**2.1.3 Histological grade**

HGAs are classified as grade III and IV tumors. Various studies suggested the significant effect of histological grade on SRS treatment outcome. Yoshikawa et al reported an effectiveness rate and TCR of 27.2% and 63.3% for GBM respectively at least four weeks after SRS. Nevertheless, they found 18.2% and 45.5% for AA. Another study reported by Kong et al suggested a significant increase in overall median survival rate with SRS for GBM group and no difference in AA group as compared with control group (Kong et al., 2008). These results suggest that SRS may have a potential benefit on grade IV HGA.

#### **2.1.4 Tumor location and extent of surgical resection**

Extent of surgical resection and effective post-operative RT are important prognostic factors for HGA. However, extensive surgical resection is not always possible particularly for tumors located in eloquent areas as optic nerves, brainstem and midbrain. Surgical

Stereotactic Radiosurgery for Gliomas 283

LGA accounts for 15% of all primary CNS tumors in adult (Heppner et al., 2005). However the peak age for LGA is 35; the pilocytic astrocytoma is more frequent in pediatric population. Gross total resection is the golden standard in the treatment of LGA. RT is especially preferred in older patients underwent subtotal resection (Morantz, 2001). Survival rate for LGA is inversely correlated with histologic grade and age. While the 10 year median survival for pilocytic astrocytoma in pediatric age is above 90%, it's about 7% for diffuse astrocytoma patients in sixth decade (Henderson et al. 2009). A brief review of available

studies on effectiveness of SRS for LGA is given below (Table 4).

**Tumor type Med** 

PA (n:37), Grade II (n:12)

PA (n:5), Non-PA (n:5), NHP\* (n:10)

Kano, 2009a 14 Grade I 32.3 4.7 13.3 36.3

Kano, 2009b 50 Grade I 10.5 2.1 14.5 55.5

**age** 

14 (PA), 25 (Grade II)

**Med target volume (ml)** 

2002b 37 Grade I 14 3 15 28 NA 68% Boethius, 2002 19 Grade I 10.6 2.2 10 56.4 NA 94.7%

**Med dose (Gy)**

astrocytoma 25 4.6 15 52 67% for 52 mns NA

II 27 2.4 15 63 44 mns NA

II 20 2.4 14.5 67 65% (10 year) NA

II 17.4 4.4 13 48.2 75% for 48 mns NA

Park, 2011 6 SEGA\*\* 16.5 2.75 14 73 NA 67%

Table 4. Review of available literature on SRS treatment for LGA. *(NHP\*: Not histologically* 

*proven, SEGA\*\*: Subependymal giant cell astrocytoma, NA: Not available, PA: Pilocytic* 

19.1 2.5 12.8 78 NA 80%

89.3%, 31.5% and 31.5% for 1,3 and 5 years

91.7%, 82.8% and 70.8% for 1,5 and 10 years

NA

NA

**Med follow up (mns)**

3.3 15 32 NA 67%

**PFS or PFS rate TCR** 

**First author / Year** 

Hadjipanayis,

Hadyipanayis,

Hadjipanayis,

<sup>2003</sup><sup>49</sup>

Yen, 2007 20

Henderson,

Heppner, 2005 49 Grade I and

Wang, 2006 21 Grade I and

2009 12 Grade I and

*astrocytoma, TCR: Tumor control rate.)* 

**Number of patients**

2002a 12 Fibrillary

approach generally remains limited with biopsy for these locations. While the median survival is only 6 months in HGA patients who underwent biopsy followed by RT and SRS. The survival rises up to 21 months in patients who undergo gross total resection in anytime during the course of disease (Villavicencio et al., 2009). Pouratian et al reported more favorable overall survival rates following SRS in RTOG (Radiation Therapy Oncology Group) Class-III patients (patients who underwent extensive surgical resection and without need for steroids at the time of SRS). Adjuvant treatments like RT and chemotherapy come forward when the surgical resection is not feasible. Different biological structures have different radiation limits. For example, the calculated cumulative radiation maximum point dose limits for lens is 10 Gy, retina 50 Gy and optic nerve, chiasm and brainstem is 55 Gy. Biological equivalents of these limits are lesser for SRS (lens: 1-2 Gy, optic nerve & chiasm: 8-10 Gy and brainstem: 12 Gy) (Sharma et al. 2008). Unfortunately, a cumulative dose of >60 Gy is required for effective irradiation HGA. This requirement let the physicians to combine lower dose RT with SRS to achieve an effective treatment. A median 18 months survival was achieved for GBM patients within eloquent locations with combination of 50 Gy RT, 10 Gy SRS and temazolamide following biopsy (Oermann et al., 2010). Contrarily, no significant difference was observed by means of overall survival rates in another study comparing RT only with RT plus gamma knife following biopsy for unresectable GBMs (Kong et al., 2006). Interestingly, the Karnofsky performance scores (KPS) of RT+SRS group has been found to be significantly higher than the RT only group in first 3 months follow-ups.

#### **2.1.5 Tumor control and functional outcome**

Because the recurrences typically occur within 2-3 cm of the tumor resection bed in 63-90% of the patients, local control of the tumor has a particular importance in the management of HGA. Preliminary results for HGA suggest that SRS increases local tumor control rate, progression free and overall survival, and quality of life (Blomquist et al., 2005; Gerosa et al., 2003). It's shown that the SRS delays neurological deterioration in HGA and provides better KPS during the course of the disease (Jagannathan et al., 2004). Pre-SRS >90 KPS is also associated with better overall survival.

#### **2.1.6 Other aspects of SRS for HGA**

SRS is preferable for patients with progressive or recurrent disease following initial surgical resection and RT if re-resection is not feasible. However, a significant difference has been shown on median survival between patients responsive to initial RT and irresponsive (15.8 vs. 7.3 months, respectively) (Patel et al., 2009). There are not definite evidences for the role of age and gender as prognostic factors.

Current treatment modality for HGA includes surgical resection as extensive as possible, post-operative RT and administration of temazolamide (Sathornsumetee & Rich, 2008). SRS is considerable only for a limited number of patients with particularly WHO grade IV, recurrent, well circumscribed and small lesions as a palliative.

#### **2.2 Low grade astrocytoma**

Low grade astrocytoma (LGA) includes grade I (subependymal giant cell astrocytoma and pilocytic astrocytoma) and grade II (pilomyxoid, diffuse astrocytoma and pleomorphic xanthoastrocytoma) tumors according to WHO classification system (Louis et al., 2007).

approach generally remains limited with biopsy for these locations. While the median survival is only 6 months in HGA patients who underwent biopsy followed by RT and SRS. The survival rises up to 21 months in patients who undergo gross total resection in anytime during the course of disease (Villavicencio et al., 2009). Pouratian et al reported more favorable overall survival rates following SRS in RTOG (Radiation Therapy Oncology Group) Class-III patients (patients who underwent extensive surgical resection and without need for steroids at the time of SRS). Adjuvant treatments like RT and chemotherapy come forward when the surgical resection is not feasible. Different biological structures have different radiation limits. For example, the calculated cumulative radiation maximum point dose limits for lens is 10 Gy, retina 50 Gy and optic nerve, chiasm and brainstem is 55 Gy. Biological equivalents of these limits are lesser for SRS (lens: 1-2 Gy, optic nerve & chiasm: 8-10 Gy and brainstem: 12 Gy) (Sharma et al. 2008). Unfortunately, a cumulative dose of >60 Gy is required for effective irradiation HGA. This requirement let the physicians to combine lower dose RT with SRS to achieve an effective treatment. A median 18 months survival was achieved for GBM patients within eloquent locations with combination of 50 Gy RT, 10 Gy SRS and temazolamide following biopsy (Oermann et al., 2010). Contrarily, no significant difference was observed by means of overall survival rates in another study comparing RT only with RT plus gamma knife following biopsy for unresectable GBMs (Kong et al., 2006). Interestingly, the Karnofsky performance scores (KPS) of RT+SRS group has been found to

be significantly higher than the RT only group in first 3 months follow-ups.

Because the recurrences typically occur within 2-3 cm of the tumor resection bed in 63-90% of the patients, local control of the tumor has a particular importance in the management of HGA. Preliminary results for HGA suggest that SRS increases local tumor control rate, progression free and overall survival, and quality of life (Blomquist et al., 2005; Gerosa et al., 2003). It's shown that the SRS delays neurological deterioration in HGA and provides better KPS during the course of the disease (Jagannathan et al., 2004). Pre-SRS >90 KPS is also

SRS is preferable for patients with progressive or recurrent disease following initial surgical resection and RT if re-resection is not feasible. However, a significant difference has been shown on median survival between patients responsive to initial RT and irresponsive (15.8 vs. 7.3 months, respectively) (Patel et al., 2009). There are not definite evidences for the role

Current treatment modality for HGA includes surgical resection as extensive as possible, post-operative RT and administration of temazolamide (Sathornsumetee & Rich, 2008). SRS is considerable only for a limited number of patients with particularly WHO grade IV,

Low grade astrocytoma (LGA) includes grade I (subependymal giant cell astrocytoma and pilocytic astrocytoma) and grade II (pilomyxoid, diffuse astrocytoma and pleomorphic xanthoastrocytoma) tumors according to WHO classification system (Louis et al., 2007).

**2.1.5 Tumor control and functional outcome** 

associated with better overall survival.

**2.1.6 Other aspects of SRS for HGA** 

of age and gender as prognostic factors.

**2.2 Low grade astrocytoma** 

recurrent, well circumscribed and small lesions as a palliative.

LGA accounts for 15% of all primary CNS tumors in adult (Heppner et al., 2005). However the peak age for LGA is 35; the pilocytic astrocytoma is more frequent in pediatric population. Gross total resection is the golden standard in the treatment of LGA. RT is especially preferred in older patients underwent subtotal resection (Morantz, 2001). Survival rate for LGA is inversely correlated with histologic grade and age. While the 10 year median survival for pilocytic astrocytoma in pediatric age is above 90%, it's about 7% for diffuse astrocytoma patients in sixth decade (Henderson et al. 2009). A brief review of available studies on effectiveness of SRS for LGA is given below (Table 4).


Table 4. Review of available literature on SRS treatment for LGA. *(NHP\*: Not histologically proven, SEGA\*\*: Subependymal giant cell astrocytoma, NA: Not available, PA: Pilocytic astrocytoma, TCR: Tumor control rate.)* 

Stereotactic Radiosurgery for Gliomas 285

3 and 5 year PFS rates were found 75%, 50% and 50% for solid, and 88.9%, 17.8% and 0% for mixed solid-cystic tumors respectively in a study (Kano et al, 2009a). Another study reported 3, 5 and 10 year PFS rates of 100%, 94.4% and 85% for solid, and 53.1%, 21.3% and 0% for mixed solid-cystic tumors respectively (Kano et al., 2009b). Peripheral contrast enhancement and cystic changes on MRI are related with poor prognosis (Park et al., 2010). SRS may also be performed for multicentric LGA, but the prognosis of multicentric tumors

Administration of maximal dose to a minimum volume without damaging normal tissue is one of the major goals of SRS. The probability of direct and indirect surrounding tissue damage due to radionecrosis and edema increases in proportion to the tumor volume and radiation dose. However the SRS dose above 15Gy is known as a good prognostic criterion for LGA, high TCR rate (94.7%) with low dose SRS for PA has also been reported (Boethius et al., 2002). Tumor volume less than 6-8 cc is significantly related with better prognosis (Park et al, 2010). Despite the lack of a definite dose range for LGA, doses ranging between 10-15 Gy are currently used. Dose modification or reduction should be considered for

patients who have undergone fractionated cranial RT before SRS (Wang et al., 2006).

Pilocytic astrocytoma has a better prognosis than grade II astrocytomas. Grade II astrocytoma carries a potential to transform into malignant glioma. Pilocytic astrocytoma also has better prognosis in children than in adults. Median 1, 3 and 5 year PFS rates are 91.7%, 82.8% and 70.8% for pediatric PA; and 83.8%, 31.5% and 31.5 for adult PA respectively (Kano et al., 2009a, 2009b). SRS as an alternate to RT has been found very effective for PA patients in whom the re-resection is not feasible or with early recurrence. But the place of SRS in multimodal treatment of grade II astrocytoma is controversial. 91.3%, 54.1% and 37.1% PFS rates for 1, 5 and 10 years respectively has been reported for radiosurgical treatment of residual or recurrent grade II astrocytomas (Park et al, 2010). More studies are needed for determining definite indications and criteria of SRS for LGA.

> **Good prognosis Poor prognosis**  Pilocytic astrocytoma Grade II astrocytoma

Volume < 6-8 cc Larger volume

Teenagers Age <10 year or >70 year Solitary tumors Multicentric tumors History of long term effective RT History of unsuccessful RT Effective SRS dose Lower SRS dose No contrast enhancement on MRI Peripheral contrast enhancement

Solid, well circumscribed tumors Cystic tumors

is poorer than the solitary tumors (Hadjipanayis et al., 2002a).

Prognostic factors of SRS for LGA are listed below (Table 5).

Table 5. Prognostic factors of SRS for LGA

**2.2.3 Tumor volume and radiation dose** 

**2.2.4 Histological grade and age** 

### **2.2.1 Timing of SRS**

SRS may either be performed alone or as a boost in combination with RT for residual tumor in early post-operative period; or as salvage treatment at the time of recurrence. Whether or not to perform and when to perform is the moot point. Boost SRS concurrent with RT was found to cause more adverse radiation effect in comparison with salvage (adjuvant) SRS (Wang et al., 2006). 10 year median survival rate was found 88.9% for PA patients underwent partially resection or biopsy followed by SRS alone as the principal treatment. The ratio was also found 44.5% for PA patients received delayed SRS for recurrent disease. Delayed SRS for recurrent tumor seems to be associated with poor PFS (Kano et al., 2009b). On the other hand, it doesn't seem so reasonable to make a generalization for timing of SRS because the tumors highly tended to recur already have poor prognosis. Another study reported TCR of 56.3 months for boost SRS versus 44.4% for late SRS. However, this difference was not statistically significant (Park et al., 2010). The beginning of shrinkage following SRS occurs between a median 13-16 months (range; 3-92.4) for LGA (Yen et al., 2007; Kano et al. 2009a & 2009b). In case of progression, the mean time from SRS to the beginning of progression has been found about 23 months (Hadjipanayis et al., 2002a). That's why the patients should be periodically followed-up in a long time period. Despite the lack of large series on effectiveness of repetitive SRS for recurrent LGA; achievement of effective tumor control has been reported for sporadic cases. More studies are needed intended to timing of SRS for LGAs. Available literature suggests better tumor control for residual PA with early SRS.
