Clinical Results of Conformal Radiotherapy and Radiosurgery for Pituitary Adenoma

Neurosurg Clin N Am 17 (2006) 129–141

Clinical Results of Conformal Radiotherapy and Radiosurgery for Pituitary Adenoma Dheerendra Prasad, MD, MCh (Neurosurgery)a,b,* a

Department of Radiation Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA b Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA

Current therapeutic options for the treatment of pituitary adenomas include medical treatment, surgery, and radiotherapy. Outcomes depend on tumor size, location, suprasellar extension, dural microinvasion, and the presence and severity of hormonal disturbance. For all but prolactinomas, surgical resection remains the first treatment consideration. Transsphenoidal resection with the subsequent integration of endoscopic techniques for small tumors has been instrumental in making surgery a safe and viable option for most patients. Surgical resection offers immediate decompression of the optic nerves and chiasm by removal of the tumor, and thus improvement of vision symptoms, rapid relief from symptoms of hormonal excess, debulking, and histologic confirmation. With increasingly available follow-up statistics and the increasing sophistication of endocrine laboratory testing, however, it has become apparent that microsurgery alone is plagued with failure because of residual and recurrent disease. Adjuvant therapies are thus standard fare for the patient in a multidisciplinary pituitary clinic. Advances in pharmacology have increased the available armamentarium of medical options for secretory tumors; however, there are associated side effects that limit therapy in some patients. Radiation therapy offers significant improvements in local control rates, with control rates approaching 95% at 5 and 10 years with radiation as

* Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: [email protected]

compared with 50% at 5 years and 20% at 10 years [1] with surgery alone. Surgery is generally the first choice, primarily because of the historic data on potential radiation damage to the hypothalamic-pituitary axis. With the modern techniques described in this article, this concern is largely ameliorated, although not entirely eliminated; in many patients, we can now avoid the ventral hypothalamus, which is more likely to produce hypothalamic-pituitary axis dysfunction than pituitary irradiation itself. In fact, with techniques like radiosurgery in the instance of microadenomas, it may even be possible to avoid surgery all together [2], although this is by no means an established standard of care. Conventional radiotherapy for pituitary adenoma Radiation therapy has been used in the adjuvant management of these lesions for several decades. There has been remarkable progress in the techniques of radiation delivery and our associated understanding of the dosage and side effects of such treatment. Radiation therapy may be used in combination with surgery or, in some cases, in lieu of it. Long follow-up data from so-called ‘‘conventional’’ techniques, such as radiation with telecobalt or with simple opposed lateral fields, have demonstrated good disease control. Zaugg and colleagues [3] retrospectively analyzed the results in 89 patients with macroinvasive adenomas from the treatment period 1973 to 1992, of whom 66 received radiation therapy immediately after subtotal surgical removal (combined treatment modality) and 22 received radiation therapy

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as a primary treatment or after surgical recurrence. Only 1 patient was reirradiated. For most (79 of 89) patients with a mean follow-up of 8.1 years (0.5 to 19 years), the total tumor dose ranged between 40 and 45 Gy at a dose per fraction of 1.8 to 2.25 Gy. All patients had bilateral opposed fields with telecobalt. Eleven patients had an additional arc rotation. The 10-year progression-free survival rate for all 89 patients independent of treatment modality was 88.1%. The 10-year progression-free survival rate for patients treated by surgery and adjuvant radiation therapy (40–45 Gy at 1.8–2.25 Gy [60 of 79 patients]) was 90.3%, and for radiation therapy alone (40–45 Gy at 1.8–2.25 Gy [19 of 79 patients]), it was 100% (P ¼ .32). Zierhut and coworkers [4] reported the outcomes of radiotherapy as a sole or combined treatment in pituitary adenoma cases. A total of 138 patients were irradiated for pituitary adenoma from 1972 to 1991. Seventy patients had nonfunctional pituitary adenoma, 50 patients had growth hormone–producing adenomas, 11 had prolactinomas, and 7 had corticotropin-producing pituitary adenomas. In 99 patients, surgery was followed by radiotherapy in case of suspected remaining tumor (eg, invasive growth of the adenoma, assessment of the surgeon, pathologic CT after surgery, persisting hormonal overproduction). Twenty-three patients were treated for recurrence of disease after surgery, and 16 patients received radiation as a primary treatment. Total doses from 40 to 60 Gy (mean ¼ 45.5 Gy) were given with single doses of 2 Gy four to five times a week. Tumor control was achieved in 131 patients (94.9%). In 7 patients, recurrence of disease was diagnosed in the mean 2.9 years (range: 9–98 months) after radiotherapy and salvaged by surgery. A statistically significant dose-response relation was found in favor of doses greater than 45 Gy. Ninety percent of the patients with hormonally active pituitary adenomas had a benefit from radiotherapy in terms of complete control (38%) or at least reduction (52%) of hormonal overproduction. These investigators conclude that to achieve optimal tumor control, doses of 45 to 48 Gy (conventionally fractionated) should be applied. Sasaki and colleagues [5] reviewed the records of 91 patients with pituitary adenomas, who were first treated between 1969 and 1994 and had been followed for more than 2 years (median ¼ 8.2 years.) Of these patients, 86 had received postoperative radiotherapy and 5 had received

radiotherapy alone. The median total dose was 51 Gy. Mass-effect symptoms improved in 72% of the nonsecreting adenomas and in 79% of the secreting adenomas, respectively. Symptoms of endocrine hypersecretion abated in 67% of patients. Excessive hormone levels normalized in 74% of patients. The greatest size reduction was seen 3 years after the completion of radiotherapy. The 10-year local control rates were 98%, 85%, 83%, and 67% for nonsecreting adenomas, growth hormone–secreting adenomas, prolactinomas, and Cushing’s disease, respectively. Radiotherapy alone may be used in lieu of surgery in high-risk patients with nonfunctioning adenomas. Shihadeh and coworkers [6] evaluated the long-term efficacy of external beam radiotherapy alone for nonfunctioning pituitary adenomas compared with surgery followed by postoperative radiation. In a retrospective review of 135 patients with nonfunctioning pituitary adenomas who were treated between 1961 and 1996, the treatment outcome of 38 patients who received radiation alone was compared with that of 97 patients treated with surgery followed by postoperative radiation. Most of the patients in the radiationalone group were considered to be at high surgical risk or refused surgery. In the combined-modality group, most underwent transsphenoidal resection. The remainder of patients underwent an open craniotomy. The median follow-up period was 7 years, with a maximum of 33 years. Radiation doses ranged between 1600 and 6000 cGy (median ¼ 4500 cGy) in a daily fraction of 180 to 250 cGy. The tumor recurrence rate was 13% (5 of 38 patients) in the radiation-alone group and 9.3% (9 of 97 patients) in the combined-modality group. The 10-year tumor progression-free survival rate was 82.8% for the first group and 88.8% for the second group. These rates were not statistically different by the log-rank test. Thus, these investigators concluded that radiation alone is a reasonable management option, especially in this subgroup of high-risk patients. In addition to tumor control and hormonal excess, resolution of visual symptoms can be achieved in patients who are not candidates for surgery. Rush and colleagues [7] treated 25 patients for pituitary macroadenomas causing visual impairment by radiation therapy alone between 1972 and 1988. Radiation treatment consisted of 4000 to 5000 cGy over 4 to 5 weeks. The median follow-up period was 36 months (range: 2–192 months). Eighteen patients (78%) experienced

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CONFORMAL TREATMENT FOR PITUITARY ADENOMA

visual field improvement documented on a neuroophthalmologic examination. Deterioration occurred in 4 patients because of tumor recurrence, tumor hemorrhage, possible optic nerve necrosis, or optic chiasm herniation. Visual field improvement occurred predominantly in patients whose pretreatment visual field defects were less than a dense hemianopsia, who did not have diffuse optic atrophy, and who were younger than the median age of 69 years (P ! .001). Visual acuity improvement occurred in patients without diffuse optic atrophy, with only mild impairment of the visual acuity, and with only mild visual field loss before radiation therapy (P ! .002). Table 1 summarizes the results of these and other series by Clarke and coworkers [8], Fisher and colleagues [9], Jaffrain-Rea and coworkers [10], and Hughes and colleagues [11].

Conformal techniques applicable to pituitary adenomas In the parlance of radiation delivery, conformality refers to a process of closely matching the radiation field with the three-dimensional shape and contours of the tumor. One of the earliest attempts at the treatment of pituitary adenomas in a conformal manner was with the use of particle beams from the Harvard cyclotron by Kjellberg and his colleagues during the late 1960s [12]. The primary element of conformality seen in this technique was in the limitation of the exit dose to the brain stem and the temporal lobes. Using photons, the exit dose delivered by a beam as it passes through the tumor cannot be completely eliminated. The exit dose to any one

area, such as the temporal lobe, can be reduced by multibeam arrangements that distribute the exit dose over a large volume of normal tissue, thereby not exceeding the tolerances of any one structure. Conventional irradiation of the sellar region was achieved by parallel opposed fields of megavoltage photons, as depicted in Fig. 1. This technique was used on thousands of patients in the pre-CT era, with beams being directed according to bony anatomy. Each of the two beams contributes dose to both temporal lobes. Dose delivered to the temporal lobes is significantly reduced by threedimensional multibeam arrangements, as shown in Fig. 2. Furthermore, multileaf collimation of each of the beams is capable of ensuring significantly increased conformality of the field along each beam’s eye view of the tumor. Small highly conformal fields can be treated in a single sitting instead of the 5-week fractionated treatment using stereotactic radiosurgery (SRS) (Fig. 3). The cornerstones of conformal radiation delivery in the sellar region for single- and multifraction treatments are as follows: Immobilization of the patient Imaging-based planning Conformal beam’s eye view portals Multiple radiation beams Beam arrangements The number and arrangement of radiation fields best suited for dose delivery in this region are dependent on individual patient parameters. Perks and coworkers [13] reported that the mean volume of normal brain receiving greater than 80% and greater than 60% of the prescribed dose decreased by 22.3% (range: 14.8%–35.1%,

Table 1 Clinical results of radiation therapy using nonstereotactic techniques for pituitary adenomas

Series Sasaki et al [5] Shihadeh et al [6] Zierhut et al [4] Zaugg et al [3] Clarke et al [8] Fisher et al [9] Jaffrain-Rea et al [10] Hughes et al [11]

Local control (%) No. Complications Year cases NF PRL CUSH NELS GH (%)

Hypopituitarism (%)

Recurrence (%)

2000 1999 1995 1995 1993 1993 1993

91 135 138 89 44 134 33

1 0.8 1.4 5 11 7 nr

nr 27 27 31 23 nr nr

nr 0 5 8 nr 9 8

1993

160

4

74

nr

98 83 89 98 100 100 89 d 86 55 55 92 d 82

50

67

85

100

d

50 55 d

d 55 d

d 83 67 55 d

75

d

64

Most pituitary fractionated radiation is now carried out stereotactically (see Table 2). Abbreviations: CUSH, Cushing’s adenomas; GH, growth hormone–secreting tumors; NELS, Nelson’s syndrome; NF, nonfunctioning; nr, not reported; PRL, prolactinomas.

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Fig. 1. Dose distribution from classic parallel opposed radiation treatment. Note that the high-dose zone (red) extends to include both temporal lobes.

standard deviation [s] ¼ 7.5%) and 47.6% (range: 25.8%–69.1%, s ¼ 13.2%), respectively, with a four-field noncoplanar technique when compared with a conventional three-field coplanar technique. Adding two further fields, from four to

six noncoplanar fields, reduced the mean normal brain volume receiving greater than 80% of the prescribed dose by a further 4.1% (range: 26.5%– 11.8%, s ¼ 6.4%) and the volume receiving greater than 60% by 3.3% (range: 25.5%–12.2%,

Fig. 2. Dose distribution for a three-dimensional conformal treatment plan shows dose distribution in the axial and sagittal planes (top left and right), with the high-dose region (red) now conforming to the sellar region with sparing of the temporal lobes. The fluence map (bottom right) shows that the dose cloud is sparing the optic nerve (yellow cylinder). This is achieved with a five-beam noncoplanar arrangement (bottom left).

CONFORMAL TREATMENT FOR PITUITARY ADENOMA

133

Fig. 3. A Gamma Knife dose plan (top) highlighting the 8-Gy isodose line is off the optic pathways in the coronal and sagittal views, and the three-dimensional dose cloud (top right) is not intersecting the three-dimensional model of the optic pathways (orange). A prototypical result is shown in the bottom panel for a nonfunctioning adenoma before (left) and 1 year after (right) Gamma Knife radiosurgery.

s ¼ 5.4%), neither of which was statistically significant. They concluded that four to six widely spaced fixed conformal fields provide the best class solution for the treatment of sellar and parasellar lesions in terms of normal brain tissue sparing and providing a relatively straightforward patient setup. Physical comparisons have been made of beam arrangements, such as two-field, parallel opposed, single- or dual-rotational arc techniques, wherein the radiation source is rotated around the patient’s head while the radiation beam is turned on with the intent of reducing entry dose to any one brain region while maintaining focus on the target, and a noncoplanar arc technique using dose-volume histograms. Keeping the prescribed dose constant (45 Gy) and using two different photon energies 6 and 18 MV, the following conclusions were reached by Sohn and colleagues [14]. Higher energy photons (18 MV) photons deliver a lower dose to the temporal lobe than 6-MV photons in the two-field technique, but this advantage is not evident for the other techniques. The arc techniques are superior to a stationary twofield technique for sparing the temporal lobes. The four-field noncoplanar arc technique delivers lower doses to the temporal and frontal lobes than the other techniques. The eye lens dose (3.6 Gy per 25 fractions) was higher compared with the other techniques, however [14].

Fractionation and radiosurgery There is a growing literature base for singlesession treatment of pituitary adenomas by radiosurgery that has outrun the publications on conformal fractionated techniques in recent years. Table 2 [15–45] summarizes all the currently available literature in this regard. Fractionated radiation delivery is performed using linear accelerators equipped with appropriate collimator cones or multileaf devices that allow conformal therapy. Some setups also include relocatable fixation devices that make the technique stereotactic, giving rise to the term stereotactic radiation therapy (SRT), or fractionated stereotactic radiation therapy (FRST), to distinguish it from SRS, where the dose is not fractionated. The biologic advantages cited by the advocates of fractionation are as follows: 1. Allowing resortment of tumor cells into a more radiosensitive phase of the mitotic cycle (G2/M) 2. Interfraction recovery of the normal tissues by repair of radiation damage, improving normal tissue functional preservation in this case for the optic pathways and the pituitary axis The proponents of SRS refute these arguments by claiming that the biologic equivalent dose

134

Table 2 Clinical results of conformal radiation therapy and radiosurgery for pituitary adenomas with current techniques

Year Technique Dose (Gy)

Colin et al [19] Paek et al [20] Milker-Zabel et al [15] Milker-Zabel et al [21] Mitsumori et al [18] Milker-Zabel et al [15] Yoon et al [22]

2005 SRT 2005 SRT 2004 SRT

50.4 46–50.4 52.2

110 79 20

91 98 80

89 98

2001 SRT

52.2

42

98

98

1998 SRT

45

30

2004 SRSa

13–16 to 80%

1998 SRSa

Mitsumori et al [18] Voges et al [23] Muron et al [24] Valentino [25] Kwok et al [16] Wowra and Stummer [26] Pollock et al [27]

1998 SRSa

10–27 to 100% 10 at 85% to 15 at 65% 8–20 15 10–20 6–20 11–20

1996 1993 1991 2004 2002

SRSa SRSa SRSa SRSb SRSb

2002 SRSb

12–25

Latency of response NF PRL CUSH NELS GH (months) Control (%)

100

Hypopituitarism (%)

Recurrence (%)

29 48 nr 80 26

2 3 5

32 10 10

5 0 0

34

7

5

2

85

18

3

21

nr

5

75

75 21

0

0

0

24

87

75 12

0

29

18

100

17

23

26 12 52 74 45

44 50 67 99 93

9

78

88

25

Complications (%)

84

8.5 54 50 d 99 93

25

d

50

67

d

d

78

50 d

11.6 20 nr 0 0

nr nr nr 0 14

nr nr nr nr 0 0

PRASAD

Series

Overall control Number (%)

Pollock et al [28] 2002 SRSb Sheehan et al [29] 2002 SRSb Hoybye et al [30] 2001 SRSb 2001 SRSb

Izawa et al [32] Landolt and Lomax [17] Pan et al [2] Sheehan et al [33] Shin et al [34]

2000 SRSb 2000 SRSb

Vladyka et al [35] Zhang et al [36] Kim et al [37] Ikeda et al [38] Motti et al [39] Park et al [40] Pollock et al [41] Steiner et al [42] Ganz et al [43] Stephanian et al [44] Ra¨hn et al [45] Ra¨hn et al [45]

2000 SRSb

2000 SRSb 2000 SRSb 2000 SRSb

2000 1999 1998 1996 1996 1994 1994 1993 1992

SRSb SRSb SRSb SRSb SRSb SRSb SRSb SRSb SRSb

1991 SRSb 1991 SRSb

43 42 18

61 100 83

17

82

74 20

85 80

9–35 128 3.6–30 43 NF: 14–18 16 Others: 20–49 16–35 163

80 63 77 75

28.7 22 12.5–30 Gy 25 12.5–37.5 12–30 3.6–30 8–25 25

79 37 13 30 19 35 46 16 16

96 82 95 75 67 78 82 71 67

25–50 25–50

8 51

100 82

29

78

42 14

0 2 0

26 0 50*

0 0 0

82

0

0

0

0.5 5

2 0

0 0

67

0 2.5 0

4 16 6

0 7 0

43

0.6

100 83

91

80 80 80 63 50

100 61

85

22

96

d 66 d

90 100 71 72 90 75 75

1 nr nr 0 nr nr nr nr 11

d d

d d

nr nr

82 100 50 d 71 100 64 100 d 66 d d d d

d d

50 60 67 66 50 50 100 82

d

3.7

0

4

0

0 0 nr 0 nr nr 2 0 0

0 55

0 0

nr 0 0 nr nr 0 nr

Abbreviations: CUSH, Cushing’s syndrome; GH, growth hormone secreting tumors; NEL, nelson’s syndrome; NF, nonfunctioning; nr, not reported; PRL, prolactinomas; SRSa, stereotactic radiosurgery, linear-accelerator based; SRSb, stereotactic radiosurgery, Gamma Knife based; SRT, stereotactic radiation therapy.

CONFORMAL TREATMENT FOR PITUITARY ADENOMA

Ikeda et al [31]

14.4–30 10–34 25–50 (1–4 treatments) 16.7–30 NF: 19.5 CUSH: 24.2 20–35

135

136

PRASAD

delivered in a single session is higher than that of fractionated regimens and that stereotactic localization avoids any need to expand the target volume into normal tissue to compensate for possible day-to-day setup variations incurred by fractionated delivery. Dose Doses ranging from 45 Gy in 1.8- to 2.25-Gy fractions to 54 Gy in similar fractionation have been used in the treatment of these lesions. Although some authors think that doses in excess of 45 Gy are not needed [46], much of the literature points to doses greater than 45 Gy. Some FRST advocates prefer doses up to 52 Gy [15]. In linear accelerator–based radiosurgical series, the dose varies from 10 to 27 Gy, corresponding to maximal doses of 15 to 32 Gy. The minimum dose delivered in Gamma Knife radiosurgery (GKRS) settings varies from 6 Gy [16] to 35 Gy [17], but the more usual dose range is 15 Gy [15] to 25 Gy, with a corresponding maximum dose of 22 to 60 Gy. The lower doses are applied to nonfunctioning adenomas, previously irradiated tumors, and large tumors (to avoid complications), and the higher doses are applied to secretory tumors. Clinical results The current results of conformal radiation of pituitary adenomas, including SRT and SRS, with a linear accelerator or Gamma Knife are abstracted in Table 2. Overall, conformal radiation and radiotherapy are effective in controlling pituitary adenomas after surgery and directly. The complication rates are low and improve as experience accrues with each technique, so that the latest published reports even within the same technique show better results and fewer complications. Several important features need to be highlighted. At the outset, all the series are nonrandomized and, for the most part, retrospective data analyses. The outcome end points are not comparable across the series; thus, the interpretations of the respective authors are presented. These series span 15 years, and the available endocrine testing and stringency of the response criteria have changed considerably as well. The dose delivered by different modalities is prescribed differently as well. In linear accelerator–based SRS, the normalization of the dose is usually to isodose lines around 80%, resulting in

a smaller difference between the prescribed margin dose and the maximum dose. In GKRS, conversely, the dose is usually prescribed to the 50% line, resulting in a much higher maximum dose relative to the dose prescribed to the margin of the tumor. A decrease in serum growth hormone concentrations to normal levels is seen in approximately 85% of patients, with somewhat more control in the radiosurgery literature than in the FSRT or conventional radiation literature, for a given duration of follow-up. Growth hormone levels decrease at a rate of 10% to 30% per year with fractionated radiotherapy; thus, several years may be required for the levels to normalize. The probability of endocrine cure is highest for modest growth hormone levels (25–50 ng/mL), becoming less likely with higher growth hormone levels. Serum insulin-like growth factor-1 (IGF-1) levels remain elevated longer [47], and long-term treatment with somatostatin or its analogues may be required [48]. There is more rapid normalization of IGF-1 with GKRS in our experience, usually in the 6- to 18-month time frame. Control of corticotropin excess is seen in 50% to 75% of adults and 80% of children with Cushing’s disease. Response occurs earlier than in growth hormone– secreting tumors, often within 6 to 9 months [18]. Nonfunctioning tumors require lower doses than functioning tumors. SRS and GKRS produce earlier responses than conventional radiotherapy, with comparable rates of hypopituitarism. It is hard to compare the relative risk of optic nerve–related complications with the two techniques, however, because the rates are quite low with radiosurgery and with modern fractionated techniques. Improvement in visual function is reported with both techniques as well. Recurrence rates reported by various authors are uniformly low. Factors affecting outcome The prognostic factors for progression-free survival include the subtype of adenoma [3], with Ryohei and Masao [49] reporting a 10-year local control rate of 98% in nonsecreting adenomas treated with conventional fractionated treatment, which is significantly superior to that for each type of secreting adenoma (85% for acromegaly, 83% for prolactinoma, and 67% for Cushing’s disease). Colin and colleagues [19] reported the worst hormonal response with growth hormone adenomas (P ! .001) as compared with other subtypes

137

CONFORMAL TREATMENT FOR PITUITARY ADENOMA

in a series of patients treated with SRT. According to them, the sole unfavorable predictive factor for tumor response was preoperative suprasellar extension greater than 20 mm (P ! .01). This significance of the extent of suprasellar extension as well as the presence of visual symptoms at the time of diagnosis and the initial hormone levels is reiterated by the findings of Zaugg and coworkers [3] with conventional radiation therapy. Meij and colleagues [50] reported an increased incidence of dural invasion in reoperations, indicating that dural invasion is an adverse prognostic factor for disease control with surgery, whereas for radiation therapy, Zaugg and coworkers [3] did not find the presence of infiltration of adenoma cells in the basal dura or in the mucosa of the sinus sphenoidalis to represent a prognostic factor, indicating special biologic behavior of those pituitary adenomas. This could be interpreted to indicate that the presence of dural invasion should be an indication for postoperative adjuvant radiation therapy so as to prevent surgical failure. In the series reported by Ryohei and Masao [49], the radiation field size was identified as a statistically significant prognostic factor for local control in univariate analysis, whereas age and the radiation field size were statistically significant in multivariate analysis (P ! .05). Total dose (45 Gy versus O50 Gy), extent of resection. Hardy’s grade, and suprasellar extension were insignificant in tumor control in their univariate and multivariate analyses. Radiation dose was not significantly predictive of control in the University of Florida experience [46] with a narrow dose range. No benefit was seen in a study for doses greater than 45 Gy (10-year progression-free survival was 91% for doses less than 45 Gy, 95% for 45–49.9-Gy doses, and 100% for doses of 50 Gy or more). The differences were not statistically significant. With other studies indicating the need for at least 40 Gy [51] and other reports suggesting superiority for 50 Gy, the University of Florida group recommends 45 Gy as the lowest dose with proven efficacy. It is our policy to operate to control suprasellar extension as much as possible for relief of optic nerve compromise and for improving control rates. We offer early postoperative radiotherapy in contrast to a wait-and-watch approach in patients with a high Ki-67 labeling index [52], dural invasion, or gross residual disease. Multiplebeam arrangements are standard for fractionated radiation, and GKRS is used when feasible as a single-fraction modality.

Complications Optic neuropathy The optic pathways, particularly the optic chiasm, are at particular risk in the irradiation of this region. Because they are sensory nerves, the optic pathways are radiosensitive, and severe visual impairment can be caused by radiotherapy. Damage to the visual pathways is reported in less than 2% of historical series and occurred predominantly in patients using fractionation schemes that are no longer used (Table 3 [53–59]). Fraction size has a large impact on the rate of this complication, being less than an approximately 1% fraction of 2 Gy or less and increasing to approximately 8% fractions of 2 to 2.5 Gy. The interval between radiotherapy and the appearance of these changes may be as long as 4 years and as short as 2 to 3 months. The risk is directly related to the total dose, dose per fraction, and length of the visual pathways irradiated. The most probable explanation is damage to the vasa nervorum. There is a correlation between the preexisting state of the visual pathways and the likelihood of radiation injury in our material [60]. Because prior surgery and tumor compression can cause injury to the vasa nervorum, they may make the optic pathways relatively less tolerant to radiation. Conformal techniques have made damage to the optic chiasm extremely rare. When treated with

Table 3 Series reporting cases of optic neuropathy after fractionated radiation for pituitary adenomas

Series Harris and Levene [53] Aristizabal et al [54] Vlahovitch et al [55] Flickinger et al [56] Zierhut et al [4] Grabenbauer et al [57] Colao et al [58] Breen et al [59]

No. Dose Year cases (Gy)

Dose/ % Optic fraction neuropathy (Gy) (%)

1976 35 42–59

2–2.5

11.43%

1977 52 40–46

2–2.2

1.92%

1988 61 40–50

2–2.5

1.64%

1989 112 47.5–50

2

0.89%

1995 152 40–60

2

0.7%

1996 50 46–63

1.9–2.25 4.00%

1998 59 45

1.8

1998 120 37.6–65.6 1.5–2.5

1.69% 0.83%

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PRASAD

modern techniques with doses of 4500 to 5400 cGy in 180-cGy fractions, optic complications are rare [61]. Radiosurgical results indicate a less than 2% incidence of optic neuropathy below a dose of 8 Gy to the optic pathways [62]. It is usually feasible to respect these dose limitations if a physical distance of approximately 2 mm is available at all points between the tumor and the optic pathways. In summary, there was a significant risk to the optic pathways with the now outdated radiation therapy modalities that may be of only historic significance with the current techniques as long as dose limits are respected. Hypopituitarism The normal pituitary gland and portions of the stalk and hypothalamus are included in the fractionated radiation fields, making hypopituitarism a possible consequence of fractionated pituitary irradiation. Tables 1 and 2 summarize the incidence of hypopituitarism. Zaugg and coworkers [3] report the incidence of hypopituitarism after a combined treatment modality (with currently obsolete radiation techniques) with irradiation between 40 and 45 Gy at 1.8 to 2.25 Gy at 36% (21 of 60 patients). According to Shihadeh and colleagues [5], hypopituitarism was the most common long-term complication, developing in 7 (18.4%) of 38 patients in the radiation-alone group and 29 (29.9%) of 97 patients in the postoperative radiation group (P ¼ .l7). Less clear is the speed of onset of this side effect. Zierhut and coworkers [4] report partial or complete hypopituitarism that developed after radiotherapy, depending on the hormonal axis, in 12% (prolactin) to 27% (follicle-stimulating hormone [FSH]) of patients who had not already had hypopituitarism before radiation. These effects occurred after a latency period of 3 months up to 9 years. By most statistics, the incidence approaches 50% at 5 years for historical radiotherapy. Radiosurgery and modern intensity-modulated radiation therapy (IMRT) cases have not been followed up long enough for good statistics in this regard. In our material, the incidence of postradiosurgery hypopituitarism for one or more hormones approached 30% at 7 years using the Gamma Knife. Cerebrovascular accidents Brada and colleagues [63] report that longterm studies suggest increased mortality independent of tumor control, with cerebrovascular

accidents (CVAs) as the major contributing cause. They analyzed a cohort of 331 United Kingdom residents with pituitary adenoma treated with obsolete radiation techniques at the Royal Marsden Hospital (RMH) between 1962 and 1986. Sixtyfour of 331 patients developed CVAs after primary treatment of pituitary adenoma. The actuarial incidence of CVAs was 4% (95% confidence interval [CI], 2%–7%) at 5 years, 11% (95% CI, 8%– 14%) at 10 years, and 21% (95% CI, 16%–28%) at 20 years measured from the date of radiotherapy. The relative risk of CVAs in these individuals as compared with the general population in the United Kingdom was 4.1. Age was an independent predictive factor for CVAs; however, the relative risk in comparison to the general population was independent of age. The relative risk of developing a CVA was higher in women compared with men, in patients undergoing debulking surgery compared with less radical procedures, and in patients diagnosed and treated in the 1980s compared with previous decades. The dose of radiotherapy was an additional independent prognostic factor on multivariate analysis. No similar data have been reported in the North American literature, and no group has reported results using current IMRT fractionated techniques. There is one report from Germany of vascular complications after FSRT [64] and a single report from Korea of a CVA after GKRS [65]. Pollock and colleagues [28] reported narrowing of the cavernous carotid artery in two cases after GKRS without clinical sequelae. Secondary tumor formation The potential for the induction of a second malignancy exists with any exposure to ionizing radiation. Several authors have extensively addressed this issue in reference to pituitary adenomas [66–68]. The overall risk seems to be hard to assess, but figures around 2.4% at 20 years are described [66]. The latency of solid tumor induction is often long, and 25 to 30 years may elapse before these lesions appear [67]. Although radiationinduced neoplasia often includes sarcomas and meningiomas, gliomas have been reported in the pituitary context [69]. Radiosurgery, by virtue of a larger single dose, may be less likely to create a population of sublethally injured cells that would result in radiation-induced cancer, although this is entirely speculative. Over the entire gamut of Gamma Knife procedures for a variety of benign and

CONFORMAL TREATMENT FOR PITUITARY ADENOMA

malignant indications, a total of 16 cases of secondary neoplasia have been reported. The relatively long follow-up period required to obtain reliable statistics makes far-reaching conclusions impossible, however.

Summary Radiation therapy provides a valuable adjunct to surgery as well as a viable management alternative to surgery for pituitary adenomas. The availability of conformal radiotherapy has dramatically reduced complication rates, and the advent of radiosurgery has reduced the latency of response in these patients. Although extended follow-up is needed to elucidate the long-term outcomes of these treatments, they are likely to be a permanent part of the therapeutic armamentarium for these patients for the near future. References [1] Bergh AV, Berg GV, Schoorl M, et al. Immediate postoperative radiotherapy for residual non-functioning pituitary adenoma: eminent local control without negative impact on pituitary function and overall survival. Proceedings of the American Society for Therapeutic Radiology and Oncology 47th Annual Meeting. Int J Radiat Oncol Biol Phys 2005;63(Suppl 1):S107. [2] Pan L, Zhang N, Wang EM, et al. Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg 2000;93(Suppl 3):10–3. [3] Zaugg M, Adaman O, Pescia R, et al. External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 40–45 Gy. Int J Radiat Oncol Biol Phys 1995;32(3):671–80. [4] Zierhut D, Flentje M, Adolph J, et al. External radiotherapy of pituitary adenomas. Int J Radiat Oncol Biol Phys 1995;33(2):307–14. [5] Sasaki R, Murakami M, Okamoto Y, et al. The efficacy of conventional radiation therapy in the management of pituitary adenoma. Int J Radiat Oncol Biol Phys 2000;47(5):1337–45. [6] Shihadeh ED, Ryu S, Bogart JA, et-al. Outcome of radiation therapy alone and post-operative radiation for non-functioning pituitary adenoma. 41st Annual Meeting of the American Society for Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys 1999;45(3 Suppl. 1):326–7. [7] Rush SC, Kupersmith MJ, Lerch I, et al. Neuroophthalmological assessment of vision before and after radiation therapy alone for pituitary macroadenomas. J Neurosurg 1990;72(4):594–9.

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