**5. Radiation therapy**

treatment. There are no well-defined management protocols for recurrent GBM. Options for second-line treatment are limited and include repeat surgery, re-irradiation, chemotherapy,

**The standard neuroimaging modality** for the follow-up of GBM is contrast-enhanced MRI, which is performed every 2–3 months while the patient is on therapy. Criteria to assess treatment response and progression have been established by the Response Assessment in Neuro-Oncology (RANO) Working Group [48]. Progression is defined as at least 25% increase in the contrast-enhancing MRI lesion (the product of the maximal cross-sectional enhancing diameters of tumor area). Diagnosing a true progressive tumor growth after chemoradiation by MRI alone remains a challenge, because it is very difficult to distinguish between post-treatment radiation effects (such as pseudoprogression or radiation necrosis) and tumor recurrence. Post-treatment radiation effects can be divided into pseudoprogression and radiation necrosis. Pseudoprogression appears several weeks up to 3 months after RT (5.5–31%), whereas radiation necrosis occurs 3 months to years after irradiation (3–24%) [49]. Radiation necrosis is a space-occupying necrotic lesion, with mass effect and neurological dysfunction. It is irreversible and progressive. Its features on MRI are often identical to that of recurrent GBM. The differentiation is very important, because the management is different. Advanced MRI techniques such as DWI, DTI and PWI provide additional information. Metabolic imaging techniques like PET, single-photon emission computed tomography (SPECT) and MR spectroscopy (MRS) are helpful in differentiating between tumor recurrence and therapy-related changes. Tumor recurrence appears as a lesion metabolically active, while radiation necrosis appears metabolically inactive. However, no imaging modality has sufficient specificity and

novel therapies, supportive care or, better, a combination of these.

20 Brain Tumors - An Update

tissue biopsy remains the gold standard to obtain a definitive diagnosis.

with involvement of eloquent brain regions.

followed by adjuvant therapies.

GBMs typically recur focally and in many cases surgery is possible. **Repeat surgery** is performed in approximately 25% of cases. Although a repeat surgery is associated with a higher complication rates than the initial surgery, this increase is rather small and clearly acceptable [50, 51]. However, its efficacy is debated. Many recent studies reported a survival benefit and an improvement of quality of life resulting from repeat resections in selected patients. Performing an overview of the current literature on second surgery for recurrent GBM, Montemurro et al. found the median overall survival from diagnosis being 18.5 months and the median survival from second surgery being 9.7 months [51]. Extent of resection at reoperation has been demonstrated to improve overall survival, thus a maximum safe excision should be the surgical goal. The decision of a second surgery should be individualized and should involve a multidisciplinary team approach. The age and the preoperative performance status are the most important predictors of a prolonged survival. A more favorable prognosis following surgery for recurrence is associated with a younger age (< 60 years) and a good preoperative performance status (KPS ≥ 70) [51]. Reoperation is not recommended for patients

Thus, patients with recurrent GBM may benefit from resection of tumor whenever safely possible. Repeat surgery can help in providing symptom relief and differentiating tumor recurrence from pseudoprogression, radiation necrosis, respectively. But surgery should be **The SoC for newly diagnosed GBM** consists of maximal safe surgical resection followed by radiotherapy (RT) plus concomitant and adjuvant TMZ.

Following gross-tumor removal, the final histological diagnosis is established, and RT should start. **The optimal time to initiate** radiation is controversial. There are studies showing worse outcomes and even decreased survival when radiation is delayed [52, 53]. Irwin et al. found that a 6 weeks delay (from 2 weeks postoperative to 8 weeks) reduces median survival by 11 weeks for a "typical" patient [52]. But there also studies showing no association between timing of radiation initiation and outcomes [54, 55] and studies suggesting a possible benefit of delay (however, up to a reference range of time) [56, 57]. Blumenthal et al. analyzed the relationship between the delay of RT and the outcome on a large cohort of more than 2800 patients. They observed no obvious reduction in survival with increasing delay (within relatively narrow temporal limits—6 weeks). Indeed, median survival time was unexpectedly greater in the group with the longest interval (>4 weeks) than in those with the shortest delay (≤2 weeks), respectively, 12.5 months versus 9.2 months (P < 0.0001). The authors do not exclude the possibility that an adjuvant treatment initiated beyond 6 weeks postoperatively may be detrimental [56]. In other studies, Han et al. found a narrow range of time (from 30 to 34 days after surgery) where there is prolonged overall survival and prolonged progression-free survival compared with early initiation of concurrent chemoradiation [57, 58]. In common practice, the patient commonly waits about 4 weeks before adjuvant therapies. It is generally agreed that a postoperative delay of 6 weeks may not be critical.

**Concomitant TMZ and RT** (known as the Stupp regimen) have been shown to be more effective than radiation alone with minimal additional toxicity. **After the end of radiation, an adjuvant treatment with TMZ is indicated.** Patients who received RT and concurrent TMZ presented a median survival of 14.6 months versus 12.1 months with RT alone [59]. Furthermore, the two-year survival rate was 26.5% with RT plus TMZ versus 10.4% with RT alone. This is the current SoC for patients with newly diagnosed GBM up to age 70, with a good performance status (Karnofsky Performance Status (KPS) ≥ 60).

RT using three-dimensional conformal beam or intensity-modulated RT is used now. The typical total dose delivered is 60 Gy in 2 Gy fractions, administered 5 days per week for 6 weeks and there is no evidence that higher doses improve outcome [60, 61]. The RT involved fields should include the tumor bed with a 2–3 cm margin, based on the observation that GBM commonly recurs within 2 cm of the original tumor location in 80–90% of cases.

The optimal management of **elderly patients** is controversial. In practice, for patients >70 years old or for patients <70 years old with a poor performance status (KPS < 60), an alternative hypofractionated regimen can be considered. For elderly not suitable for radiation, chemotherapy alone may be an option.

Despite maximal multimodal treatment, GBM invariably recur, disease progression occurring within the first year in about 70% of cases. In selected cases of **recurrences**, a second course of radiation may be possible, but tolerance of local brain tissue to radiation is limited and there is an increased risk of radiation necrosis. This may lead to neurological dysfunction, edema and mass effect. Radiation necrosis is very difficult to distinguish from progressive disease solely by imaging techniques. Histology remains the gold standard for diagnosis. Combs et al. investigated the role of re-irradiation using the fractionated stereotactic approach and demonstrated a median survival of 8 months and a progression-free survival of 5 months for patients with GBM [62].

**For newly diagnosed GBM,** TMZ is typically given following surgical resection, concurrent

during irradiation, followed by a rest period of about 1 month after RT is completed (concur-

for 6 cycles (adjuvant treatment). If tolerated, the dose of the adjuvant treatment can be esca-

some medical centers have attempted to prolong TMZ administration for 12–18 months. Some evidence suggests that long-term therapy with TMZ in selected patients is superior to Stupp

The use of standard or hypofractionated RT plus concomitant and/or adjuvant TMZ has been extended to **elderly** (> 70 years old) with a good performance status (KPS ≥ 60). For patients

At the time of **recurrence**, reoperation should be proposed if the tumor is resectable and if prognostic factors suggest a benefit. Local chemotherapy can be administered during surgery by implantation of Gliadel wafers. Second-line chemotherapy is indicated based on MGMT promoter methylation, time to disease recurrence and toxicity profile. The nitrosourea-based regimen is the preferred choice. Restarting therapy with TMZ may be an option in MGMTmethylated patients. Other agents, such as carboplatin, etoposide, irinotecan may be tried as

**Gliadel wafers** are composed of a biodegradable polymer impregnated with carmustine (BCNU), an alkylating agent of the nitrosourea family. During the surgery, after removal of the tumor, up to 8 wafers (containing a maximum of 61.6 mg BCNU) are deposited along the wall of the resection cavity and left in situ. BCNU will be release over a period of 2–3 weeks, the tumor cells being directly and efficiently exposed to high levels of drug starting immediately after surgery. Gliadel has received FDA (USA) approval for use in both newly diagnosed GBM and recurrences. Studies have consistently reported an increase of median survival by about 2 months [74–76]. Local delivery of carmustine reduces systemic adverse events, but sometimes induces complications: cerebral edema, seizure, poor wound healing, cerebrospinal fluid (CSF) leak, infection, headache, hemiparesis, hydrocephalus, particularly in patients with recurrent GBM. Combining local and systemic chemotherapy offers advantages that may explain the prolonged survival. First, systemic TMZ is most effective in regions of the tumor that are most vascular, whereas local release of BCNU allows direct access to relatively avascular areas of walls of the surgical cavity. Second, following the Stupp protocol, between surgery and chemoradiotherapy there is a period without treatment. Gliadel allows treatment of residual tumor cells within this period. Therefore, the combination of different treatment modalities allows continuous therapy up to 9 months, beginning immediately following surgery [77].

**Optune (formerly NovoTTF-100A) is a device that delivers tumor-treating fields (TTFields)**, meaning low-intensity, intermediate-frequency, alternating electric fields that have

>70 years old with a poor performance status (KPS < 60), TMZ alone can be an option.

daily. This is the well-known Stupp regimen. In common practice,

for 6 weeks

23

daily for 5 days every 4 weeks

Current Trends in Glioblastoma Treatment http://dx.doi.org/10.5772/intechopen.75049

and adjuvant, in addition to RT. It is administered daily at a dose of 75 mg/m2

rent treatment). When restarted, TMZ is dosed at 150 mg/m2

regimen [71–73], but there is no definitive data to prove this.

lated up to 200 mg/m2

single agents or in regimens.

**7. Other therapies**

**Stereotactic radiosurgery** offers the potential of providing a "boost" radiation to a portion of the radiation field in newly diagnosed patients or treating a small recurrence, being an alternative to open surgery [63]. However, its applicability remains very limited in absence of studies which could demonstrate a statistically significant benefit.

**Intracavitary brachytherapy** using the GliaSite system can be used in selected newly diagnosed patients or in recurrent disease, intending to deliver an additional radiation to the surgical cavity wall. It is a medical device, composed of a balloon that will contain a radioactive solution with 125I during the period of irradiation, connected through a catheter to an infusion port. The balloon is placed in the resection cavity during surgery and the radioactive solution is injected later. Re-irradiation of recurrent GBM with GliaSite Radiation Therapy System after resection seems to provide a median survival of approximately 9 months [64, 65].
