RADIATION THERAPY ONCOLOGY GROUP

RTOG 98-02

A PHASE II STUDY OF OBSERVATION IN FAVORABLE LOW-GRADE GLIOMA AND PHASE III STUDY OF RADIATION WITH OR WITHOUT PCV CHEMOTHERAPY IN UNFAVORABLE LOW-GRADE GLIOMA





ECOG (R9802)
Radiation Oncology
Minesh Mehta, M.D.
(608) 263-8500
FAX (608) 263-9167		 Study Chairs
RTOG(98-02)
(Coordinating Group)
Medical Oncology
Mark R. Gilbert, M.D.
(404) 727-3818
FAX (404) 727-3157		 Radiation Oncology Edward G. Shaw, M.D.
Wake Forest University School of Medicine
Medical Center Blvd.
Winston-Salem, NC 27157-1030
(336) 716-4647
FAX (336) 716-5972
NCCTG (R9802)
Radiation Oncology
Paul D. Brown, M.D.
(507) 284-2949
FAX (507) 284-0079 		Medical Oncology Jan C. Buckner, M.D.
(507) 284-4320
FAX (507) 284-1803
Medical Oncology
Jan C. Buckner, M.D.
(507) 284-4320
FAX (507) 284-1803 		Neuro-Oncology Geoffrey R. Barger, M.D.
(313) 577-1242
FAX (313) 745-4216
SWOG(R9802)
Radiation Oncology
Keith J. Stelzer, M.D., Ph.D.
(206) 548-4115
FAX (206) 548-6218		 Neuropathology Stephen W. Coons, M.D.
(602) 406-7088
FAX (602) 406-7169
Medical Oncology
Geoffrey R. Barger, M.D.
(313) 577-1242
FAX (313) 745-4216		 Neuroradiology Peter E. Ricci, M.D.
(303) 788-8734
FAX (303) 788-6546
Neurosurgery Dennis E. Bullard, M.D.
(919) 785-3500
FAX (9190 783-7810
Activation Date: October 31, 1998
Closure Date: June 27, 2002
Version Date: August 18, 2003 (Broadcast: 9/15/03)
Includes Revision 1



This protocol was designed and developed by the Radiation Therapy Oncology Group (RTOG) of the American College of Radiology (ACR). It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by RTOG nor does RTOG assume any responsibility for unauthorized use of this protocol.









Schema
Eligibility Check
1.0 Introduction
2.0 Objectives
3.0 Patient Selection
4.0 Pretreatment Evaluations
5.0 Registration Procedures
6.0 Radiation Therapy
7.0 Drug Therapy
8.0 Surgery
9.0 Other Therapy
10.0 Pathology
11.0 Patient Assessments
12.0 Data Collection
13.0 Statistical Considerations
References
Appendix I-A Sample Consent Form - Observation (Arm 1)
Appendix I-B Sample Consent Form - Treatment (Arms 2 & 3)
Appendix II Karnofsky Performance Status
Appendix III Pathology Checklist
Appendix IV Late Radiation Morbidity Scoring Scheme
Appendix V Adverse Reaction Reporting Guidelines
Appendix VI General Intergroup Guidelines
Appendix VII NCCTG Supply Request Form









RADIATION THERAPY ONCOLOGY GROUP

RTOG 98-02

A PHASE II STUDY OF OBSERVATION IN FAVORABLE LOW-GRADE GLIOMA AND PHASE III STUDY OF RADIATION WITH OR WITHOUT PCV CHEMOTHERAPY IN UNFAVORABLE LOW-GRADE GLIOMA

SCHEMA




*Stratify: (8/18/03) Tumor Subtype (astrocytoma [mixed-astro dominant] or equal (astro/oligo mix) vs. oligodendroglioma [mixed-oligo dominant]); Age (< 40 vs. > 40); KPS (60-80 vs. 90-100); Contrast Enhancement on Pre-Op scan (present vs. absent).

Treatment (must begin within 4 weeks after registration)

a. Radiation - External Beam Radiation Therapy (EBRT)
EBRT: 54 Gy/30 fractions over six weeks, 5 days a week to gross tumor volume defined by a T2 weighted post-op MRI scan (pre-op MRI acceptable if biopsy only) plus a 2 cm margin (tumor edge to block edge. There will be no boost volume.

b. PCV Chemotherapy - Procarbazine/CCNU/Vincristine
Procarbazine 60mg/m2 po, Days 8-21
CCNU 110mg/m2 po, Day 1
Vincristine 1.4mg/m2 iv, Days 8,29 (maximum dose 2 mg)
PCV must start within one month following last day of RT. Repeat PCV at 8 week intervals x 6 cycles

Eligibility (See Section 3.0 for details) [8/18/03]

- Histologic proof of supratentorial WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma confirmed by central pathology review prior to randomization
- Age > 18 years
- KPS > 60
- Neurological Function Status < 3
- Absolute granulocyte count > 1500, platelets within institutional normal range, and serum creatinine < 1.5 x normal (Arms 2/3)
- Total bilirubin and alkaline phosphatase < 2 x normal, transaminases (SGOT [AST] or SGPT) < 4x normal
- Pre- and post-op MRI scans with and without contrast must be available for patients on Arm 1; post-op MRI scans with and without contrast must be available for patients on Arms 2 & 3 (not necessary on biopsy-only patients as long as pre-op MRI is available)
- No chronic lung disease unless DLCO > 60% of predicted
- Signed study-specific consent form

Required Sample Size: 252 (Arms 2 & 3)








RTOG Institution # ___________
RTOG 98-02 ELIGIBILITY CHECK (8/18/03)
RTOG Case # ___________



_______(Y) 1. Does the patient have a histologically proven supratentorial WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma confirmed by central pathology review?

_______(Y) 2. Was the tissue used to make the histologic diagnosis obtained within the last 12 weeks?

_______(Y) 3. Does the patient's laboratory values meet the criteria specified in Section 3.1.5 of the protocol?

_______(Y/N) 4. Were both pre-operative and post-operative MRI scans with and without contrast obtained within 12 weeks of date of surgery? _______(N) 5. Does the tumor location include the optic chiasm, optic nerve(s), pons, medulla, cerebellum, or spinal cord?

_______(N) 6. Is there evidence of spread to spinal meninges or non-contiguous cranial meninges?

_______(Y) 7. Is the patient free of synchronous malignancies, except for in situ carcinoma of the cervix or non-melanomatous skin cancer?

_______(Y/N) 8. Any prior malignancies?
_______(N) 9. Has the patient received any prior radiation to the brain or head/neck or chemotherapy for any reason?

_______(Y/N) 10. Does the patient have any chronic lung disease?
_______(N) 11. Does the patient have an active infectious process?



The following questions will be asked at Study Registration:

_______(Y) 1. Has the Eligibility Checklist (above) been completed?

_______(Y) 2. Is the patient eligible for this study?

______________ 3. Date the study-specific Consent Form was signed? (must be prior to study entry)

______________ Patient's Name

______________ Verifying Physician

______________ Patient ID #

______________ Referring Institution # (if different)

______________ Tumor Subtype (astrocytoma or mixed astro/oligo [astro > oligo component] vs oligodendroglioma or mixed astro/oligo [oligo > astro component]. )

______________ Age (< 40 vs. > 40)

______________ KPS (60-80 vs. 90-100)

______________ Contrast Enhancement on Pre Op Scan (present vs. absent)

______________ Extent of Resection (gross total resection vs. subtotal resection/biopsy)

______________ Medical Oncologist

______________ Birthdate

______________ Sex

______________ Race

______________ Social Security Number

______________ Zip Code (9 digit if available)

______________ Method of Payment

______________ Will any component of the patient’s care be given at a military or VA facility?

______________ Treatment Start Date (must be within 4 weeks after randomization)

______________ Treatment Assignment

Completed by _______________________________ Date ____________________









1.0 INTRODUCTION

1.1 Background

The low-grade gliomas (LGG) are a diverse group of glial tumors found throughout the central nervous system, including sites in the brain and spinal cord. The annual incidence is about 1800 cases. They occur in adults and children. Histologic subtypes of LGG include the diffuse fibrillary astrocytomas (WHO grade II astrocytomas), oligodendrogliomas, mixed oligoastrocytomas, and pilocytic astrocytomas (WHO grade I astrocytomas). Pilocytic astrocytomas usually occur in the cerebellum of children. They are usually well circumscribed, often completely resectable, and associated with a 10-year survival rate of >80% (Hayostek et al.). For the purposes of this protocol, only supratentorial, non-pilocytic LGG in adults will be considered, including WHO grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas (Zulch et al.), which are similar in prognosis to the St. Anne-Mayo grade I-II astrocytomas, oligodendrogliomas, and oligoastrocytomas (Daumas-Duport et al.). Factors influencing survival in these tumors include histologic subtype, age, extent of surgical resection, and radiation therapy.

The table below shows the median survival time and 2-, 5-, 10-, and 15-year survival rates for the various histologic subtypes of supratentorial LGG:

Survival Astrocytomas
 Oligo-Astros Oligodendrogliomas
Median (yr) 4.7 7.1 9.8
2-yr (%) 80 89 93
5-yr (%) 46 63 73
10-yr (%) 17 33 49
15-yr (%) 17 17 49


The differences in survival between astrocytomas, oligoastrocytomas and oligodendrogliomas are statistically significant (Shaw et al.). Age also has a significant impact on survival, as shown in the table below. Age 40, which is the most consistently used age cut-off for better versus worse survival, is also the median age at the time of tissue diagnosis for adults with supratentorial LGG.

Series Age Survival Median (Yrs.)
Eyre et al. < 30 30-49 > 50 Not Reached 5.5 1.6
Medberry et al. < 40 > 40 6.75 1.0
Piepmeier < 40 > 40 8.7 4.9
Shaw et al. < 35.5 > 35.5 6.3 4.2


The majority of series in the literature have identified more aggressive surgical resection as having a statistically significant beneficial effect on survival, as summarized in the table below:

Series Extent of Resection 5-yr Survival Mean Survival
Janny et al. Gross Total Subtotal/Biopsy 88% 57%
North et al. Gross Total Subtotal Biopsy 85% 64% 43%
Philippon et al. Gross Total Subtotal Biopsy 80% 50% 45%
Piepmeier Gross Total Subtotal Biopsy 8.12 yrs 7.08 yrs 5.88 yrs


However, in the series of Shaw et al, and Shibamoto et al, survival was not significantly affected by the extent of surgical resection, with 5-year survival rates of 52-64% for patients undergoing biopsy, subtotal, or gross total resection. Of note, in all the quoted surgical series, the determination of the extent of resection was based on the neurosurgeon's assessment, without the potential benefit of postoperative imaging. In a more recent retrospective study by Berger et al, pre- and postoperative tumor volumes were estimated from magnetic resonance imaging (MRI) scans. Low-grade glioma patients with residual tumor volumes less than 10 cc's had a recurrence rate of 15% (median time to recurrence 50 months), compared to a recurrence rate of 40 % (median time to recurrence 30 months) if the residual tumor volume was greater than 10 cc's.

The most controversial issue in the management of the adult patient with a supratentorial LGG is whether or not to administer immediate versus delayed (until the time of recurrence) radiation therapy. The literature to date, virtually all of which is retrospective, is quite split on the issue, as shown in the table below:

Series Postoperative Radiation 5-yr Survival 10-yr Survival Median Survival
Leighton et al. No (Surgery only) Yes 84% 62% 70% 35% 13 yrs 8 yrs
Philippon et al. No Yes 65% 55%
Piepmeier No Yes 8.76 yrs. 6.45 yrs
Shaw et al. No Yes (< 53 Gy) Yes (> 53 Gy) 32% 47% 68%
Shibamoto et al. No Yes 37% 60%


The difficulty in interpreting the above data is in the unknown bias that determines whether or not a patient receives postoperative radiation. For example, in the series by Leighton et al, patients who did not receive postoperative radiation were significantly more likely to have gross total resection and oligodendroglioma histology, in contrast to those receiving postoperative radiation, who were more likely to have subtotal resection/biopsy and astrocytoma histology. Over a decade ago, when the Brain Tumor Study Group tried to randomize adults with supratentorial LGG to immediate versus delayed postoperative radiation, the study failed due to poor accrual, in part because some physicians didn't want their good prognosis patients to potentially be randomized to receive immediate postoperative radiation, whereas other physicians with poor prognosis patients didn't want the possibility that postoperative radiation might not be given. Another controversial issue regarding radiation therapy is the appropriate dose to give. Despite Shaw et al's observation that doses >53Gy were associated with significantly better survival than doses < 53Gy, a recently published phase III prospective randomized trial from the European Organization for the Research and Treatment of Cancer (EORTC) failed to detect a significant difference in either overall or relapse-free survival between 45Gy/25 fractions and 59.4 Gy/33 fractions in adults with supratentorial LGG (Karim et al.). A similar prospective study was completed in 12/94 by the North Central Cancer Treatment Group (NCCTG), Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG), randomizing between 50.4Gy/28 fractions and 64.8Gy/36 fractions. Until results of this trial become available, the majority of radiation oncologists prefer to treat these patients with total doses in the mid-50Gy range. A recent poll of nearly 100 radiation oncologists showed that the preferred dose was 54Gy/30 fractions, when given the choice between 50.4, 54, 55.8, and 59.4Gy in 1.8Gy fractions (Shaw et al, unpublished data, 5/9/97).

The value of chemotherapy in patients with low-grade glioma has not been clearly demonstrated. Most studies have not reported response to treatment in relationship to tumor grade. There has been one randomized trial assessing the role of adjuvant chemotherapy in adult patients with supratentorial low-grade gliomas. The Southwest Oncology Group (SWOG) randomized 54 patients to either 55 Gy radiation (RT) alone (n-19) or RT plus CCNU (n=35); 1:2 randomization. Median survival was comparable between the two groups (2.8-3.1 years)(Eyre et al.), and was considerably lower than in other series (Shaw et al.).

More recently reported studies suggest a potentially beneficial role of chemotherapy. In a multi-institutional phase II trial, Cairncross et al noted responses in 9 of 10 patients with recurrent oligodendroglioma who had presented initially with low-grade pure oligodendroglioma. Buckner et al reported responses in 5/15 (33%) patients with recurrent low-grade astrocytoma and 2/5 (40%) patients with recurrent low-grade oligoastrocytoma treated on a phase II North Central Cancer Treatment Group (NCCTG) trial with BCNU plus recombinant interferon alpha. In a subsequent NCCTG phase II trial using nitrogen mustard, procarbazine, and vincristine, Buckner et al reported responses in 4/20 (20%) patients with recurrent low-grade glioma. In both NCCTG trials, patients with recurrent low-grade glioma had higher response rates to the investigational regimen than those with any other histologic type, including anaplastic oligodendroglioma. As a group, these studies suggest modest chemosensitivity of recurrent low-grade gliomas.

Less is known about chemoresponsiveness of previously untreated low-grade glioma patients. Mason et al reported a case series of 8 low-grade oligodendroglioma patients treated with procarbazine, CCNU, and vincristine. All responded to treatment with either standard or intensified dosing regimens (Mason et al.). In preliminary data from an ongoing NCCTG phase II trial of chemotherapy ("Intensive" PCV for 6 cycles every 8 weeks) followed by radiation for patients with newly-diagnosed low-grade glioma, Buckner et al have noted responses in 5 of 15 patients who have completed the chemotherapy portion of the trial (unpublished data). Patients with astrocytoma, oligodendroglioma, and oligoastrocytoma have experienced tumor regression. Unfortunately, five patients have developed MRI scan evidence of tumor progression prior to radiation. In one, only necrosis was noted at resection post radiation, so interpretation of progression is problematic. In another patient who progressed, the clinical scenario was consistent with gliomatosis cerebri, distinctively different from most low-grade glioma patients. Two patients developed delayed myelosuppression, requiring initiation of radiation per protocol prior to completion of chemotherapy. At this point, the actual response rate and progression rate remain uncertain. Six out of the twelve planned additional patients have been accrued to the study and remain on chemotherapy. While there is evidence of antitumor activity of PCV in some untreated low-grade glioma patients, the frequency and duration of response are unclear. Nevertheless, preliminary data suggest that these patients are at least as responsive to chemotherapy as high-grade glioma patients in which adjuvant chemotherapy confers modest but reproducible survival benefit, especially in younger patients and those with anaplastic astrocytoma (Nelson et al.). Given the uncertain frequency of tumor progression in patients receiving chemotherapy alone prior to radiation, we propose to administer radiation first, followed by PCV chemotherapy. Most of the efficacy information available to date (Cairncross et al., Buckner et al [unpublished data], and in some patients by Mason et al.) has been obtained using the higher dose schedule of PCV. This schedule is currently the one utilized as adjuvant therapy in RTOG 94-02. However, most investigators who will be participating in the proposed study prefer the lower dose schedule of PCV. For this reason, we would propose using the lower dose schedule for six cycles at eight week intervals to accommodate delayed and cumulative myelosuppression common in all PCV regimens.

Histologic grading systems for gliomas usually have acknowledged the importance of tumor proliferative activity on prognosis. Estimate of proliferation based on mitotic activity is a cornerstone of most grading systems for astrocytomas and oligodendrogliomas. There are two basic methods to evaluate mitotic activity: their presence or absence, or their frequency. The latter is either measured quantitatively or estimated. These approaches have specific advantages and disadvantages but also share common issues. Mitoses are present during only a very limited portion of the cell cycle. As a result, the number of mitoses greatly underestimates the number of cells that are proliferating at any time. This fact may permit accurate comparisons of proliferative activity between tumors and even accurate estimates of overall proliferation. However, it does make mitosis estimates more susceptible to sampling errors, which are more of a problem when the event being measured is relatively rare. The result of these inherent and methodological problems is inconsistent estimates of mitotic activity in tumors with less proliferative activity and fewer mitoses. Unfortunately, this is precisely the situation in low-grade and borderline anaplastic gliomas, and explains why the tumor grade often fails to predict the outcomes of these tumors.

The limitations inherent in estimates of mitotic activity in regard to gliomas have led to interest in other proliferation markers. A number of molecular markers of proliferation have been identified and evaluated to varying degrees. The markers use a variety of approaches to estimate tumor proliferative activity, including nucleotide analog incorporation [3H-thymidine, bromodeoxyuridine (BrdU); antibodies to nuclear proteins expressed during the proliferation Ki-67/MIB-1, proliferating cell nuclear antigen (PCNA)/cyclin, DNA polymerase (, cytometric cell analysis; and probes for in situ hybridization (Histone 3). These molecular markers evaluate different portions of the cell cycle, but all identify a broader range than microscopic identification of mitoses and promise to provide more accurate estimates of cellular proliferation.

Numerous studies involving all of the proliferation markers have shown an association between proliferative activity and patient survival that was significant after accounting for patient age and histological grade. In the first studies that documented the prognostic value of proliferation markers in low-grade tumors, Hoshino et al found BrdU LI prognostic thresholds of 5% in a series of low-grade astrocytomas, and 5% in a series of oligoastrocytomas. However, methodological and financial issues make BrdU unsuitable for general application.

Using flow cytometry, Coons et al found that median patient survival in a series of 232 astrocytomas was 49, 24, and 13 months for SPF of 0-2.9%, 3-5.9%, and > 6%, respectively. Similar results were obtained in a series of 60 oligodendrogliomas. Using the same thresholds, patient survival was significantly different among the three groups. Of particular importance, a similar significance was found when the problematic grade 2 and 3 tumors, which comprise the majority of oligodendroglial tumors, were considered alone. The SPF identified both more aggressive grade 2 tumors and less aggressive grade 3 tumors. Sallinen et al also has documented the prognostic usefulness of flow cytometry SPF measurements in astrocytomas. However, flow cytometry requires expensive equipment and a dedicated operator. Accurate results are dependent on meticulous attention to preparation techniques. Also, relatively large tissue samples are required compared to immunohistochemistry methods.

The most promising of the immunohistochemistry proliferation markers is Ki-67/MIB-1. This marker identifies cells in the proliferative (G1, S, G2-M) phases of the cell cycle, but does not label cells in G0 phase. The newer antibodies work in routinely prepared formalin-fixed paraffin-embedded tissue, and interpretation is less problematic than with PCNA, where non-cycling cells are sometimes stained. Using Ki-67/MIB-1 immunohistochemistry, Montine et al analyzed 36 astrocytomas and found an association between LI and patient survival. When only grade 2 tumors were considered, a LI>3% identified a group of more aggressive tumors. Ellison et al analyzed 123 astrocytomas, including 24 well differentiated astrocytomas and found that patients whose tumors had MIB-1 LI<2 had better survival. Coons et al evaluated the relationship between the MIB-1 and survival in a series of 96 low-grade32 and anaplastic64 astrocytomas. Patient survival was highly associated with the LI for all tumors. LI<1, LI=1-4, and LI>4 classified the tumors into prognostic groups with median survival of 1122, 603, and 199 days, respectively. Survival within each group was also associated with the LI. For the LGA, the same thresholds were identified, with median survivals or 1485, 688, and 404 days.

Due to their relative rarity, the evaluation of oligodendroglial tumors lagged behind that of astrocytomas. However, three recent series suggest that Ki-67/MIB-1 LI may be more useful in oligodendrogliomas. Heegaard et al analyzed 32 oligodendrogliomas and found an association between patient survival and the LI as a continuous variable. Kros analyzed 108 oligodendrogliomas. A multivariate analysis confirmed the prognostic usefulness of the MIB-1 LI, taking into account patient age at diagnosis and histologic grade. Three prognostic groups were found, with L1<10, 10-20, and >20. In a series of 81 oligodendrogliomas and oligoastrocytomas, Coons et al also demonstrated independent prognostic significance of the Ki-67/MIB-1 LI. Tumors with LI<5% and >5% were associated with significantly different patient survival. The median survival of the high proliferation group was 452 days, whereas the median survival was at least 1718 days in the group with LI<5%. The LI more accurately predicted survival among grade 2 and 3 tumors than the grade itself. As a whole, the median survival of grade 2 tumors was 1420 days. The grade 2 tumors with LI>5 had a significantly different median survival of 612 days, which corresponded closely to the survival of grade 3 tumors as a whole (575.5 days). Similarly, the four grade 3 tumors with LI<5 had survivals closer to those of grade 2 tumors.

Taken together, these data suggest that measurement of proliferative activity can identify a subset of low-grade glioma tumors that behave like anaplastic tumors. However, the prognostic usefulness of proliferation markers has never been evaluated in a prospective clinical trial. It is important that such a study be done at a single site where the methods will be consistent, as proposed in this study. Sallinen et al showed that antibody clone, immunohistochemistry method, and even the counterstain affect the LI. Other factors, including counting method, also affect the LI. These issues are reflected in the differences in LI thresholds in the retrospective studies that found proliferation markers to be prognostically significant. Flow cytometry measurements are even more subject to problems with inter-institutional reproducibility.

For contemporary CNS clinical trials in the RTOG, quality of life (QOL) is assessed by a combination of tools including Karnofsky Performance Status (KPS)(Appendix II), Neurologic Function Status (NFS)(Appendix II) and the Mini-Mental Status Exam.

1.2 Rationale for Study Design

In this study, we propose to divide adult patients with supratentorial LGG (astrocytoma, oligodendroglioma, or oligoastrocytoma) into two risk groups, based on the known prognostic factors of age and extent of surgical resection, and treat accordingly. Patients who are < 40 years old and who undergo gross total resection of their tumor will be categorized as low-risk. Patients who are > 40 years old or who undergo subtotal resection or biopsy will be categorized as high-risk. Low-risk patients will be observed as part of a phase II study, whereas high-risk patients will be randomized between localized external beam radiation therapy, 54Gy/30 fractions, alone or followed by 6 cycles of Procarbazine/CCNU/Vincristine (PCV) chemotherapy. As with prior and ongoing RTOG studies in LGG and non-GBM malignant glioma, central pathology review will be required. Both paraffin embedded tissue and peripheral blood will be collected for future molecular genetic, molecular epidemiological, and other correlative studies.


2.0 OBJECTIVES

2.1 To identify the overall (and relapse-free) survival of low-risk adult patients with supratentorial LGG (<40 years old who undergo gross total resection of a WHO grade II astrocytoma, oligodendroglioma, or mixed oligoastrocytoma) who are observed postoperatively.

2.2 To compare the overall (and relapse-free) survival of high-risk adult patients with supratentorial LGG (> 40 years old regardless of the degree of surgical resection, or age > 18 who undergo subtotal resection or biopsy, of a WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma) who receive postoperative external beam radiation therapy with or without PCV chemotherapy.

2.3 To compare the severe or worse toxicities (> grade 3) of unfavorable patients receiving postoperative radiation therapy alone or radiation therapy plus PCV chemotherapy.

2.4 To compare the neurosurgeon's assessment of gross total resection with that of a postoperative MRI scan interpreted by a neuroradiologist.

2.5 To collect and store archival, paraffin embedded tissue and peripheral blood samples for concomitant and future correlative studies which will be funded by other mechanisms.


3.0 PATIENT SELECTION (8/18/03)

3.1 Eligibility Criteria

3.1.1 Histologic proof of a unifocal or multifocal supratentorial WHO grade II astrocytoma (diffuse fibrillary, protoplasmic, or gemistocytic), oligodendroglioma, or oligoastrocytoma. Patients with prior suspected or proven LGG are eligible provided they now have a histologically proven eligible histology. Patients with neurofibromatosis are eligible. Stereotactic biopsies are permitted providing the tissue sample is adequate to make an unequivocal histologic diagnosis. For all patients, tissue must be obtained no more than 12 weeks before the date of registration or randomization.

3.1.2 Age > 18 years.

3.1.3 KPS > 60.

3.1.4 Neurologic Function Score (NFS) < 3.

3.1.5 For high risk patients (Arm 2 and 3): 3.1.6 Pre-operative and post-operative MRI scans with and without contrast obtained within 12 weeks of date of surgery are required for patients on Arm 1

3.1.7 Post-operative MRI scans with and without contrast must be available for patients on Arms 2 & 3 ( not necessary on biopsy-only patients as long as pre-op MRI is available) obtained within 12 weeks of date of surgery. Post-op CT scans are not acceptable.

3.1.8 Signed study-specific informed consent prior to study entry.

3.2 Ineligibility Criteria

3.2.1 Other LGG histologies including pilocytic astrocytoma, subependymal giant cell astrocytoma of tuberous sclerosis, subependymoma, pleomorphic xanthoastrocytoma, presence of a neuronal element such as ganglioglioma, or DNET (dysneuroembryoplastic epithelial tumor). Presence of any high grade glioma including anaplastic astrocytoma, glioblastoma multiforme, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma.

3.2.2 Tumors in non-supratentorial or other locations including optic chiasm, optic nerve(s), pons, medulla, cerebellum, or spinal cord.

3.2.3 Evidence of spread to spinal meninges or non-contiguous cranial meninges (i.e., leptomeningeal gliomatosis) based on a MRI scan of the spine or positive CSF cytology. MRI of the spine/CSF cytology are not required in patients without symptoms of spinal/cranial meningeal spread.

3.2.4 Gliomatosis cerebri.

3.2.5 Synchronous malignancy excluding in situ carcinoma of the cervix or non-melanomatous skin cancer; prior malignancy unless disease free > 5 years.

3.2.6 Prior radiation to the brain or head/neck (unless head/neck radiation clearly excluded the brain, e.g., radiation for localized vocal cord cancer).

3.2.7 Prior chemotherapy.

3.2.8 Chronic lung disease unless pulmonary function tests demonstrate a DLCO > 60% of predicted.

3.2.9 Active infectious process.

3.2.10 Pregnant or nursing women because of the potentially adverse effects of treatment on the developing fetus or newborn.

3.9.11 For premenopausal women or men of reproductive potential, inability or unwillingness to consider effective contraception until the completion of therapy.


4.0 PRETREATMENT EVALUATION [8/18/03] (all tests and imaging studies must be obtained within 2 weeks prior to registration)

4.1.1 Central pathology review (Section 10.0) is mandatory prior to randomization to confirm eligibility.

4.1.2 History and physical exam (including neurologic exam) with documentation of baseline signs, symptoms, and medications including steroids and anticonvulsants.

4.1.3 Assessment including KPS, NFS, Mini Mental Status Exam (MMSE).

4.1.4 Laboratory Tests (for High Risk Patients)

4.1.4.1 Hematology: hemoglobin, WBC with differential (AGC), and platelet count.

4.1.4.2 Biochemistry: sodium, potassium, creatinine, total bilirubin, glucose, SGOT (AST), SGPT, and alkaline phosphatase.

4.1.5 Imaging Studies:

4.1.5.1 Chest X-ray

4.1.5.2 Pre-op MRI with and without contrast

4.1.5.3 Post-op MRI scan with and without contrast. Post-op CT scan not acceptable. The MRI must include T1 weighted images with and without contrast, and T2 weighted images. Patients who undergo biopsy only do not need a post-op MRI.

4.1.6 Pulmonary

4.1.6.1 Pulmonary function tests including DLCO if patient has an abnormal CXR or a history of or active chronic lung disease.

4.1.7 For premenopausal women of childbearing potential: pregnancy test.

4.1.8 Risk Group Determination
5.0 REGISTRATION PROCEDURES

5.1 Central pathology review (see Section 10.0) must be completed prior to randomization.

Registration must take place within 12 weeks after tissue diagnosis.

5.2 RTOG Institutions

Patients can be registered only after pretreatment evaluation is completed and eligibility criteria are met. Patients are registered prior to any protocol therapy by calling RTOG headquarters at (215) 574-3191, Monday through Friday 8:30 am to 5:00 pm ET. The patient will be registered to a treatment arm and a case number will be assigned and confirmed by mail. The following information must be provided:

5.3 ECOG Institutions

5.3.1 A signed HHS 310 Form, a copy of the institution's IRB-approved informed consent document, and written justification for any changes made to the informed consent for this protocol must be on file at the ECOG Coordinating Center before an ECOG institution may enter patients. These will be submitted to: ECOG Coordinating Center, Frontier Science, Attn: IRB, 303 Boylston Street, Brookline, MA 02445-7648. Patient must not start protocol treatment prior to registration. Treatment must begin within four weeks after randomization. See Section 10.0 for pre-randomization pathology requirements.

5.3.2 To register eligible patients on study, the investigator will telephone the Randomization Desk at the ECOG Coordinating Center at (617) 632-2022 Monday-Friday between the hours of 9:00 am and 4:30 pm ET, to allow time to call RTOG that same day. ECOG members should not call RTOG directly. The following information will be requested: Protocol Number; Investigator Identification (including institution and/or affiliate name and investigator's name); Patient identification (including patient's name or initials and chart number, patient's social security number, patient demographics [sex, birth date, race, nine-digit zip code and method of payment]); Treatment start date; Pathology block number(s) for diagnostic primary tumor; Eligibility Verification. Patients must meet all of the eligibility requirements listed in Section 3.0. The randomization specialist will verify eligibility by asking questions from the checklist and will also verify IRB approval. The ECOG Randomization Desk will contact RTOG to enter the patient, after which the ECOG Coordinating Center will contact the institution to relay the treatment assignment for that patient.

5.3.3 RTOG will send a Confirmation of Registration and a Forms Due Calendar to ECOG for each case registered. ECOG will forward copies to the participating institution.

5.3.4 If a patient does not receive any protocol therapy, written notification and an explanation must be received at ECOG Headquarters (who will route it to RTOG) as soon as this has been determined. The Onstudy Form (I1) and Eligibility Checklist should also be submitted. RTOG will notify ECOG if the patient may be canceled. Once a patient has been given protocol treatment, all forms must be submitted.

5.3.5 On a case-by-case basis, patients entered through ECOG institutions may decline to participate in the Quality of Life component of the study.

5.3.6 Additional Intergroup information is in Appendix VI.

5.4 SWOG Institutions

5.4.1 Investigators will call the Southwest Oncology Group Statistical Center at (206) 667-4623 between the hours of 6:30 a.m. and 1:30 p.m. (PT) Monday through Friday, excluding holidays. This must be done in order for the Southwest Oncology Group Statistical Center to complete the registration with RTOG prior to the close of business. The Statistical Center will obtain information as per Section 5.2, RTOG Registration. In addition, the Statistical Center will request the date informed consent was obtained and the date of IRB approval for each entry. The Statistical Center will then contact RTOG to register the patient after which the Statistical Center will contact the institution to confirm registration and relay the treatment assignment and case number for that patient. RTOG will forward a confirmation of treatment assignment to the Statistical Center for routing to the participating institution.

5.4.2 Patients must be registered prior to the initiation of treatment (no more than 4 weeks prior to the planned start of treatment). The information listed on the RTOG Eligibility Checklist must be completed as well as the SWOG Registration Form. The caller must also be prepared to provide the date of Institutional Review Board approval for this study. Patients will not be registered if the IRB date is not provided or is > 1 year prior to the registration date.

5.5 NCCTG Institutions

A signed HHS 310 form is to be on file at the NCCTG Randomization Center before patient entry.

To register a patient, call the NCCTG Randomization Center (507) 284-4130 8 a.m. to 3 p.m. (CT) Monday through Friday. The NCCTG Randomization Center will verify eligibility by completing the eligibility checklist and will call the RTOG Headquarters at (215) 574-3191, Monday through Friday 8 a.m. to 3 p.m. (CT) to register a patient. NCCTG will also verify that both a radiation oncologist and a medical oncologist have consulted with the patient and verified that the patient is a suitable candidate for this study. The treatment assignment and case number will be relayed to the registering institution. RTOG will send a Confirmation of Registration and a Forms Due Calendar to NCCTG who will forward this information to the participating institution.


6.0 RADIATION THERAPY

6.1 General Requirements 6.2 Treatment Volumes

The target volume is based on the T2 weighted images from the postoperative MRI scan (the preoperative MRI scan can be used in patients who underwent biopsy only) and will include any T2 abnormality suspected of containing tumor plus a 2 cm margin (to block edge). If the tumor has been completely resected, the target volume will be the surgical defect and any T2 abnormality surrounding the surgical defect plus a 2 cm margin (to block edge). There will be no boost volume. The margin may be reduced to a 1 cm margin (to block edge) around critical structures (See Section 6.4) and/or natural barriers to tumor growth (e.g. skull and tentorium).

6.3 Dose, Schedule, Dosimetry, and Compliance Criteria

Treatment will be given in 1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week and must begin within four weeks after randomization. The total dose will be 54 Gy in 30 fractions over approximately 6 weeks. The target volume must receive 95-105% of the prescribed total dose to be per protocol (encompassed by the 51.3 to 56.7 Gy isodose line).

If the target volume receives 90-94% or 106-110% of the prescribed total dose, an acceptable variation will be assigned.

If the target volume receives < 90% or >110% of the prescribed total dose, an unacceptable deviation will be assigned.

Other variances from protocol radiotherapy will be assigned as follows:
< 5% variation from protocol specifications-per protocol;
6-10% - acceptable variation;
>10% - unacceptable deviation.

The isodose distribution in the transverse (axial) plane through the geometric center of the target volume must be submitted to RTOG for review.

6.4 Critical Structures

Every attempt should be made to shield the globes (including lenses and retinae) from any direct radiation beams. A portion of one globe may receive < 10 Gy. The pituitary gland, optic chiasm, or brainstem (medulla, pons, midbrain) may not receive > 105% (56.7 Gy) of the prescribed total dose of 54 Gy. Uninvolved contralateral normal brain may not receive > 36 Gy.

6.5 Radiation Toxicity

Radiation toxicity will be scored using the NCI Revised Common Toxicity Criteria Version 2.0 (3/98) for toxicities appearing < 90 days after RT start and the RTOG/EORTC Late Radiation Morbidity Scoring Criteria (Appendix IV) for toxicities appearing or persisting > 90 days after start of RT. Potential acute toxicities include: skin, eye, ear and CNS. Potential late toxicities include skin, subcutaneous tissue, brain, and eye.


7.0 DRUG THERAPY

Institutional participation in chemotherapy studies must be in accordance with the Medical Oncology Quality Control guidelines stated in the RTOG Procedures Manual. All chemotherapy toxicities will be scored using the revised NCI Common Toxicity Criteria, Version 2.

7.1 Procarbazine Hydrochloride (P)

Procarbazine is an orally administered lipid soluble hydrazine-derivative. It freely crosses the blood-brain barrier. While its mode of action is not fully understood, procarbazine appears to inhibit both protein and nucleic acid synthesis. It is used to treat Hodgkin's disease, brain tumors and other cancers. Procarbazine is manufactured by Roche and available commercially in 50 mg capsules. Its major toxicities include myelosuppression, both leukopenia and thrombocytopenia, anorexia, nausea, vomiting, diarrhea, stomatitis, and allergic reactions (rarely anaphylaxis). Procarbazine produces mild monoamine oxidase inhibition necessitating a low tyramine diet. It may cause transient CNS side effects such as personality change, confusion, or somnolence and can evoke a disulfiram-like reaction. Food and beverages to avoid include alcohol, yogurt, ripe cheese, and bananas. Over-the-counter cold medications should be avoided. Since procarbazine may inhibit monoamine oxidase, a thorough review of concurrent medications for potential drug interactions should be undertaken prior to initiating procarbazine. Continued vigilance for drug interactions is necessary with the addition of medications during procarbazine therapy. Caution patients not to take any new medications (including over-the-counter medications) without consulting a physician or pharmacist during procarbazine therapy. Use of meperidine should be considered contraindicated during or within two weeks following procarbazine therapy.

7.2 Lomustine (CCNU)(C)

CCNU is an orally administered lipid soluble nitrosourea. It freely crosses the blood-brain barrier. CCNU exerts cytotoxic effects by alkylating DNA and RNA. It is used primarily to treat brain tumors. CCNU is manufactured by Bristol and available commercially in 100, 40 and 10 mg capsules. Its major toxicities include delayed myelosuppression, both leukopenia and thrombocytopenia, nausea and vomiting. Pulmonary fibrosis may occur at higher cumulative doses (>1100 mg/m2). Hepatotoxicity and nephrotoxicity are uncommon side effects.

7.3 Vincristine (V)

Vincristine is a parenterally administered naturally occurring water soluble antineoplastic. It does not cross the blood-brain barrier. Vincristine is a mitotic spindle poison and arrests dividing cells in metaphase. It is used to treat a variety of hematologic and solid-tissue malignancies. Vincristine is manufactured by Eli Lilly and available commercially in 1, 2 and 5 mg vials. Its major toxicities include sensorimotor and autonomic neuropathy. Myelosuppression is rare. Fatal if given intrathecally; for intravenous use only. Syringes containing the product should be labeled "Warning- for IV Use Only". Extemporaneous prepared syringes containing Vincristine must be packaged in an overwrap labeled "Do Not Remove Covering Until Moment of Injection. Fatal if Given Intrathecally. For Intravenous Use Only"

7.4 Treatment Prescription

7.4.1 PCV Regimen

Patients assigned to the chemotherapy arm will receive six cycles of PCV at eight week intervals. PCV must start within one calendar month following the last day of radiation therapy. Procarbazine, CCNU and Vincristine will be prescribed as follows:

DRUG DOSE ROUTE SCHEDULE
Procarbazine
CCNU
Vincristine		 60 mg/m2
110 mg/m2
1.4 mg/m2*		 p.o.
p.o.
i.v.		 Days 8- 21
Day 1
Days 8,29

* Maximum dose 2 mg

Each cycle will last 8 weeks, i.e., will be defined as the period of therapy as outlined above plus 4 weeks.

7.4.2 Dose Calculations

Doses will be calculated using actual body weight. CCNU doses will be rounded to the nearest 10 mg (e.g. 242 give 240 mg., 245 or 248 give 250 mg). The total number of procarbazine capsules to be administered on days 8 through 21 will be calculated as follows: (60 x surface area in m2 x 14) ¸ 50 rounded to the nearest whole number (e.g. 39.2 give 39 tabs, 39.5 or 39.8 give 40 tabs). To minimize nausea and vomiting, procarbazine may be introduced gradually as follows: e.g., 50 mg po day 8, 100 mg po day 9 and following. Vincristine doses will be rounded to the nearest tenth of a milligram up to 2.0 mg. There will be a 2 mg limit on each dose of vincristine.

7.4.3 Dose Modifications

Patients will have a complete blood count on a weekly basis while receiving PCV. There will be no dose escalations. Doses will be reduced for hematologic and other toxicities and scored using the NCI Common Toxicity Criteria. All dose reductions will be maintained in subsequent treatment cycles.

7.4.3.1 Hematologic Toxicity

The doses of CCNU and Procarbazine will be reduced based on nadir blood counts of the previous cycle as follows:

Absolute Granulocyte (nadir)   Platelet Count (nadir) Dose Next Cycle CCNU & Procarbazine
> 0.5 x 109/L
(> 500)		 and > 50 x 109/L
(> 50,000)		 No change
< 0.5 x 109/L
(< 500)		 or < 50 x 109/L
(< 50,000)		 Reduce previous cycle's dose by 25%
Vincristine dose will not be reduced for low treatment-day blood counts. Vincristine will be given days 8 and 29 of each cycle.

7.4.3.2 Neurotoxicity

Vincristine will be stopped for grade 3 or grade 4 neurosensory or neuromotor toxicity. CCNU and procarbazine continue as per protocol. For severe abdominal or jaw pain, reduce vincristine dose by 50% on all subsequent doses.

7.4.3.3 Nausea/Vomiting

If grade 3 or grade 4 nausea or vomiting persist despite antiemetics, the doses of CCNU and procarbazine may be reduced as described for "other toxicity" in Section 7.4.3.7.

7.4.3.4 Skin Toxicity

Procarbazine will be discontinued should an urticarial rash develop from PCV. Note: a generalized erythematous rash may be a manifestation of Dilantin, Tegretol, or other drug allergy. Procarbazine may be continued or stopped at the discretion of the investigator for non-urticarial rashes. CCNU and vincristine will continue per protocol.

7.4.3.5 Pulmonary Toxicity

CCNU will be stopped if cough, shortness of breath, or other pulmonary symptoms develop and if the DLCO is < 60% of predicted. Procarbazine and vincristine will continue per protocol.

7.4.3.6 Hepatic Toxicity

Hold all drugs for SGOT (AST) or SGPT >3x normal and resume with 25% dose reduction when SGOT or SGPT is < 2x normal.

7.4.3.7 Other Toxicity

Doses will be reduced by 25% for grade 3 toxicity, and 50% for grade 4 toxicity. PCV may be discontinued for any grade 4 toxicity (see Section 7.4.5) but only after discussion with the medical oncology study co-chair.

7.4.4 Treatment Delays

Doses of vincristine will not be delayed for hematologic toxicity on days 8 or 29. Cycles 2 through 6 will be delayed for low treatment day counts as outlined below:

Absolute Granulocyte Count (at retreatment)   Platelet Count(at retreatment) Dose This Cycle CCNU & Procarbazine
> 1.5 x 109/L
(> 1500)		 and > 100 x 109/L
(> 100,000)		 Proceed - dose dictated by nadir counts
< 1.5 x 109/L
(< 1500)		 or < 100 x 109/L
(< 100,000)		 Delay treatment until hematologic recovery


7.4.5 Duration of Treatment

Toxicity permitting, there will be 6 cycles of PCV. PCV will be discontinued for: Note: if the scan is unchanged, the investigator should be careful to exclude causes of clinical deterioration that mimic tumor progression such as radiation effects, anticonvulsant or other drug toxicity, occult infection, pulmonary embolism with hypoxemia, precipitous steroid withdrawal, intratumoral hemorrhage, etc.

7.4.6 Antiemetics

Antiemetics may be prescribed as required but steroids may not be used as antiemetics. It is strongly recommended that patients receive either granisetron or ondansetron orally as prophylaxis for CCNU and at least the first 3 days of procarbazine (e.g., granisetron 1 mg po or ondansetron 8 mg po TID beginning 1 hour before chemotherapy).

7.5 Toxicity Reporting/RTOG Members

7.5.1 The revised NCI Common Toxicity Criteria Version 2.0 (3/98) will be used to score chemotherapy and acute radiation (( 90 days) toxicities. The following guidelines for reporting adverse drug reactions (ADRs) apply to any research protocol that uses commercial anticancer agents. The following ADRs experienced by patients accrued to these protocols and attributed to the commercial agent(s) should be reported to the Investigational Drug Branch, Cancer Therapy Evaluation Program, within 10 working days.

7.5.1.1 Any ADR which is both serious (life threatening, fatal) and unexpected.

7.5.1.2 Any increased incidence of a known ADR which has been reported in the package insert or the literature.

7.5.1.3 Any death on study if clearly related to the commercial agent(s).

7.5.1.4 Acute myeloid leukemia (AML). The report must include the time from original diagnosis to development of AML, characterization such as FAB subtype, cytogenetics, etc. and protocol identification.

7.5.2 The ADR report should be documented on Form FDA 3500 (Appendix V) and mailed to:

Investigational Drug Branch
P.O. Box 30012
Bethesda, Maryland 20824
(301) 230-2330
available 24 hours
FAX (301) 230-0159

7.6 Adverse Drug Reaction Reporting Requirements/ECOG Members

This study will utilize the CTC version 2.0 for toxicity and Adverse Event reporting. A copy of the CTC version 2.0 should be available at your institution. It can be downloaded from the CTEP home page. All appropriate treatment areas should have access to a copy of the CTC version 2.0.

7.6.1 The following adverse reactions must be reported to ECOG, the NCI, and your local IRB in the manner described below:

  Grades 4-5 unexpected1 Death due to RX or within 30 days of RX2
ECOG ADR Form to NCI within 10 days X  
ECOG ADR Form to ECOG Coordinating Center within 10 days X X
Notify local IRB within 10 days X X

1. Any unexpected toxicity not reported in the literature or the package insert must be reported.

2. Any death from any cause while a patient is receiving treatment on this protocol or up to 30 days after the protocol treatment has ended but which is felt to be treatment related, must be reported.

ECOG suggests ADRs be reported to on the Adverse Reaction (ADR) Form for Investigational Drugs (Form 391RF). The form must be signed by the treating investigator.

7.6.2 Reporting of All Second Primary Cancers

  NCI/CTEP
Secondary AML/MDS Report Form 1		 ECOG Second
Primary Form2
(Form #630)
AML/MDS X  
All other secondary cancers   X
1. To be completed within 30 days of diagnosis of AML/MDS that has occurred during or after protocol treatment. A copy is to be sent to ECOG and to the NCI, accompanied by copies of the pathology report (and when available, a copy of the cytogenetic report).

2. To be submitted to ECOG within 30 days of diagnosis of a new primary cancer during or after protocol treatment, regardless of relationship to protocol treatment. Not for use for reporting recurrence or metastatic disease. A copy of pathology report should be sent, if available.

7.6.3 The ECOG Coordinating Center will call the RTOG Operations Office to report the telephone ADR calls. The ADR forms will be forwarded to the RTOG Operations Office by the ECOG Coordinating Center.

NCI Telephone Number: (301) 230-2330
NCI FAX: (301) 230-0159
NCI Mailing Address
IDB
P.O. Box 30012
Bethesda, MD 20824 		ECOG Telephone Number: (617) 632-3610
ECOG FAX: (617) 632-2990
ECOG Mailing Address:
ECOG Coordinating Center
ATTN: ADR
Frontier Science
303 Boylston Street
Brookline, MA 02445-7648
7.6.3 Non-Treatment Related Toxicities

Toxicites which fall within the definitions listed above must be reported as an ADR/second primary regardless if they are felt to be treatment or not. Toxicities unrelated to treatment that do NOT fall within the definitions above, must simply be clearly documented on the Data Forms which is submitted to the ECOG Coordinating Center (ATTN: DATA) according to the Data Collection Section (Section 12.0).

7.7 Adverse Drug Reaction Reporting/SWOG Members

7.7.1 All Southwest Oncology Group (SWOG) investigators are responsible for reporting of adverse drug reactions according to the NCI and Southwest Oncology Group Guidelines. SWOG investigators must:

  • Call the SWOG Operations Office 210/677-8808 within 24 hours of any suspected adverse event deemed either drug-related, or possibly drug-related. Instructions will be given as to the necessary steps to take depending on whether the reaction was previously reported, the grade (severity) of the reaction, study phase, and whether the reaction was caused by investigational and/or commercial agent(s). The SWOG Operations Office will immediately notify the RTOG Headquarters Data Management Staff as listed in the RTOG reporting guidelines.

  • Within 10 days the investigator must send the completed (original) Adverse Reaction Form (ADR) for Investigational agents (#391RF) or FDA 3500 form (for regimens using only commercial agents) to the NCI:

    Investigational Drug Branch
    P.O. Box 30012
    Bethesda, Maryland 20824

  • In addition, within 10 days the investigator must send:
    - a copy of the above report,
    - all data records for the period covering prestudy through the adverse event, and
    - documentation of IRB notification to the following address:

    ADR Program
    SWOG Operations Office
    14980 Omicron Drive
    San Antonio, TX 78245-3217

    7.8 Adverse Drug Reaction Reporting/NCCTG Members

    7.8.1 Fax, then report in writing to NCCTG Operations Office (no telephone calls necessary) within five working days:

    1. Any ADR that is both serious and unexpected: life threatening (grade 4) or fatal (grade 5).
    2. Any increased incidence of a known ADR that has been reported in the package insert or the literature.
    3. Any death on study, if clearly related to the commercial agent(s).

    7.8.2 The ADR report must be documented on the ADR form (Form FDA 3500) and the original mailed to:

    North Central Cancer Treatment Group
    Operations Office
    200 First Street, SW
    Rochester, MN 55905

    7.8.3 The NCCTG Operations Office will immediately forward a copy of the ADR form to RTOG and IDB if deemed a reportable ADR.


    8.0 SURGERY

    8.1 Definitions of Extent of Surgical Resection

    8.1.1 Gross Total Resection (GTR) - removal of all grossly abnormal tumor tissue as defined by the neurosurgeon. Patients <40 years old who underwent GTR will be registered to Arm 1, and will be observed with close follow-up. Patients > 40 years old who underwent GTR will be randomized to either Arm 2 or 3, and will undergo radiation therapy +/- PCV chemotherapy.

    8.1.2 Subtotal Resection (STR) - removal of less than all grossly abnormal tumor tissue as defined by the neurosurgeon. All patients who underwent STR, regardless of age will be randomized to either Arm 2 or Arm 3, and will undergo radiation therapy +/- PCV chemotherapy.

    8.1.3 Biopsy Only- removal of a tissue specimen for the purpose of making a histologic diagnosis. May be performed stereotactically or via craniotomy. All patients who undergo biopsy only, regardless of age, will be randomized to either Arm 2 or Arm 3, and will undergo radiation therapy +/- PCV chemotherapy.

    8.2 Postoperative Imaging

    8.2.1 At the discretion of the clinician entering a patient to Arm 1 of this trial, if postoperative imaging strongly suggests the presence of significant residual tumor, the patient may be randomized to either Arm 2 or Arm 3 (radiation therapy +/-PCV chemotherapy). For the purpose of stratification, such patients will still be considered to have undergone GTR.


    9.0 OTHER THERAPY

    9.1 Steroid Use

    Steroids may be used as required to control CNS symptoms due to tumor-associated or RT-associated cerebral edema, but wherever possible, should be tapered and stopped. Steroid doses at study entry and at specific time points after treatment (see Sections 11.0 and 12.0) will be recorded. Investigators should avoid radical changes in steroid dose during periods critical for response evaluation so as not to complicate the assessment of response to PCV in the experimental arm.

    9.2 Anticonvulsant Use

    Anticonvulsants may be used as clinically indicated. Doses at study entry and at specific time points of the treatment must be recorded.


    10.0 PATHOLOGY

    10.1 Prerandomization Central Pathology Review for all Groups (8/18/03)

    10.1.1 Central pathology review is mandatory prior to study entry to confirm eligibility. It should be initiated as soon as a tissue diagnosis has been made. Central pathology review will be performed by Dr. Stephen Coons. Pathology materials must be sent directly to Dr. Coons (Section 10.1.3).

    10.1.2 To be eligible for this study, the patient's tumor must be a WHO grade II astrocytoma, oligodendroglioma, or oligoastrocytoma. The tumor may have atypia but not other histologic features such as mitoses, endothelial proliferation, and/or necrosis that would result in a designation of anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, or GBM. Low grade glioma variants, such as pilocytic astrocytoma, subependymal giant cell astrocytoma of tuberous sclerosis, subependymoma, pleomorphic xanthoastrocytoma, ganglioglioma, or DNET (dysneuroembryoplastic epithelial tumor) are not eligible.

    All pathology materials sent to Dr. Coons for central review must be accompanied by the "local" pathology report and a Pathology Checklist completed by the local pathologist.

    10.1.3 The following materials will be sent by overnight mail to Dr. Coons:
    - Pathology Checklist (Appendix III) completed by the local pathologist (left side only)
    - PreRandomization Pathology Submission Form (available from RTOG HQ)
    - Representative slides (H&E sections).
    - In the lower left hand corner of the address label or mailing envelope, write: "LOW GRADE GLIOMA PROTOCOL".
    - Name, phone and fax number of person to whom the results of the central pathology review should be transmitted. Notify Dr. Coons' office by phone or fax that a case is coming for review. Send to:

    Stephen W. Coons, M.D.
    Division of Neuropathology
    Barrow Neurologic Institute
    St. Joseph Hospital and Medical Center
    350 W. Thomas Rd.
    Phoenix, AZ 85013-4496
    Phone (602) 406-7088
    Fax (602) 406-7169


    10.1.4 After the pathology materials have been reviewed, Dr. Coon's office will call the institution notifying them of whether or not the case is eligible. This will be confirmed by fax.

    10.1.5 If the patient enters the study, the patient's RTOG case number will be added to the Pathology Checklist and a copy of the completed form will be sent to RTOG. Representative H&E slides will be retained by Dr. Coons. The remaining materials will be returned to the submitting institution (or Group, for intergroup cases.

    10.1.6 If the patient does not enter the study, all slides and forms will be returned to the submitting institution.

    10.1.7 ECOG Institutions: Please follow RTOG guidelines.

    10.2 Peripheral Blood Samples (8/18/03)

    10.2.1 Following confirmation of eligibility, the institution entering the patient will be required to send six tubes of peripheral blood. A specimen mailing kit will be sent to the institution by Mayo Medical Laboratories, Rochester, MN with specific instructions on how to properly return the blood samples. Blood should not be drawn until the mailing kit is received. Do not ship blood samples without the special mailing kit.

    10.2.2 Submission of Blood Samples

    Following confirmation of eligibility, the institution entering the patient will send six tubes of peripheral blood, 5 cc each, four in EDTA vacutainer tubes, and two in Heparin vacutainer tubes; the blood is to be received within 48 hours of collection. The registering institution will need to notify Mayo Medical Laboratories of the RTOG case number; this number must appear on all labels. If you have any questions regarding specimen collection, processing, and/or courier arrangements, contact Darla Schletty (Mayo Medical Laboratories) at 1-800-826-5561.

    Kits will be supplied through Mayo Medical Laboratories (MML). Participating institutions may obtain kits by submitting the attached FAX Supply Request Form (Appendix VII) to Darla Schletty (fax: 507/266-0188) who will then federal express the kit to you. Do not ship blood samples until the kit has been received.

    The appropriate type and number of collection tubes and a three-part MML requisition form will be contained within each specimen collection kit. The RTOG case number must appear on the requisition form adjacent to the RTOG protocol number and on all specimen labels.

    The pink copy of the form is for submitting institution’s records, the remaining two copies of the form are to be returned with the specimens to MML. MML will forward one copy to the Operations Office of the appropriate Cooperative Group, upon receipt of the specimen.

    If a site has a Mayo courier, use this courier to send in the specimens. If not, ship Federal Express according to the following instructions.

    10.2.3 Shipment of Peripheral Blood by Federal Express (for sites without Mayo courier)

    Federal Express may be either your primary courier service or backup to your regular courier service. However, shipments by Federal Express may be made at any time your regular courier service is unavailable.

    10.2.3.1 Specimens must be completely packaged in shipping containers prior to Federal Express pickup. NOTE: Freeze and store cold packs in the freezer, not on dry ice. Dry ice freezes the cold packs at a temperature that may cause samples to freeze more readily. Place the frozen cold pack in the bottom of the Styrofoam® container. Place a paper towel between the cold pack and the sample(s) to minimize the risk of freezing.

    Between November 15 and March 15, use a refrigerated cold pack rather than a frozen cold pack if you are located North of the Mason-Dixon line. This will help to prevent the specimens from freezing during the Winter.

    10.2.3.2 Call Federal Express at 1-800-238-5355 by noon for same-day service. Provide the following information: 10.2.3.3 Assist the Federal Express courier in finding the shipping box(es), if requested.

    Please contact Mayo Laboratory Inquiry at 1-800-826-5561 if you have questions regarding these arrangements.

    10.3 RTOG Tumor Bank (for RTOG, ECOG, and SWOG Institutions)

    10.3.1 Patients entered on this study should participate in the RTOG Tissue Bank.

    10.3.2 The following must be provided:

    10.3.2.1 One paraffin block of tumor or 15 unstained slides (on "plus" coated slides). Block/slides must be clearly labeled with the pathology identification number that agrees with the pathology report.

    10.3.2.2 Pathology report documenting that submitted block or slides contain tumor.

    10.3.2.3 A Pathology Submission Form must be included and must clearly state that it is being submitted for the RTOG Tissue Bank.

    10.3.3 RTOG will reimburse pathologists from submitting institutions $100 per case if proper materials are submitted (reimbursement is handled through an invoice submitted to RTOG Administration, ATT: Path Reimbursement).

    10.3.4 Patient consent form should give the Pathology Department authority and responsibility to comply with this request (pathology blocks belong to the patient from whom tissue has been removed).

    10.3.5 Materials will be sent to:

    LDS Hospital
    Department of Pathology
    E.M. Laboratory
    8th Avenue and C Street
    Salt Lake City, UT 84143
    (801) 321-1314
    FAX (801) 321-5020


    10.3.6 ECOG Institutions

    One paraffin block of tumor or 15 unstained slides along with the completed ECOG Pathology Material Submission Form #638 and the institutional pathology report, should be submitted to the ECOG Pathology Coordinating Office (PCO). A copy of the completed submission form will be sent to the ECOG Study Chair and to the ECOG Coordinating Center by the Pathology Coordinating Office. The submitting pathologist should be informed that the blocks will not be returned unless requested. The blocks or slides and form should be sent to: ECOG Pathology Coordinating Office, Evanston Hospital Room B634, 2650 Ridge Avenue, Evanston, IL 60201-1797. The PCO will retain this material until requested by RTOG.

    10.4 NCCTG Institutions

    Per Section 10.1, central pathology review is mandatory prior to study entry and patient's tumor must meet the requirements as stipulated in Section 10.2. Central pathology review (representative slides only) will be performed by Dr. Stephen Coons.

    10.4.1 NCCTG Submission of Representative Slides

    Prior to study entry, confirmation of eligibility must be verified by submission of materials, listed below, overnight mail, to Dr. Coons at the address noted in Section 10.1.3. It should be initiated as soon as the diagnosis has been made.

    - Pathology Checklist (Appendix III) completed by the local pathologist (left side only)
    - PreRandomization Pathology Submission Form
    - Representative slides (H&E sections)
    - In the lower left hand corner of the address label or mailing envelope, write "LOW GRADE GLIOMA PROTOCOL".
    - Name, phone, and fax number of a person to whom the results of the central pathology review should be transmitted. Notify Dr. Coons' office by phone or fax that a case is coming for review.

    10.4.2 NCCTG Submission of Paraffin Blocks

    Within 30 days of registration, inform the submitting pathology department that the paraffin blocks will be forwarded to the NCCTG Operations Office where they will be catalogued and retained for future laboratory correlative studies. If there is an insufficient amount of tissue available, a letter from the pathologist stating such must be submitted to the NCCTG Operations Office. Submit the paraffin blocks, operative and pathology reports to:

    NCCTG Operations Office
    200 First Street, SW
    Rochester, MN 55905
    Attention: Pathology Coordinator

    Each block should be placed in individual plastic bags and each bag labeled with the NCCTG membership name, study patient number, patient's initials, protocol number, surgical accession number and source (e.g., tumor location), pathology and operative reports.


    11.0 PATIENT ASSESSMENTS

    11.1 Study Parameters - Arm 1 (Observation) [8/18/03]

    Parameter On-Study q 4 mos x 1 yr q 6 mos x 2 yrs q year
    Central Path Review (pre randomization) X      
    Clinical Assessment, incl. KPS & NFS X X X X
    Record Steroid & Anticonvulsant Doses X X X X
    MRI without and with Contrast Xa,b X X X
    Mini-Mental Status Exam X X X X


    11.2 Study Parameters - Arm 2 (Radiation Alone) [8/18/03]

    Parameter On-Study At Completion of RT q 4 mos x 1 yr q 6 mos x 2 yrs q year
    Central Path Review (pre randomization) X        
    Clinical Assessment, incl. KPS & NFS X X X X X
    Record Steroid and Anticonvulsant Doses X X X X X
    Hematology: Hgb, WBC, diff, AGC, plts X        
    Biochemistry: Na, K, creatinine, SGOT (AST), SGPT, alk phos., total Bili, glucose X        
    MRI without and with Contrast Xb   X X X
    Chest X-ray Xc        
    Pulmonary Functionsd X        
    Pregnancy Teste X        
    Mini-Mental Status Exam X X X X X
    Toxicity Evaluation   X X X X


    11.3 Study Parameters - Arm 3 (Radiation + PCV) [8/18/03]

    Parameter On-Study At end of RT Pre-cycles
    1-6    		 Pre-cycles 3&5 4 mos after end of last cycle of chemo q 6 mos x 2 yrs q year
    Central Path Review (pre randomization) X            
    Clinical Assessment incl KPS & NFS X X X   X X X
    Record Steroid & Anticonvulsant Doses X X X   X X X
    Hematology: Hgb, WBC, diff, AGC, plts X   X (and weekly during PCV)   X X X
    Biochemistry: Na, K, creatinine, SGOT (AST), SGPT, alk phos., total Bili, glucose X   X   Xc Xc Xc
    MRI without and with Contrast Xb     X X X X
    Chest X-ray Xc            
    Pulmonary Functionsd X       Xd    
    Pregnancy Teste X            
    Mini-Mental Status Exam X X   X X X X
    Toxicity Evaluation   X X X X X X

    Key and Footnotes to Sections 11.1, 11.2, and 11.3:

    KPS = Karnofsky Performance Status (Appendix II), NFS = Neurologic Function Score (Appendix II), AGC = Absolute Granulocyte Count, RT = Radiation Therapy

    a. (8/18/03) Pre-op imaging study, suggested MRI technique: MRI should include the following: pre-contrast sagittal T1, axial T1 without and with contrast, axial T2 (fast spin echo preferred, spin echo acceptable), coronal T1 post-contrast. Axial slice thickness should be 5 mm/skip 2.5 mm with 22 cm field of view, parallel to the AC/PC line. Sagittal slice thickness should be 6 mm/skip 33 mm with a 24 cm field of view. Coronal slice thickness should be 5 mm/skip 2 mm with a 22 cm field of view, perpendicular to the AC/PC line.

    b. (8/18/03) Post-op and follow-up imaging studies: MRI with and without contrast (patients who had biopsy only do not need post-op MRI if pre-op MRI with and without contrast was performed).

    c. As clinically indicated thereafter.

    d. (8/18/03) Pulmonary function testing including DLCO is only needed at baseline in patients with an abnormal CXR or those symptoms suggesting CCNU toxicity, such as unexplained cough or dyspnea.

    e. A pregnancy test is required for women of child-bearing potential.

    11.4 Survival

    Patients will be followed until death. The cause of death will be recorded for each patient and if possible the histologic type and extent of tumor reassessed at autopsy. Survival time will be the interval between the date of registration/randomization and the date of death.

    11.5 Time to Progression

    Patients will be followed clinically and radiologically as outlined in Sections, 11.1-11.3. The date at which the tumor is documented to have progressed (see Section 11.6) will be considered the date of tumor progression. Time to progression will be the interval between the date of registration/randomization and the date of tumor progression. Tumor progression will be confirmed by central review. In the event of a discrepancy and for the purposes of analysis, the treating physician's date of tumor progression will be deemed to be correct. Tissue confirmation of suspected tumor progression is encouraged. For patients suspected of having tumor progression in whom tissue confirmation is not possible, MRI spectroscopy, Thallium SPECT, or PET scanning is strongly recommended.

    11.6 Response Assessment

    11.6.1 The majority of supratentorial non-pilocytic low-grade astrocytomas, oligodendrogliomas, or oligoastrocytomas are non-enhancing on a MRI scan. Therefore, two sets of response data will be collected, one set for tumors that have an enhancing component and the second for tumors that are non-enhancing.

    11.6.2 Responses will be confirmed by central review. For the purposes of classifying response, post-operative change, surgical defects, and areas of calcification will be ignored; tumor size will be the maximum cross-sectional area of the enhancing tumor on axial or coronal images. For tumors whose shape precludes maximum cross-sectional area measurement, the TR rather than PR response criterion should be used (see below). For patients who are deemed responders (CR, PR, or TR), response must be sustained on their consecutive imaging studies.

    11.6.3 Response Criteria for Tumors with an Enhancing Component

    Complete response (CR) - disappearance of all enhancing tumor on consecutive enhancing T1 MRI images on stable , decreasing, or no steroids, with a stable or improved KPS/NFS.

    Partial response (PR) - 50% or greater decrease in enhancing tumor cross-sectional area on consecutive enhancing T1 MRI images on stable, decreasing, or no steroids, with a stable or improved KPS/NFS.

    Tumor regression (TR) - A substantial (~ 50% or greater) decrease in enhancing tumor cross-sectional area on consecutive enhancing T1 MRI images on stable, decreasing, or no steroids, with a stable or improved KPS/NFS.

    11.6.4 Response Criteria for Tumors without an Enhancing Component

    Complete response (CR) - disappearance of all tumor on consecutive T2 MRI images on stable, decreasing, or no steroids, with a stable KPS/NFS.

    Partial response (PR) - 50% or greater decrease in tumor cross-sectional area on consecutive T2 MRI images on stable, decreasing, or no steroids, with a stable KPS/NFS.

    Tumor regression (TR) - A substantial decrease (~ 50% or greater) in tumor cross-sectional area on consecutive T2 MRI images on stable, decreasing, or no steroids, with a stable KPS/NFS.

    11.6.5 Definition of Stable Disease

    Stable disease (SD) - all situations other than those outlined in Sections 11.6.2, 11.6.3, 11.6.4, and 11.6.6.

    11.6.6 Definition of Tumor Progression

    For all patients, tumor progression will be defined as follows:

    Progressive disease (PD) - 25% or greater increase in the cross-sectional area of enhancing or non-enhancing tumor on consecutive MRI scans, or any new area(s) of tumor. Under exceptional circumstances, disease progression may be declared in the absence of an increase in tumor size based on "clinical deterioration" including the need for increasing doses of steroid and/or a worsening KPS/NF.

    11.7 Toxicity Evaluation

    11.7.1 Acute Toxic Reactions

    Patients randomized to post-RT PCV chemotherapy will have a complete blood count on a weekly basis while receiving PCV and a screening biochemical evaluation prior to each cycle of PCV (see Section 11.3). Other tests such as CXR and pulmonary functions will be performed as necessary to assess pulmonary (and other) toxicity due to chemotherapy. All unexpected radiation reactions will be reported.

    11.7.2 Mental Status Evaluation

    All patients will be given the Mini Mental Status Examination prior to the start of protocol treatment, at the end of protocol treatment, and subsequently in followup.

    11.7.3 Other Toxicities

    All second malignancies, myelodysplastic syndromes, infections, neuromuscular disorders, dementias and other illnesses probably or possibly related to PCV or RT will be reported.

    11.8 Documentation of Progression

    Every attempt should be made to pathologically document tumor progression (biopsy or resection). When this is not possible, an attempt should be made to obtain a physiological imaging study such as MRI spectroscopy, a PET scan, or a Thallium SPECT scan.

    11.9 Treatment at Progression

    Treatment(s) at the time of progression will be at the discretion of the treating physician(s). The treatment(s) given should be recorded. Patients will be followed until death following documented progression.

    11.10 Central Film Review (8/18/03)

    Pre-op MRI scans and post-op/follow-up MRI scans will be reviewed on all patients who have responded, progressed (Section 11.6), died, or experienced a grade 3, 4, or 5 neurotoxicity.


    12.0 DATA COLLECTION

    12.1 Summary of Data Submission
    (RTOG, 1101 Market Street, Philadelphia, PA 19107, FAX#215/928-0153)

    Item Due
    Demographic Form (A5)
    Pathology Checklist (P4)
    (copy, original to reviewer)
    Specimen Transmittal Form (ST)
    (copy, original to reviewer)
    Initial Evaluation Form (I1)
    Pathology Report (P1)
    Pathology Slides/Blocks (P2)
    Initial Mini-Mental Status Evaluation (MS)
    Pre-op MRI and post-op MRI scans (C1)
    and reports (C3)
    		 Within 2 weeks of study entry
    Radiotherapy Form (T1)
    Complete treatment record (T5)
    Isodose Curves (T6) (see Section 6.3 for details)
    		 Within 2 weeks of RT end (Arms 2 & 3)
    Follow-up MRI scans (C2) and reports (C3)
    		 At 4 months post RT
    Chemotherapy Flowsheet (M1) At the end of each cycle and 3 months after day 29 of last cycle
    Initial Followup-Form (FS)
    Mini-Mental Status Evaluation (MS)
    		 At end of RT and at 90 days from the start of RT (Arms 2 and 3)
    Follow-up MRI scans (C2) and reports (C3) At regression, progression, and at > grade 3 neurotoxicity
    Follow-up Form (F1)
    Mini-Mental Status Evaluation (MS)
    		 q 4 mo x 1 yr, q 6 mo x 2 yr then annually. Also at progression /relapse and death (F1 only).
    Autopsy Report (D3) As applicable


    12.2 Dosimetry and Film Submission

    12.2.1 Items will be sent directly to RTOG Headquarters by all Groups.

    12.2.2 MRI scans and reports must be submitted on all patients who respond, progress, die, or experience grade > 3 neurotoxicity. These must be submitted to RTOG within 2 weeks of scan date.

    12.3 ECOG, SWOG AND NCCTG DATA SUBMISSION

    12.3.1 ECOG: The original data forms as listed in Section 12.1 should be submitted to the ECOG Coordinating Center 303 Boylston Street, Brookline, MA 02445-7648 (ATTN: DATA). Include the RTOG and ECOG study and case numbers. The ECOG Coordinating Center will forward the forms to RTOG. Do not use ECOG Forms for this study, with the exception of the Adverse Reaction (ADR) form (Form #391RF), the ECOG Second Primary Form (Form #630), the NCI/CTEP Secondary AML/MDS Report Form and the ECOG Pathology Materials Submission Form (Form #638).

    12.3.2 SWOG: The original data forms as listed in this section should be submitted at the required intervals to the Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, MP-557, Seattle, WA 98104-2092. Include the RTOG protocol number and patient case number as well as the Southwest Oncology Group study number and patient number. It is not necessary to submit extra copies.

    12.3.3 NCCTG: All forms listed in Section 12.1 are to be submitted to the NCCTG Operations Office, 200 First Street SW, Rochester, MN 55905. NCCTG will forward to RTOG.

    12.3.4 Both the ECOG, NCCTG, or SWOG and RTOG assigned case and study numbers must be recorded on all items submitted. Unidentified data will be returned.

    12.3.5 Request for Study Information and Forms Request:

    Requests for additional information or clarification of data will be routed through ECOG/NCCTG/SWOG for distribution to the individual institution. The RTOG memo requesting the additional information must be returned with the response. Responses should be returned according to the procedure used to submit data forms. You may receive reminders prompting response. Periodically (generally three times per year) computer generated lists identifying delinquent material are prepared and are routed through ECOG/NCCTG/SWOG for distribution.


    13.0 STATISTICAL CONSIDERATIONS

    13.1 Study Endpoints

    13.1.1 The primary endpoint of this trial is overall survival. Progression will also be examined.

    13.1.2 The frequency and severity of toxicities will be examined.

    13.1.3 Estimate overall survival and progression of low risk-patients when no adjuvant therapy is delivered.

    13.1.4 Assess the agreement between neurosurgeon's and the central neuroradiologist's assessment of tumor resection.

    13.2 Sample Size

    The primary endpoint of this trial is survival. The standard arm is radiotherapy (RT) and the experimental arm is RT followed by PCV. Low-grade glioma patients classified as high-risk have an estimated five year survival of 70%. High-risk patients are defined as patients over age 40 or undergoing less than a gross total resection. This trial will test for a 21% improvement in five-year survival. The RT +PCV arm is expected to have an estimated 85% five-year survival rate.

    The estimated sample size is 120 patients per arm. This sample size will ensure a 90% probability of detecting the specified improvement, if it exists, while rejecting the null hypothesis at the 95% level (a=0.05, two-sided type I error). This sample size is designed to test a difference between survival using a modified Wilcoxon statistic. The sample size of 240 patients is the maximum accrual assuming three interim analyses and an expected 80 deaths overall. Assuming a 5% ineligibility rate, the total sample size required for Arms 2 and 3 is 252 patients.

    The grade 3 or worse toxicity from standard radiation therapy is expected to be 5% or less. A sample size of 126 patients per arm will provide at least 90% power to test a 19% or greater rate of grade 3 or worse toxicity on the RT + PCV arm. This assumes a two-sided statistical test. It is expected that 50 low risk patients will be accrued which will permit survival to be estimated within 8-11% error.

    Assessing the agreement between the neurosurgeon's and the central neuroradiologist's assessments of resection will be performed using the kappa statistic. Assuming that 25% of the patients receive complete resection, a 0.05 level two-sided test that the intraclass kappa is 0.50 will have at least 89% statistical power to detect an alternative kappa of 0.70 when the sample size is 252.

    13.3 Patient Accrual

    The patient accrual is projected to be 4 patients per month. This trial should complete the accrual phase in 5 years. If the monthly accrual is less than 2 cases per month, the study will be re-evaluated with respect to feasibility.

    13.4 Randomization Scheme

    The randomization of high-risk patients will be stratified by tumor histologic subtype (astrocytoma [mixed-astro dominant] vs. oligodendroglioma [mixed-oligo dominant]); age (< 40 vs. > 40); KPS (60-80 vs. 90-100); and balance by accruing institution.

    13.5 Other Stratification Factors

    Contrast enhancement on pre-op scan: present vs. absent.

    13.6 Analysis Plans

    13.6.1 Interim Analyses of Accrual and Toxicity Data

    Interim reports with statistical analyses will be prepared every six months until the initial paper reporting the treatment results have been submitted. In general, the interim reports will contain information about:

    a) the patient accrual rate with projected completion date for the accrual phase;
    b) the distribution of patients with respect to pretreatment characteristics including race and gender;
    c) compliance rate of treatment delivery with respect to the protocol prescription;
    d) the frequency and severity of the toxicities.

    13.6.2 Interim Analyses of Study Endpoints

    There will be three interim analyses of the primary study endpoint (survival). The interim analyses will proceed according to the following table:

    Total Number of Deaths Null Hypothesis Alternative
    20 0.00004 0.86
    40 0.0026 0.336
    60 0.011 0.0942


    If a significance level is smaller than the values listed for the null hypothesis then the null hypothesis will be rejected. On the other hand, if a significance level is larger than the values listed for the alternative then the alternative will be rejected. These significance levels were calculated to ensure an overall significance level of 0.05. The results of these interim analyses will only be reported, in a blinded fashion to the Data Monitoring Committee. A report with recommendations will be given to the study chairman. Any problems or recommendations identified by the data monitoring committee, not results, will be reported to the brain committee, which is responsible for this study and, if necessary, the RTOG executive committee, so that corrective action can be taken.

    13.6.3 Analysis and Reporting of Initial Treatment Results

    This major analysis will be undertaken when every patient has been potentially followed for a minimum of five years or a maximum of 80 deaths have occurred. The usual components of this analysis are:

    1) Tabulation of all cases entered and any excluded from the analysis with the reasons for such exclusions;

    2) reporting institutional accrual;

    3) distribution of the important prognostic factors by assigned treatment;

    4) observed results with respect to the study endpoints.

    Further subgroup analyses may be conducted (depending upon the sizes within the subgroups) for the purpose of identifying patterns of treatment responses. The p-value of 0.0478 will be used if all three interim analyses have been performed, thus correcting for previous interim tests.

    13.7 Inclusion of Women and Minorities

    In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minority in clinical research, we make the following observation. The recursive partitioning analysis of the RTOG database for patients entered into glioma trials failed to show any treatment interaction with gender (Curran et al.). The RTOG found no difference in survival of glioblastoma multiforme patients by race (Simpson et al.). Since there are no publications found to support a possible interaction between different radiation therapy schedule and either gender or race, the sample size will remain the same. A statistical analysis will be performed to examine the possible difference between the genders and among the races. The projected accrual is shown below:



    American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total
    Female 0 1 6 6 80 0 93
    Male 0 2 11 6 140 0 159
    Unknown 0 0 0 0 0 0 0
    Total 0 3 17 12 220 0 252









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