volume
| Issue : 4 | Page : 117-121
An audit of over two decades of treating pituitary adenomas at a tertiary care facility
Rohini Khurana1, Mranalini Verma2, Prakash Kumar Swain2, Vijaylakshmi Bhatia3, Preeti Dabadghav3, Sanjay Behari4, Deepu Banerji5, Shaleen Kumar2
1 Department of Radiotherapy, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
4 Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
5 Department of Neurosurgery, Fortis Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||1-Feb-2017|
Department of Radiotherapy, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Aims: This retrospective audit of long-term outcomes and treatment sequelae with conventional radiotherapy (RT) is presented with an objective to provide baseline data with which outcomes of high precision techniques (fractionated radiosurgery and intensity-modulated RT [IMRT]) may be compared.
Materials and Methods: Between the years 1990 and 2012, a total of 182 patients of pituitary adenoma were registered in the Department of Radiotherapy. Of these, 156 received RT. Immobilization consisted of a plaster of Paris cast (1990–1995), acrylic cast (1996–2000), a three-point head fixation thermoplastic cast (2001–2006), and now we are using “U”-IMRT thermoplastic cast since 2007 onward. A 2-field technique was used in 7% patients, whereas in the remaining 93% patients, 3-field technique was used. Forty-seven percent of patients were treated on a telecobalt unit and the remaining 53% patients on 6 MV linear accelerator. Rectangular fields, no field shaping, and appropriate wedges were used with mean field sizes (standard deviation [SD] and range) being 41.4 cm2 (16, 25–100). Mean dose (SD, range) was 47.5 Gy (SD 3.2; range 45–55) given in 1.8–2.0 Gy/fraction, 5 fractions/week.
Results: Sixty percent of patients were (93/156) males. Median age was 37 years (mean - 37, SD - 13.2, range 12–66); 40.4% (63/156) had functional tumors. Presenting features were mainly headache 125 (80%), field defects 91 (58.3%), menstrual disturbances 33 (53% of women), and acromegalic features 38 (24.4%). Suprasellar extension, 129 (82.7%), was most common. All patients underwent resection; out of them, 28.2% patients had multiple surgeries. At a median (range) follow-up of 33 months (2–212) of all patients, the estimated freedom from progression was 96% at 2 years and 92% at 5 and 10 years with no patient failing beyond 18 months.
Conclusions: Conventional external RT as described in postoperative cases of pituitary adenoma is safe and effective for tumor control with a median time to normalization of hormonal hypersecretion being about 30 months.
Keywords: Hormonal control, pituitary adenoma, radiotherapy
|How to cite this article:|
Khurana R, Verma M, Swain PK, Bhatia V, Dabadghav P, Behari S, Banerji D, Kumar S. An audit of over two decades of treating pituitary adenomas at a tertiary care facility. J Radiat Cancer Res 2016;7:117-21
|How to cite this URL:|
Khurana R, Verma M, Swain PK, Bhatia V, Dabadghav P, Behari S, Banerji D, Kumar S. An audit of over two decades of treating pituitary adenomas at a tertiary care facility. J Radiat Cancer Res [serial online] 2016 [cited 2020 Aug 10];7:117-21. Available from: http://www.journalrcr.org/text.asp?2016/7/4/117/199308
| Introduction|| |
Pituitary tumors are fairly common in the general population with one estimate suggesting a prevalence of 16.7% (14.4% in autopsy data and 22.5% in radiological studies) and a rate of 1 in 600 persons exclusively for macroadenomas, based on a meta-analysis of published literature. Another estimate recorded an incidence of 6.4% of all intracranial tumors from a compilation of six population-based cancer registries from the United States over a 10-year period. In a prospective analysis of incidence of central nervous system tumors presenting in a tertiary cancer center from India, the proportion of pituitary tumors registered was about 8% annually. The most frequent symptoms on presentation include visual defects, extraocular cranial nerve palsies, and hormone hypersecretion. Surgery either through the transsphenoidal or transcranial approach is considered the appropriate first-line treatment with the aims of removal of tumor mass to reverse visual defects, control hormonal hypersecretion, and prevent recurrence. Many tumors may not be completely resectable due to their location adjacent to critical neurovascular structures, or significant extension beyond the pituitary fossa into the cavernous sinus. In such cases, recurrence after subtotal resection is more likely. In cases of postoperative residual or persistent hormone elevation after complete surgery, adjuvant external beam radiotherapy (RT) is often indicated. RT produces long-term tumor control in more than 90% of patients treated either postoperatively or as definitive treatment. Furthermore, persistent hormone elevation often returns to normal levels after RT but may require a long time. Doses of 45–50 Gy (1.8–2.0 Gy/fraction) result in acceptable local control and with limited field sizes employed; limit long-term sequelae in these patients. Further, visual complications are rare with appropriate fractionation schemes. Deteriorating hormonal functions after treatment are commonly encountered and need lifelong endocrine follow-up.
Currently, increasing conformation of the high-dose radiation envelope is possible with three-dimensional conformal RT, stereotactic RT (SRT), and stereotactic radiosurgery and is offered in the belief that neurocognitive sequelae are possibly lesser than with conventional treatment. This retrospective audit of long-term outcomes and treatment sequelae with conventional RT is presented with a view to provide baseline data with which outcomes of high precision techniques may be compared.
| Materials and Methods|| |
Between September 1990 and December 2012, 182 patients of pituitary adenoma were registered in the Department of Radiotherapy. Of these 182 patients, 156 eventually received RT and their outcomes are reviewed in this audit. Reasons for referred patients not receiving RT were a change in management strategy (n = 1), or they elected not to take treatment at this center (n = 25). There were no other exclusions.
Over the years, radiological assessment changed from contrast-enhanced computed tomography scans (CECT) (74 [47.4%]) to magnetic resonance imaging (MRI) studies (75 [48.1%]) with MRI scans being increasingly used after 2003, whereas in seven patients (4.5%), both imaging modalities were used. Other evaluation and diagnostic workup included physical, neurological, and ophthalmic examination, endocrinological assessment of gonadal, thyroid, and adrenal axis in almost all patients. Patients underwent conventional RT after immobilization of head in flexion using a plaster of Paris cast between the years 1990–1995, acrylic cast from 1996 to 2000, a three-point head fixation thermoplastic cast in normal head position from 2001 to 2006, and now with a “U”-intensity modulated RT (IMRT) thermoplastic cast. Patients were planned using a 2-field technique in 7% (11/156) and 3-field technique in 93% (145/156). Patients were treated on a telecobalt unit (Theratron 780C, Ottawa, Canada) in 47% (73/156) or a 6 MV linear accelerator in the remaining 83 (53%) (Mitsubishi ML20 MDX, Japan, or a Clinac 600C, Varian Medical Systems, Palo Alto, USA). Rectangular fields, no field shaping, and appropriate wedges were used with mean field sizes (standard deviation [SD], range) being 41.4 cm 2 (16.0, 12–100). Field edges were placed 1–1.5 cm beyond radiologically visible residual tumor. Mean dose (range) was 47.5 Gy (SD: 3.2, range 45–55 Gy) given in 1.8–2 Gy/fraction, 5 fractions/week in a median overall treatment time of 39 days and prescribed at mid-plane or at beam intersection points.
Demography and intervention variables are presented using summary measures, while freedom from progression (FFP) and median time to normalization (MTN) of hormonal function were computed with Kaplan–Meier method. Patients lost to follow-up (LFU) were censored when last seen for computation of FFP.
| Results|| |
Mean age was 37 years (SD - 13.2, range 12–66) with 63 patients (40.4%) of functional tumors being on average, 5 years younger than those with nonfunctional adenomas (n = 93). Sixty percent (93/156) were males. Median Karnofsky Performance Score (KPS) was 90, with 28 patients (17.9%) having a KPS of ≤70. All except one patient underwent initial surgery and 28.2% had multiple surgeries. The histology was pituitary adenoma (not otherwise specified) in 86 (56.4%) patients, chromophobe in 32 (20.5%) patients, acidophil in 28 (17.9%) patients, prolactinoma in 4 (2.6%) patients, basophil in 3 (1.9%) patients, and one patient was not operated. Immunohistochemistry was not routinely performed. The presenting features and extent of spread seen on first imaging (CECT, [47.4%; n = 74] or MRI, [48.1%, n = 75]) and functional status are presented in [Table 1]. Nonsecretory tumors were defined as no clinical syndrome of hypersecretion and an absence of elevated serum hormone levels (Insulin-like growth factor-1, prolactin, and adrenocorticotropin-secreting hormone). Acromegaly was diagnosed when postglucose growth hormone levels were ≥1 ng/ml. Prolactinoma was defined as serum prolactin >3 times the normal limit of 400 nmol/l, and for Cushing's syndrome, the criterion was a lack of suppression of plasma cortisol to <5 µgm/dl on standard low-dose dexamethasone test.
The cranial nerves involved most frequently in descending order were sixth, third, fourth, and fifth. When taken up for RT, the residual tumors had a median size of 3 cm in their largest dimension (mean 3.14 cm, SD 1.18, range 0–7 cm). Most patients, i.e., 71.2% (111/156) were referred after one surgery. 24.4% (38/156) patients had two surgeries, 3.2% (5/156) patients had three surgeries, and 0.6% (1/156) patients had four surgeries. The transsphenoidal approach was used most often in 65.4% (102/156) followed by a transcranial approach in 25.6% (40/156). Indications for RT and time to start of RT since the most recent surgery are listed in [Table 2].
|Table 2: Indications and time to start of radiotherapy since most recent surgery|
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Follow-up and assessment
The first follow-up was usually done 3 months following RT when a baseline imaging was advised. Subsequent follow-ups were at 6 months for 5 years and then annually, as per appointments with the endocrinologists. On each follow-up visit, a general examination, neurological examination, and visual field assessments were performed, while endocrinological studies were ordered routinely on follow-up at regular intervals; however, not all patients could afford them and were convinced to undergo these tests only if there were some symptoms. About half the patients 90 (57.7%) were assessed both clinically and with imaging (CT or MRI) while 59 patients (37.8%) were assessed clinically at last follow-up. A repeat imaging study during follow-up was performed only if the patient had a deterioration of vision/worsening of symptoms. Tumor progression was defined in nonfunctioning adenomas (NFA) as tumor enlargement detected clinically with worsening of signs and symptoms and by comparison of sequential CECT or MRI images. In secreting tumors, a rise in hormone levels was also considered progression. FFP was calculated from the date of start of RT. Record files and electronic medical records of patients were looked into and patients who had not been reporting for 1 year were contacted telephonically, and postal reminders were sent, if no further information available, they were taken as LFU (n = 38). At a median follow-up of all patients of 33 months (range 2–212), the FFP was 94% at 2, 5. and 10 years with no patient failing beyond 18 months [Figure 1].
Data on biochemical control were available in 27 out of 43 secretory tumors with a MTN ranging between 15.5 and 32 months [Table 3] and [Figure 2].
Pituitary hypofunction was seen in at least one axis out of the three investigated (GH, ACTH, and PRL) in sixty (38.5%) patients who received RT. Most of these patients required hormone replacement as advised by the endocrinologist. Cerebrovascular events (CVA) were seen in two patients, with one succumbing to a clinical diagnosis of thrombosis. No patient was known to have temporal lobe necrosis or second malignancy; however; one patient had a synchronous meningioma. Neurocognition was not assessed.
| Discussion|| |
The purpose of this audit was to document the profile of pituitary tumors presenting in a Radiotherapy Department and to assess the efficacy of postoperative RT in patients with recurrent/residual/hormone hypersecretion status, delivered using conventional techniques. The median age of patients was 37 years, and the proportion of males (60%) is very similar to that reported from another tertiary academic referral center in India. The relevant end points were FFP and normalization of hormonal hypersecretion. At a median (range) follow-up of 33 months (2–212) of all patients, FFP was 96% at 2 years and 92% at 5 and 10 years with no patient failing beyond 18 months which is comparable to results of conventionally delivered RT published from other centers [Table 4].
While there has not been any published randomized trial, in which the efficacy of adjuvant RT has been formally tested, Gittoes et al. reported outcomes in 126 patients with NFA more than 1 cm in size who were treated in two institutions with a routine adjuvant RT being offered at one center and rarely at the other center. FFP was 93% at 10 and 15 years with RT and 47% and 33% at similar time points when RT was not offered; with the administration of RT being the only significant prognostic factor on multivariate analysis.
The rationale for RT in benign tumors is often debated for fear of RT sequelae, increased morbidity for reoperation, lack of randomized data, and with the possibility of improving surgical results with modern techniques. The most common late toxicity observed in follow-up is secondary hypopituitarism, seen in up to 50% of patients which is attributed to RT. However, the presence of hypopituitarism in NFAs cannot be attributed solely to the effects of RT. Tsang et al. in their audit of 160 patients of NFA recruited in the years 1972–1986 found that 23%–44% of patients at diagnosis had deficiency in either the thyroid, adrenal, or gonadal axis, with 6%–19% additionally developing hypopituitarism after surgery and a further 13%–23% by RT. Another study observed that 87% patients required hormone replacement therapy for hypopituitarism. In the present study, pituitary insufficiency was documented in 38.5% which is most likely an underestimation as many patients were LFU and a proportion could not afford repeat investigations. The large number of patients' LFU in our setup is well known and decreases the reliability of all such estimates (FFP and MTN) that use the actuarial method., In addition, it is observed that patients lose motivation to visit treatment center with increasing time periods of follow-up as almost all those treated before 2001 (n = 67) are LFU, whereas only 30% of those treated later (n = 89) are LFU. When RT was given for recurrent tumors, the mean duration between last surgery and start of RT was 33.3 months as compared to 4.2 months when immediate postoperative RT was planned for residual disease (P = 0.000) which is consistent with known natural history of slow growth of pituitary tumors.
Although RT for pituitary adenomas has its merits, it might be associated with injury to the visual pathway of the order of 1.5%, and adjacent brain (0.2%), vascular changes (6.3%), neuropsychological disorders (0.7%), and carries a risk of inducing brain tumors (0.8%) if single doses of 2 Gy and total doses of 50 Gy are not exceeded. Other estimates put the risk of 2nd brain tumors at 2%–2.4% at 10–20 years. In the present audit, visual deterioration was seen in one patient who had acromegaly and diabetes mellitus and visual disturbance before the start of RT, and so the visual disturbance was unlikely to have been solely contributed by RT. Two patients reportedly had a CVA at 15.3 months and 108 months, respectively, with the former patient succumbing to the same. One patient had synchronous benign meningiomas. No second malignancies were observed in the present cohort, in part due to loss to follow-up of patients and short median duration of follow-up.
The rate of reduction of growth hormone after conventional RT is reported as a 50% drop in 27 ± 5 months, while most patients of Cushing's disease achieving normalization of plasma and urinary cortisol in the first 2 years after treatment  and those with a prolactinoma mainly go for medical treatment, the use of RT is infrequently indicated. In this audit, the evaluable 18 GH–secreting patients, 9 prolactinoma patients, and 2 patients with Cushing's disease had a MTN of 30, 31, and 15.5 months, respectively.
Given the concerns about potential late toxicity, SRT, both in the form of radiosurgery or fractionated SRT (FSRT) has been developed as a more accurate technique of irradiation with more precise tumor localization, and consequently, a reduction in the volume of normal tissue, particularly the brain outside the target volume, irradiated to high radiation doses. The early–intermediate term results of FSRT are within the range reported for conventional RT. However, there is no information on neurocognitive decline, if any, mainly because this has not been assessed rigorously, and therefore, the benefit of brain tissue sparing remains theoretical. Besides, data are only now emerging on the relationship between dose-to-volume effects of the brain.
Limitations of our study were around LFU of 40% and not all patients had endocrinological investigations.
| Conclusions|| |
Conventional external beam RT to a dose of 45–50 Gy in 1.8–2 Gy fractions for residual or hormonally active pituitary adenomas following surgery is safe and effective. The challenges for treatment of this benign disease in developing countries include poor follow-up of patients, financial constraints to periodic imaging, and biochemical and neurocognitive assessment. This audit provides baseline data on the efficacy and long-term sequelae of surgery and postoperative conventional RT for pituitary tumors from the Indian subcontinent data with which outcomes of high precision techniques (fractionated radiosurgery and IMRT) may be compared.
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Conflicts oF interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]