Two successive randomized BTSG studies, 69-01 and 72-01 demonstrated superior survival for patients with malignant glioma receiving whole brain RT to 60 Gy in single 1.8 to 2.0 Gy daily fractions with or without BCNU (69-01) or CCNU (72-01) as compared to either drug alone or to supportive care following biopsy or subtotal resection.An evaluation of these trials  suggested that an RT dose response existed to at least 60 Gy, with an increase in median survival time observed from 28 to 42 weeks. A report from the randomized trial BTCG 80-01 demonstrated that at least the final portion of the 60 Gy can be delivered via a "coned-down" field including the primary tumor plus a margin without compromise on outcome.

In RTOG 74-01 no survival difference was observed between the treatment arm using 60 Gy whole brain RT plus a 10 Gy "boost" and the treatment arm using 60 Gy whole brain without a boost. The advent of improved neuroradiologic techniques, especially computed tomography and magnetic resonance imaging, in two RTOG malignant glioma studies (83-02 and 86-12) have replaced whole brain RT with a large partial brain field encompassing the primary tumor and surrounding edema with margin followed by a smaller field to the tumor plus margin. This approach has the advantage of decreasing the volume of neural tissue irradiated and thereby decreasing treatment toxicity, without compromising tumor control. Based on these studies, current standard radiotherapeutic management of malignant gliomas involves delivery of 60 Gy in 1.8 to 2.0 Gy single daily fractions using the shrinking field technique described above. Two reports correlated the location of tumor failure of glioblastoma multiforme with pretreatment tumor and edema volumes and one of these reports observed tumor infiltration within and just beyond the peritumoral edema, confirming the need for adequate radiotherapeutic coverage of this region.
 

Several RTOG and BTSG/BTCG studies have confirmed that the nitrosourea carmustine (BCNU) confers a real but modest survival benefit to the advantage seen with RT alone in at least several patient categories. In BTSG 69-01, patients receiving BCNU + RT had an improved survival rate at 18 months compared to RT alone. While no overall survival difference was observed in RTOG 74-01 between the RT/BCNU arm and RT alone, a survival difference was observed in patients less than 60 years of age in favor of the RT/BCNU arm (median survival: 12.0 vs. 8.7 mo.). Both cooperative groups have studied other systemic agents to improve on the modest benefit seen with BCNU. No further survival advantage was seen with MeCCNU (BTSG 72-01),3 MeCCNU plus dacarbazine,(RTOG 74-01),6methylprednisone (BTSG 75-01),12misonidazole (RTOG 79-18 and BTCG 77-02),13,14 streptozotocin (BTCG 77-02),13,14 and procarbazine, hydroxyurea, and VM-26 (BTCG 80-01). In a Northern California Oncology Group study comparing post-RT BCNU versus procarbazine, CCNU, and Vincristine, (PCV), Levin et al. reported an improved survival among "adequately treated" anaplastic glioma patients treated with PCV over BCNU. This difference was less apparent when all randomized patients with anaplastic gliomas were analyzed and was not present among patients with GBM, the histology seen among 80-85% of patients enrolled on RTOG glioma trials.

Other strategies have included: (1) high dose preirradiation chemotherapy; (2) intra-arterial (IA) chemotherapy; and (3) new systemic agents. The preirradiation chemotherapy regimens have included high dose BCNU with autologous bone marrow transplantation, "eight-drugs-in-one-day" chemotherapy, and infusional BCNU and cisplatin. Despite responses, no improvement in median survival time over conventional therapy has been suggested by these pilot studies. IA chemotherapy offers the theoretical advantage of enhanced drug delivery to the tumor site while minimizing systemic side effects. While Mahaley, et al. reported a 34% response rate among recurrent irradiated gliomas using nonstandard response criteria,20 most investigators, including the Southwest Oncology Group, have reported unacceptable toxicity and lack of improved efficacy for IA versus intravenous chemotherapy.

Angiogenesis and Thalidomide Angiogenesis or vascular proliferation is one of the four major pathologic factors for malignant gliomas. Over-expression of VEGF, bFGF, TGF-a, and PDGF has been identified in malignant astrocytomas, while down regulation of thrombospondin, an angiogenesis inhibitor, and has also been identified. These are apparent mechanisms that malignant gliomas utilize to regulate the degree of neovascularization during malignant progression. Thalidomide is a potentially promising anti-angiogenic agent for the treatment of cancer based on the fact that it is an oral agent with minimal toxicity, thereby, potentially allowing long term, chronic maintenance therapy. A phase II trial of thalidomide was performed in patients with recurrent high-grade astrocytomas. Each patient received thalidomide starting at a dose of 800 mg per day and escalating to a total dose of 1200 mg per day. Although response data is still being compiled, of 32 evaluable patients, at least 4 patients had objective radiographic regressions on MRI scans lasting between 2 and 9 months, and another 12 patients had stabilization of disease for at least 2 months. Thus, it appears that thalidomide does have some biologic activity against gliomas.

New RTOG Trials

RTOG 0211

A PHASE I/II STUDY OF AN ORAL EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR (EGFR-TKI), ZD 1839 (IRESSA), [NSC# 715055] WITH RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME

RTOG BR-0023
A PHASE II TRIAL OF ACCELERATED RADIOTHERAPY USING WEEKLY STEREOTACTIC CONFORMAL BOOSTS FOR SUPRATENTORIAL GLIOBLASTOMA MULTIFORME

RTOG BR-0021
A PHASE II TRIAL OF HIGH DOSE TAMOXIFEN FOR THE TREATMENT OF
NEWLY DIAGNOSED SUPRATENTORIAL GLIOBLASTOMA MULTIFORME (GBM)

RTOG 98-13

A PHASE I/III RANDOMIZED STUDY OF RADIATION THERAPY AND TEMOZOLOMIDE VERSUS RADIATION THERAPY AND BCNU VERSUS RADIATION THERAPY AND TEMOZOLOMIDE AND BCNU FOR ANAPLASTIC ASTROCYTOMA (IND #60,265)

RTOG 93-05
A PHASE III TRIAL COMPARING THE USE OF RADIOSURGERY FOLLOWED BY CONVENTIONAL RADIOTHERAPY WITH BCNU TO CONVENTIONAL RADIOTHERAPY WITH BCNU FOR SUPRATENTORIAL GLIOBLASTOMA MULTIFORME

Arm 1:60 Gy/30 fractions/2 Gy once daily, BCNU 80 mg/m2 i.v. days 1,2,3 of RT then q 8 weeks for a total of 6 cycles.Arm 2: Radiosurgery followed by 60 Gy/ 30 fractions/2 Gy once daily, BCNU 80 mg/m2 i.v. days 1,2,3 of RT then q 8 weeks for a total of 6 cycles Arm 1: For the first 46 Gy/23 fractions, the treatment volume should include the volume of contrast enhancing lesion and surrounding edema on pre-operative CT/MRI scan plus a 2 cm margin. After 46 Gy the tumor volume should include the contrast enhancing lesion (without edema) on the presurgery CT/MRI scan plus a 2.5 cm margin. Arm 2: Radiosurgery dose will be prescribed to the isodose surface (>= 50% to <= 90% of the maximum dose) which encompasses the margin of the tumor. Radiosurgery doses will be tumor size dependent. (See Section 6.2.2.1). Conventional radiotherapy will begin within one week of the date of radiosurgery. BCNU will be given to both arms for a total of 6 cycles (maximum dose = 1440 mg/m2). 

RTOG 96-02
A Phase II Trial of Weekly Paclitaxel and Conventional Radiotherapy for Supratentorial Glioblastoma Multiforme. 60 Gy/30 Fractions/2 Gy once daily Plus Paclitaxel 225 mg/m2/3 hr infustion (to be completed 1-3 hours prior to RT) once a week x 6 weeks
 
RTOG 95-13 PHASE II STUDY OF TOPOTECAN PLUS CRANIAL RADIATION FOR GLIOBLASTOMA MULTIFORME
Topotecan 1.5 mg/m2 per day i.v. given five times per week q3 weeks x maximum 3 courses(unless there is disease progression)Cycle 1: radiation treatment days 1-5 (protocol days 1-5) Cycle 2: radiation treatment days 16-20 (protocol days 22-26) Cycle 3: protocol days 43-47 Radiation Therapy Treatment Volume 60 Gy/30 fractions/6 weeks (2 Gy fractions once a day five days a week) Total RT 60 Gy Initial Field* 46 Gy Boost Field** 14 Gy

RTOG 97-10 A PHASE II STUDY OF CONVENTIONAL RADIATION THERAPY FOLLOWED WITH RECOMBINANT INTERFERON BETA FOR SUPRATENTORIAL GLIOBLASTOMA

60.0 Gy/30 fractions x 2.0 Gy. For the first 46 Gy/23 fractions the treatment volume should include the volume of contrast enhancing lesion and surrounding edema on pre-operative CT/MRI scan plus a 2 centimeter margin. If no edema is present the margin should be 2.5 cm. After 46.0 Gy, the tumor volume should include the contrast enhancing lesion (without edema) on the pre-surgery MRI/CT scan plus a 2.5 centimeter margin.

Beginning 4-6 weeks after completion of radiation therapy, administer recombinant interferon beta (rhIFN-b) 6 million units IM once a day Monday, Wednesday, Friday, three times per week. Three weeks on drug and one week off drug.
 
RTOG 98-03 PHASE I/II RADIATION DOSE ESCALATION STUDY APPLYING CONFORMAL RADIATION THERAPY IN SUPRATENTORIAL GLIOBLASTOMA MULTIFORME

DOSE TO PTV2a,c Level 1 66 Gy ,Level 2 72 Gy ,Level 3 78 Gy Level 4 84 Gy All patients receive BCNUb
 
RTOG 98-06 A PHASE II STUDY OF CONVENTIONAL RADIATION THERAPY FOLLOWED BY THALIDOMIDE FOR SUPRATENTORIAL GLIOBLASTOMA

60.0 Gy/30 FRACTIONS X 2.0 Gy. Thalidomide will be started on the first day of radiation at a dose of 200 mg p.o. daily, at bedtime. The dose will be escalated every one to two weeks by 100-200 mg daily to a maximum dose of 1200 mg p.o. daily. Continue as long as there is no tumor progression or unacceptable toxicity.
 

Cancer 1983 Sep 15;52(6):997-1007

Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study.

Chang. The objective of this study was to evaluate the efficacy after neurosurgery of three new treatment options as compared with control treatment of radiotherapy alone. The four options were: (1) control radiation; 6000 rad/6-7 weeks to whole brain; (2) a higher radiation dose; Control dose plus a booster dose of 1000 rad/1-2 weeks to the tumor; (3) control radiation dose plus BCNU (80 mg/m2/day IV X 3 and repeat BCNU every 8 weeks); (4) Control radiation dose plus combination methyl-CCNU (125 mg/m2/day orally X 1 and repeat methyl-CCNU every 8 weeks), and DTIC (150 mg/m2/day IV X 5 and repeat DTIC every 4 weeks). Patients who were younger than age 40 years had an 18-month survival of 64%, patients who were age 40-60 years had an 18-month survival of 20%, and patients who were older than age 60 had an 18-month survival of 8%. Patients with anaplastic astrocytoma had a median survival of 27 months as compared to 8 months for patients with glioblastoma. In further evaluation of any beneficial effect of chemotherapy, it was identified that only among the 40-60-year-old groups, BCNU treated patients appeared to have significantly increased survival than patients in the control groups. Similarly, methyl-CCNU + DTIC was suggestively better than the control.. The higher radiation dose, 7000 rad/8-9 weeks appeared to give no significantly better survival over the control dose option.

NCI Monogr 1988;(6):279-84

Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group.

Nelson D. The Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a phase III trial in patients with malignant gliomas to evaluate 4 treatment arms: 1) 60 Gy to the whole brain; 2) 60 Gy plus 10-Gy boost; 3) 60 Gy plus carmustine (BCNU); and 4) 60 Gy plus semustine plus dacarbazine. There were no differences in survival among treatment arms. For patients greater than 60 years of age, the addition of chemotherapy to radiation therapy did not improve survival. For patients aged 40-60 years, there was a statistically significant increase in overall survival when BCNU was added to 60 Gy with an increase in 2-year survival from 8% to 23%. long-term survival in patients with astrocytomas with atypical and anaplastic foci who were treated with 60 Gy plus BCNU (5-yr survival, 22%) suggests no significant late CNS toxicity, compared to 60 Gy alone (5-yr survival, 15%).
 

Int J Radiat Oncol Biol Phys 1993 Jan 15;25(2):193-207

Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma--possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302.

Nelson D Initially randomization was to one of three arms: 64.8 Gy, 72.0 Gy, and 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week, with intervals of 4 to 8 hr. All patients received bis-chlorethyl nitrosourea (BCNU) 80 mg/m2 on days 3, 4, 5 of radiation therapy and then every 8 weeks for 1 year. After acceptable rates of acute and late effects were found, the randomization was changed to 81.6 Gy and 72.0 Gy with a weighting of 2:1.  Late radiation toxicity occurred in 1.3-6.8% of the patients, with a modest increase with increasing radiation dose. The best survival occurred in those patients treated with 72 Gy (median survival of 12.8 months overall, and 14 months for the final 72 Gy randomization). The difference in survival between the 81.6 Gy arm and the lower three arms approached significance (p = 0.078) with inferior survival observed in the 81.6 Gy arm. When therapy was evaluated by radiation therapy dose received (60-74.4 Gy compared with 74.5-84.0 Gy), the p value was 0.062 in favor of the lower dose range. Patients with anaplastic astrocytoma treated with 72 Gy by hyperfractionation + BCNU had at least as good a survival as those treated with 60 Gy by conventional fractionation + BCNU on Radiation Therapy Oncology Group protocols 7401 and 7918. This suggests that 72 Gy delivered by 1.2 Gy twice daily is no more toxic than 60 Gy delivered by conventional fractionation.

Cancer 1996 Apr 15;77(8):1535-43

Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02.

Werner-Wasik M. Efforts to improve local control and survival by increasing the dose of once-daily radiation therapy beyond 70 Gray (Gy) for patients with malignant gliomas has yet been unsuccessful. Hyperfractionated radiation therapy (HF) should allow for delivery of a higher total dose without increasing normal tissue late effects, whereas accelerated hyperfractionated radiation therapy (AHF) may minimize tumor repopulation by shortening overall treatment time. randomized to receive partial brain irradiation, utilizing either HF (1.2 Gy twice daily to doses of 64.8, 72, 76.8, or 81.6 Gy) of AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy). All patients received carmustine. The rate of Grade 3 of worse radiation toxicity at 5 years, calculated by the delivered does level, was 3% in the lowest total dose arms (48 and 54.4 Gy), 4% in the intermediate dose arms (64.8 and 72 Gy), and 5% in the highest dose arms (76.8 and 81.6 Gy) (p = 0.54). There were no significant differences between the treatment arms with regard to median survival time (MST), when analyzed by the originally assigned dose. The MST for all patients varied between 10.8 months and 12.7 months (P = 0.59); between 9.6 months and 11 months for patients with GBM (P = 0.43); and between 30.4 months and 85.8 months for patients with AA (P = 0.78). Analysis of the survival rates for all patients by dose received rather than by dose assigned revealed a 14% 5-year survival rate for the lower HF doses (64.8 and 73 Gy), 11% for the higher doses (76.8 and 81.6 Gy), and 10% for the AHF doses (48 and 54.4 Gy) (P = 0.1). The subgroup a AA patients had a better MST (49.9 months) in the lower received HF doses than in the higher HF doses (34.6 months) (P = 0.35). In contrast, GM patients who received the higher HF doses had survival superior to the patients in the AHF arms (MST of 11.6 months and 10.2 months, respectively, P = 0.04). CONCLUSIONS. The use of HF with BCNU and dose escalation up to 81.6 Gy is both feasible and tolerable, although late toxicity increases slightly with increasing dose. The best MST with the least toxicity were observed for AA in the lower received HF doses (72 and 64.8 Gy). Accordingly, 72 Gy in two 1.2 Gy fractions was used as the investigational arm of a completed Phase III trial (RTOG 90-06). In contrast, for GBM patients, longer survival times were noted in the higher received HF doses (78.6 and 81.6 Gy), suggesting the role for further dose escalation. The low toxicity rate with AHF arms suggest that further dose escalation is possible and is currently occurring in RTOG 94-11.