Accelerated hyperfractionated radiotherapy for malignant gliomas

ELSEVIER

l

Clinical Original Contribution ACCELERATED

JOHN

M. BUATTI,

HYPERFRACTIONATED RADIOTHERAPY FOR MALIGNANT GLIOMAS

M.D.,* ROBERT B. MARCUS, JR., M.D.,* WILLIAM M. MENDENHALL, WILLIAM A. FRIEDMAN, M.D.+ AND FRANCIS J. BOVA, PH.D.*

M.D.,*

Departments of *Radiation Oncology and ‘Neurosurgery, University of Florida College of Medicine, Gainesville, Florida

embdism after 18 Gy; one patient discontinued therapy after 2&J Gy agahxst medical advice and sequdae or progression). The 68 patients in the study group had a median age of 52 years and a median Ka&sky perfomcc status of 90. Stereotactic implant (““I> or stemotactic radiosurgery boosts were delivered to 16 patients (24%) in the study group. Mhxhnum follow-up was 6 months. Results: Median survival was 13.?3 months and median progre&on-free survival was 7 ii&&& Kaplan-Me& survival rate was 16% at 2 years and 4% at 5 prognostic impact of age, gender, histology, Kamofsky perfo tion vs. biopsy, and boost vs. nonboost therapy revealed therapy, and snrgical excision predicted significantly improved outcome. No seven? toxicity occurred in patients treated with accelerated hyperfractionated mdiotherapy atone, altho#@ 5% required steroids to is or with& chemotherapy. This regimen is a reasonable starting point for future trials and may have some advantages over standard fractionation. Computer-assisted dosage.

radiotherapy,

Brain neoplasms, Glioblastoma multiforme,

Astrocytoma,

Radiotherapy

ences is difficult. Because surgery is not curative, improved resection at the expense of significant neurologic function or quality of life is not indicated. After surgery, standard radiotherapy consists of daily treatments of 1.8-2 Gy using megavoltage beams to a total dose of 60 Gy over 6-6.5 weeks (24, 25, 28, 31, 33). The treatment is delivered to partial brain fields with a field reduction after 45-50 Gy (4, 9, 14, 17). Radiotherapy improves the length and quality of life in these patients and allows for a limited number of patients to survive beyond 2 years (17,25). Boost doses of radiation delivered in conjunction with the external beam radiotherapy may offer improved outcome in a subset of patients. However. selection for

INTRODUCTION Malignant gliomas are among the most rapidly lethal diseases known (4, 23). Standard therapy generally begins with surgery ranging from biopsy to gross total resection based on the size, location, and configuration of the tumor, as well as patient characteristics (24). The degree of resection may be important prognostically, but may also reflect a number of other selection factors (24, 25, 31, 35). For example, tumor size and location may allow for more aggressive surgery, but also predict the patient’s functional status, a known favorable prognostic factor. Thus, separation of surgical effect from other prognostic influ-

Acknowledgements-The authors thank the research support staff of the Department of Radiation Oncology for their help with statistics, editing, and manuscript preparation. Accepted for publication 19 September 1999

Reprint requests to John M. Buatti, M.D., Department of Radiation Oncology, University of Florida Health Science Center, P.O. Box 100385, Gainesville, FL 32610-0385. E-mail: [email protected] John M. Buatti is the recipient of the American Cancer Society Clinical Career Development Award 1994-1997. 785

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this boost treatment, like selection for more aggressive surgery, depends on prognostically important patient characteristics, making it difficult to definitively confirm the benefit of the boost therapy (1, 3, 6, 9, 14, 17, 26). After surgery and r~io~erapy, standard treatment often includes adjuvant chemo~erapy (5,283 1-33). Al~ough 10-40% response rates are reported after chemothe~py, and a modest survival advantage in chemotherapy-treated patients is suggested, the patient and treatment selection criteria, as well as chemo~erapy-~s~iated toxicity, make true benefit to the patient’s life less clear (5, 22, 28). For these reasons, the best proven therapy for patients with this devastating disease is external beam radiotherapy f4,28& A significant percentage of malignant gliomas progress during standard, once-daily external beam radiotherapy, with or without chemotherapy. The incidence of disease progression is poorly reported but appears to range from a minimum of 7% to 21% and may be as high as 33% in gliobiastoma mul~fo~e f9, 14). Because progression during therapy is poorly doc~ent~ in many of the larger radon trials using standard ~tiona~d radiotherapy and a variety of conco~t~tly administered chemotherapy regimens (23, 28, 31-331, many recent studies are difficult to interpret (3,6,9, 14, 17, 26). Response or progression during treatment is likely a prognostically important variable of unquantified significance. Therefore, several studies that report progressive disease dnring external beam therapy as an unplanned treatment selection factor make it difficult to evaluate the efficacy of additional therapy, despite correction for other known prognostic indicators (3,6,9, 14, 17, 26). Accelerated hy~~ac~onat~ therapy has the potential to diminish the rate of failure in a number of tumor sites (13, 20). The favorable radiobiologic parameters for accelerated hyperfractionated regimens are well described (7, 10, 16, 34). Randomized and nonrandomized trials have supported the tolerability of hyperfractionated accelerated regimens for the central nervous system (8, 13, 18, 19, 21, 29, 30). In light of these observations, a regimen of 1.5 Gy twice daily to a total target dose of 60 Gy was initiated at the University of Plorida in April 1985. The regimen was h~othesized to di~nish the rate of p~~ssio~ during therapy. The latent could be completed in 4 weeks rather than 6.5 weeks, making it convenient for patients coming for treatment from distant locations, and expedient for patients with malignant gliomas, who generally have limited longevity. We report our initial experienm with this regimen. METHOW

AND MATERIALS

Beginning in April 1985, adult patients at the University of Plorida ~p~ent of Radiation Oncology with the diagnosis of malignant as~~o~ were considers for treatment with accelerated hy~~mc~onated radio-

Volume 34, Number 4, 1996

therapy at 1.5 Gy twice daily to a total target dose of 60 Gy. In the initial years of the study, selection was rigorous for this treatment regimen, because the incidence of acute toxicity with the treatment was unknown. Patients with Karnofsky performance status of < 50 were considered unsuitable for high-dose ra~o~erapy and were generally treated to a dose of 30 Gy in 10 fractions. Patients with extremely large or multicentric lesions that would require whole-brain radiotherapy to encompass the tumor volume were also excluded from accelerated hype~actiona~d therapy and treated with short p~liative regimens. A few patients chose short palliative regimens or received splitcourse high-dose palliative regimens. A total of 62 patients were treated with putative intent during the study period, most of them before 1989. Twenty-two patients during the study period were treated with standard oncedaily fractionation. Primary reasons for deviation from the accelerated hyperfractionated regimen were poor participation at a satellite facility, and referring physician preference. A total of 70 patients were treated with accelerated hy~~actionated ra~otherapy between April 1985 and June 1994. One patient died of a pu~on~ embolus after a dose of 18 Gy, and another without si~i~c~t deficits discontinue therapy against medical advice after 28.5 Gy. The remaining 68 patients compose the study group* Patients in the study group had a median age of 52 years, with a range of 18-77 years. Forty-one were men and 27 were women, for a male-to-female ratio of 1.5. Twenty-four patients sought treatment after experiencing headaches, 19 after having a seizure, and 24 after a neurologic deficit developed. One patrent was asymptomatic but had a mild cranial nerve deficit discovered at a screening physical ex~na~on. Median ~mtion of symptoms before diagnosis was 6 weeks. The median tumor volume before surgery (estimated by mean diameter reported on computed tomography [CT], magnetic resonance imaging [MRI], or pathology specimen) was 23 cm’. Median Table 1. Treatment ch~cte~s~cs-68 Treatment Parameter Swam Biopsy Subtotal excision Gross total excision Radiotherapy-total dose 54 Gy 60GY 66 GY 69 G Boost aerapy Stereotactic implant (56-60 Gy at 0.4 GYW Stereotactic radiosurgery (12.5 Gy to the 80% isodose shell) Chemo~er~y Adjwant Saivage

patients No. Ph.

%

23 18 2-J

34.0 26.0 40.0

5: z 16

SE 4:5 9.0 24.0

5

7.0

11

16.0

1 4

1.5 6.0

Accelerated hy~~ctionated

ra~~the~~y

for malignant gliomas l BI IATI-I

I

I

,

2

3

4

7x7

et of.

--

5

Years Fig. 1. Overall absolute survival for all patients treated with accelerated hyperfractionated radiotherapy i?CaplanMeier actuarial method; n = 68). l = living patient.

vealed glioblastoma multiforme in 51 cases (75%) and anaplastic astrocytoma in 17 cases(25%). Patients witb a component of oligodendroglioma were excluded from

Karnofsky performance status was 90 with a range of so- loo. All patients had pathologic confirmation of malignant glioma. Twenty-three (34%) had this confirmed by biopsy, 18 (26%) by subtotal excision, and 27 (40%) by gross total excision. Seventeen (25%) of the surgeries were lobectomies (Table 1). Pathology specimens re-

the analysis because their prognosis is often better and less clear.

After surgery, all patients were referred for radiotherapy and were treated with 1.5 Gy twice daily with a ‘1

Karn ofsky ~80 (n=21)

80% 3 .* 60% E z a, 2g 40% 9

I i

-1 L LI ’ I-

,-

p=.OOOl 0% 0

.i

‘1

Ii 3

20%

290 (n=47)

I

Li----7

1 ;

23%

I

I

I

1

2

3

I-----T-

4

5

Years Fig. 2. Absolute survivaI stratified by Karnofsky performance status 2 90 vs. I 80 (Kaplan-Meier actuarial method). II = living patient.

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I

Surgery --_ Biopsy only (x1=23)

__

p = .0002 0%

1

I I

I

0

1

Excision (n=45)

I

/ I 2

I 4

I 3

I 5

Years Fig. 3. Absolute

survival stratified by biopsy vs. surgicalexcision (Kaplan-Meier actuarialmethod). n = living

patient.

minimum 6-h interfraction interval to a target dose of 60 Gy. All patients were treated with megavoltage beams. All were treated with partial brain fields; one patient received part of the therapy with whole brain fields. All but one patient were treated with a shrinking-field technique with a reduction at 45-50 Gy. Eighty-five percent of the 100%

,

patients (58 of 68) received the target dose of 60 Gy in 40 fractions, and 99% received at least the target dose. One patient received 54 Gy followed by a stereotactic radiosurgery boost. Nine patients had planned dose escalation because they would have been candidates for stereotactic radiosurgery or implant except for the size and

-* _I

T---L

L

- - EB RT alone

80% -

-

EB + boost

-7 : L

20%

-I

--

p= .Ol 0%

I-------.

I

I

0

1

I 2

I 3

I 4

I 5

Years Fig. 4. Absolute survival stratified by external beam therapy alone vs. external beamplus boost therapy with either stereotacticimplant or radiosurgery(Kaplan-Meier actuarialmethod).Survival rateswere asfollows: At 1 year, external beam(EB) radiotherapy(RT) alone, 48%; EB + boost, 88%. At 2 years, EB RT alone, 15%; EB + boost, 16%. n = living patient.

Accelerated

~y~~ctionated

radiotherapy

configuration of their tumors; they were treated with identical fractionation to doses > 60 Gy (three received 66 Gy and six received 69 Gy) (Table 1). Sixteen patients (24%) received a boost dose of radiotherapy. B~chy~erapy was used in 5 patients and stereotactic radiosurgery in 11 patients. Patients treated with brachytherapy received between 56 and 60 Gy at 0.4 Cy/h using temporary 125Iseeds. The median implant volume was 15.7 cm’. Patients treated with stereotactic radiosurgery received a median dose of 12.5 Gy (range, lo15 Gy), usually to a single isocenter prescribed to the 80% isodose shell. The median volume for these lesions was 10.2 cm3 (Table I). One patient received two cycles of ~tomycin during the radiotherapy. No other patient received chemotherapy until recurrence. Four patients received palliative chemotherapy at recurrence. Reoperation after treatment was performed in 13 patients (21%). In eight cases the patients had been treated with external beam therapy alone and had known recurrence. In five cases the surgery was performed because of intractable edema after boost therapy, despite steroids. Minimum potential follow-up for inclusion in the study was 6 months; no patient was lost to follow-up, The SAS LIPETEST procedure (27) was used to produce KaplanMeier p~uct-limit absolute survival curves (11). The date of death was the end point of the analyses. Living patients were censored as of the date of last follow-up, regardless of disease status at that time. Curves were compared using the Wilcoxon test (12). Multiv~ate analyses to evaluate the relative impact of the variables age, gender, Karnofsky performance status, histology, symp-

for malignant

gliomas

0 BI in-r-r1 et al.

tomatology, extent of resection, and boost vs. nonboost therapy, used a forward stepwise sequence of chi-squares for the Wilcoxon and the log-rank tests, as invoked in the SAS LIFETRST procedure (12, 27). ItJ3SULTS The median length of survival for the entire study group was 13.8 months, and the length of p~~ession-fee survival was 7.4 months. Absolute survival rates were 16% at 2 years and 4% at 5 years (Fig. 1). One patient (1.5%) had disease progression during the accelerated hyperfractionated radio~erapy. Univariate analyses for the impact of established prognostic indicators of age, Karnofsky performance status, and histoiogy revealed that only the Karnofsky performance status was significant @ = 0.001) in this small prognos~c~ly favo~ble study group (Fig. 2). Stratification by gender, duration of symptoms, and history of seizures showed no significant differences. Univariate analysis for the impact of initial surgical therapy on outcome revealed that patients receiving subtotal or total excision had higher rates of survival @ = 0.0002) than those receiving biopsy alone (Fig. 3). No significant advantage was shown for those receiving totai vs. subtotal excision nor for those receiving lobectomy vs. nonlo~tomy resections” Tumor volume before the surgical resection was not a prognostic indicator on univariate analysis. Median survival was 16.2 months for those treated with excision and 8.7 months for those who had only a biopsy. Radio~erapy was evaluated in terms of boost therapy vs. no boost therapy. Patients receiving either implant or

r ----Treatment of 80%

/ /

789

Recurrence

1 I

- Reoperation

1

-- No reoperation i.----_-. ^ ---._-I

1

Fig. 5. Absolute survival stratified by reoperation at recurrence vs. no reoperation at recurrence (Kapok-~eier actuariai method). m = Iiving patient.

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Table 2. Comparison of standard fractionation with accelerated hyperfraetionated treatment Standard Survival Complications cost Time progression during therapy Radiobiology (theoretical) Late effects Early effects

Univ. of Florida (1.5 Gy b.i.d.) No difference No difference

+ + (1.5%)

+ (lo- 15% less costly) - (T-33%) -

+ +

-I- = advantageous; - = disadvantageous. stereotactic radiosurgery boost had a significant irnprovement in survival compared with those treated with external beam therapy alone fp = O.Ol), but no difference was apparent in Z-year survival rates (Fig. 4). The median survival for those receiving boost therapy was 18.6 months and for those treated with external beam therapy alone was 12.1 months. There was no apparent advantage in survival for the limited number of patients treated with boost doses of external beam radiotherapy. On multivariate analysis, the variables age, gender, histology, Kamofsky performance status, boost vs. nonboost therapy, symptomatology, and surgical treatment (excision vs. biopsy) were evaluated for impact on absolute survival. The degree of surgical excision (p = 0.~5) was most significant in the stepwise sequence, followed by boost vs. nonboost therapy 0, = 0.0011); none of the other variables was significant at the p rs 0.05 level according to the Wilcoxon test, which weights early results most heavily. The forward stepwise sequence for the log-rank test, which assigns more weight to long-term results, showed that Karnofsky status also has a significant impact on outcome. Reoperation was used as salvage therapy in eight patients treated with external beam radiotherapy and in five patients who had in~ac~ble edema after ster~o~ctic brachytherapy or radiosurgery boost, Those who had reoperation had significautly improved survival rates 07 = 0.002) (Fig. 5). In patients who had surgery for the presence of intractable edema, all but one had significant necrosis intermixed with viable tumor cells. One patient in whom pure radiation necrosis was discovered at surgery is alive 3.8 years after initiation of therapy with external beam radiotherapy and a brachytherapy impiant. Absolute survival at 2 years was 50% for patients who had reoperation and 6% for patients who did not. Median length of survival was 24.2 months for patients who had reoperation and 12.1 months for those who did not. Toxicity attributable to the accelerated hyperfractionated radiotherapy was mild. No patient had severe toxicity requiring hospit~ization because of the radiotherapy, although one required drainage of a surgical abscess. Moderate toxicity requiring therapeutic intervention occurred in three patients (5%); ~~tment consisted of a temporary course of steroids for edema in all cases. Only one of the

patients requiring steroids had received a dose > 60 Gy. One patient had a transient aphasia after therapy that resolved rapidly without inte~ention, and one patient had significant hearing loss due to therapy. The hearing loss was not treated. In contrast to the mild toxicity associated with accelerated hy~~actionat~ extem~-~~ therapy alone, those who had the addition of boost therapy experienced significant toxicity. Of five patients treated with stereotactic brachytherapy, two had severe edema of inconclusive origin (tumor recurrence vs. ~erapy-related) that did not respond to steroids and necessitated surgery. Of 11 patients treated with stereotactic radiosurgery, 4 required steroids; 3 of the 4 showed no response and, therefore, required surgery. In summary, 31% of the patients (5 of 16) receiving the boost therapy required reoperation for significant edema that failed to respond to steroids.

DISCUSSION Present treatment of rn~i~~t gliomas is unsatisfactory. The best proven standard therapy takes approximately 6-6.5 weeks to deliver and allows for tumor progression during treatment in 7-21% of malignant gliomas and perhaps 33% of gliobl~toma m~tifo~es (9, 14). A high-dose split course of therapy consisting of 30 Gy in 10 fractions over 2 weeks followed 2 weeks later by 21 Gy in 7 fractions resulted in 13% of the patients being excluded from analysis because of deterioration during therapy (15). A recent highly accelerated trial of therapy conducted by the European Organization for Research and Treatment of Cancer (EORTC) (2 Gy three times daiIy over 9- 12 days) for glioblastoma muhiforme patients reported that 3% of the patients had disease progression before reaching target doses ranging from 42 to 60 Gy (8). In the largest randomized trial of accelerated hyperfractionated radiotherapy (RTOG 8302) for malignant glioma, the progression rate on treatment was reported as 4-S% (19). The results of the current study, as well as these two trials, suggest that the use of accelerated hyperfractionated treatment may reduce the incidence of progression during therapy. These observations may affect interpretation of many studies because patients entered on a sequential com-

Accelerated hy~~ctionated

radiotherapy for maljg~ant gfiomas0 BtIATTIet ai.

bins-m~ity arm of treatment or in nonrandomized trials of additional therapy may be excluded from the analysis because of disease progression (9, 14). In an already complex environment for randomization and selection, this adds a variable that is possibly significant and often not reported (2, 3, 6, 26). Perhaps more importantly, the impact of progression under treatment is immediate failure in a devastating disease that generally gives patients only a few weeks of symptoms before diagnosis. In light of this, reaping progression-foe survival in glioma patients may be wo~w~le because it may more accurately reflect the main achievable goal of current therapy in extending a progression-free interval with a reasonable quality of life. Conversely, progression-free interval may be difficult to determine accurately when symptoms worsen and scans are indeterminate for disease progression vs. possible toxicity of therapy. Our accelerated hyperfractionated radiotherapy at 1.5 Gy twice daily to a total dose of 60 Gy was compared with standard fractiona~on in terms of effect on survival, complications, cost, time and convenience, progression during ~eatment, and radiobiologi~ effects (Tables 2 and 3 ). The regimen does not appear to improve survival rates compared with standard therapy, although our patients were generally in a favorable prognostic group. However, we used virtually none of the adjuvant or salvage chemotherapy used in many other trials (5, 22, 28, 32). The toxicity is mild and appears equivalent to that produced by standard fractionation and other hyperfractionated accelerated regimens (8, 19, 21, 28, 30). Chemotherapy toxicity, although mild in some reports, is completely avoided (5, 28, 3 I, 32). The therapy proposed is approximately lo- 15% more expensive than standard therapy. Treatment duration is reduced by 2-3 weeks compared

791

Table 3. Radiobiologic modeling of treatment regimens -Gyx -.__l--~Gy,o

TimeCorrected Gy,(,

Standard

60 Gy in 1.8-Gy fractions

96

70.X

44.8

90

69

54

80.6

57.5

72 ----_-.-

65.1

UF 60 Gy in 1.5-Gy fractions

twice daily RTOG

72 Gy in 1.2-Gy fractions twice daily EORTC 60 Gy in 2-Gy fractions twice daily

100.8 100

-

with standard fractionation, which is advantageous because of travel considerations and the limited lifespan for many patients. Lodging costs are also reduced for the outof-town patient. Progression during treatment appears to be reduced. Radiobiologically, the regimen appears favorable in terms of diminished late effects (Gy3), equivalent acute effects (Gy!,,), and increased tirne~~~~ tumor effects, assu~ng the neoplasms are rapidly dividing. Biologic models of standard ~tion~ion, the University of Florida regimen, the best RTOG regimen of I .2 Gy twice daily to 72 Gy, and the highly accelerated EORTC regimen are shown in Table 3. In conclusion, accelerated hyperfractionated radiotherapy for the treatment of malignant glioma may be preferable from several vantage points. Its single drawback is a slight increase in cost, which may be critical in the current environment. We plan continued use of accelerated hyperfr~tionated ~dio~e~py as our sods exte~~-~~ regimen, and will continue to refine this still inad~uate standard therapy.

REFERENCES 1. Buatti, J. M.; Friedman, W. A.; Bova, F. J.; Mendenhall, W. M. Linac radiosurgery for high-grade gliomas: The University of Florida experience. Int. J. Radiat. Oncol. Biol. Phys. 32:205-210; 1995. 2. Curran, W. J., Jr.; Scott, C. B.; Horton, J.; Nelson, J. S.; Weinstein, A. S.; Fischbach, A. J.; Chang, C. H.; Rotman, M.; Asbell, S. 0.; Krisch, R. E.; Nelson, D. F. Recursive p~tio~ng anaIysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J. Natl. Cancer Inst. 85:704-710; 1993. 3. Curran, W. J., Jr.; Scott, C. B.; Weinstein, A. S.; Martin, L. A.; Nelson, J. S.; Phillips, T. L.; Murray, K.; Fischback, A. J.; Yakar, D.; Schwade, J. G.; Corn, B.; Nelson, D. F. Survival comparison of radiosurgery-eligible and -ineIigible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: A report of Radiation Therapy Oncology Group 83-02. J. Clin. Oncol. 11:857862; 1993. 4. Davis, L. W. Presidentialaddress:Malignant glioma-a

nemesis which requiresclinical and basic investigation in radiation oncology. Int. J. Radiat. Oncol. Biol. Phys. 16:1355-1365; 1989. 5. Fine, H. A.; Dear, K. B. G.; Loeffler, J. S.; Black, P. McL.;

Canellos, G. P. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 7 1:2585 -2597; 1993. 6. Florell, R. C.; MacDonald, D. R.; Irish, W. D.; Bernstein, M.; Leibel, S. A.; Gutin, P. H.; Cairncross, J. G. Selection bias,survival, and b~ch~~rapy for glioma. J. Neurosurg. 76:179-183; 1992. 7. Fowler, J. F. Brief summaryof ~~o~o~ogic~ principles

in fractionated radiofberapy. Setin.

R&at. Oncot. 2(l): 16-21; 1992. 8. Gonz&lez-Gonz;llez, D.; Menten, J.; Bosch, D. A.; van der Schueren, E.; Troost, D.; Hulshof, M. C. C. M.; Bemier, J. Accelerated radiotherapy in glioblastorna multiforme: A dose searching prospective study. Radiother. Oncol. 32:98105; 1994. 9. Gutin, P. H.; Prados,M. D.; Phillips, T. L.: Wara, W. M.; Larson,D. A.; Leibel, S. A.; Sneed,P. K.; Levin, V. A.;

Weaver, K. A.; Silver, P.; Lambom, K.; Lamb, S.; Warn, B. External irradiationfollowed by an interstitial high activity iodine-125implant “boost” in the initial treatmentof malignant gliomas:NCOG study 66-82-Z. Int, J. Radiat. On-

eel. Biol. whys.21:601-606; 1991. 10. Hall, E. J.; Brenner,D. J. The r~iobio~o~ ofradiosurgery:

1. J. Radiation Oncology 0 Biology 0 Physics

792

Rationale for different treatment regimes for AVMs and malignancies. Znt. J. Radiat. Oncol. Biol. Phys. 25:381385; 1993.

11. Kaplan, E. L.; Meier, P. Nonparametricestimationsfrom incompleteobservations.J. Am. Stat. Assoc. 53:457-481; 1958. 12. Lawless,J. E. Statistical modelsand methodsfor lifetime data. New York, Wiley; 1982. 13. Linstadt, D. E.; Edwards, M. S. B.; Prados,M.; Larson, D. A.; Wara, W. M. H~e~ractionated i~adiation for adults with brainstemgliomas.Int. J. Radiat. Oncol. Biol. Phys. 20557-760; 1991. 14. Loeffler, J. S.; Alexander, E., III; Shea, W. M.; Wen,

P. Y.; Fine, H. A.; Kooy, H. M.; Black, P. McL. Radiosurgery as part of the initial managementof patients with malignantgliomas.J. Clin, Oncol. 10:1379- 1385; 1992. 15. Mar&l-Vega, V. A.; Wharam, M. D.; Leibel, S.; Clark, A.; Zweig, R.; Order, S. E. Treatment of supratentorial high grade gliomaswith split coursehigh fractional dose ~sto~rative ra~otherapy. Int. J. Radiat. Oncol. Biol. Phys. 16:1419-1424; 1989. 16. McGinn, C. J.; Harari, P. M.; Fowler, J. F.; Ford, C. N.; Pyle, G. M.; Kinsella,T. J. Doseintensi~~ationin curative headandneck cancerradiotherapy-linear quadraticanalysis and preliminary assessment of clinical results.Int. J. Radiat. Oncol. Biol. Phys. 27~363-369; 1993. 17. Mehta, M. P.; M~ciopinto, J.; Rozental, J.; Levin, A.; Chappell, R.; Bastin, K.; Miles, J.; Turski, P.; Kubsad, S.; Ma&e, T.; Kinsella, T. Stereotacticradiosurgeryfor glioblastomamultiforme: Report of a prospective study evaluatingprognosticfactors and analyzing long-termsurvival advantage.Int. J. Radiat. Oncol. Biol. Phys. 30:541549; 1994. 18. Murray, K. J.; Nelson, D. F.; Scott, C.; Fischbach,A. J.;

Porter, A.; Farnan, N.; Curran, W. J., Jr. Quality-adjusted survival analysisof malignantglioma.Patientstreatedwith twice-daily radiation(RT) andcarmustine:A report of Radiation Therapy Oncology Group (RTOG) 83-02. Int. J. Radiat. Oncol. Biol. Phys. 31:453-459; 1995. 19. Nelson,D. F.; Curran, W. J., Jr.; Scott, C.; Nelson,J. S.; Weinstein,A. S.; Ahmad, K.; Constine,L. S.; Murray, K.; Pow&, W. D.; Mohiuddin, M.; Fischback,J. Hyperfractionatedradiationtherapy andbis-chlorethylnitrosoureain the treatmentof malignantglioma-possible advantageobservedat 72.0 Gy in 1.2 Gy b.i.d. fractions: Report of the RadiationTherapy Oncology Group Protocol 83-02. Int. J. Radiat. Oncol. Biol. Phys. 25:193-207; 1993. 20. Parsons,J. T.; Mendenhall,W. M.; Stringer, S. P.; Cassisi, N. J.; Million, R. R. Twice-a-day radiotherapy for squamouscell carcinomaof the headand neck: The University of Florida experience.Head Neck 15:87-96; 1993. 21. Payne, D. G.; Simpson,W. J.; Keen, C.; Piatts, M. E. Mali~~t ~~~ytorna: Hy~~~~~onat~ andstandardradiotherapywith chemotherapyin a randomizedprospective clinical trial. Cancer50~2301-2306;1982. 22. Rostomily, R. C.; Spence,A. M.; Duong, D.; McCormick, K.; Bland, M.; Berger, M. S. Multimodality management of recurrent adult malignantgliomas:Resultsof a PhaseII mult~agentchemo~erapystudy and analysisof cytoreductive surgery. Neurosurg.35(3):378-388; 1994. 23. Salazar,0. M.; Rubin, P.; Feldstein,M. L.; Pizzutiello, R.

Volume 34, Number 4, 1996 High dose radiation therapy in the treatment of malignant gliomas: Final report. Int. J. Radiat. Oncoi. Biol. Phys. S:I733-1740; 1979. 24. Salcman,M. Surgical resectionof malignantbrain tumors:

Who benefits?Oncology 2(8):47-63, 1988. 25. Salcman,M.; Scholtz, H.; Kaplan, R. S.; Kulik, S. Longterm survival in patientswith m~ign~t astrocytoma.Neurosurg. 34:213-220; 1994. 26. Sarkaria,J. N.; Mehta, M. P.; Loeffler, J. S.; Buatti, J. M.; Chappell,R. J.; Levin, A. B.; Alexander, E., IIk Friedman, W. A.; Kinsella, T. J. Radiosurgeryin the initial management of malignantgliomas:Survival comparisonwith the RTOG RecursiveP~itio~ng Analysis. Int. J. Radiat.Oncol. Biol. Phys. 32:931-941; 1995. 27. SAS Institute Inc. SAS technical report P-179, additional SASlSTAT procedures,release6.03. Cary, NC: SAS Institute Inc.; 1988:49-89. 28. Shapiro, W. R.; Green, S. B.; Burger, P. C.; Mahaley, M. S., Jr.; Selker, R. G.; VanGilder, J. C.; Robertson, J. T.; Ransohoff,J.; Mealey, J., Jr.; Strike, T. A.; Pistenmaa, D. A. Randomizedtrial of three chemotherapyregimens and two radiotherapyregimensin postoperativetreatment of m~ign~t glioma:Brain Tumor CooperativeGroupTrial 8001.J. Neurosurg.71:1-9; 1989. 29. Shrieve, D. C.; Wara, W. M.; Edwards,M. S. B.; Sneed, P. K.; Prados, M. D.; Cogen,P. H.; Larson, D. A,; Levin, V. A. Hy~~ractionated radiation therapy for gliomasof the brainstemin childrenandin adults.Int. J. Radiat.Oncol. Biol. Phys. 24599-610; 1992. 30. Sullivan, F. J.; Herscher,L. L.; Cook, J. A.; Smith, J.; Steinberg,S. M.; Epstein,A. H.; Oldfield, E. H.; Goffman, T. E.; Kinsella,T. J.; Mitchell, J. B.; Glatstein,E. National Cancer Institute (Phase II) study of high-grade glioma treatedwith acceleratedhyperfractionatedradiationandiododeoxyuridine:Resultsin anaplasticastrocytoma.Int. 5. Radiat. Oncol. Biol. Phys. 30(3):583-590; 1994. 31. Walker, M. I).; Alexander, E., Jr.; Hunt, W, E.; MacCarty, C. S.; Mahaley, M. S., Jr.; Medley, J., Jr.; Norrell, H. A.; Owens, G.; Ransohoff,J.; Wilson, C. B.; Gehan, E. A.; Strike, T. A. Ev~uation of BCNU an&or radio~erapy in the treatmentof anaplasticgliomas.J. Neurosurg.49:333343; 1978. 32. Walker, M. D.; Green, S. B.; Byar, D. P.; Alexander, E.,

Jr.; Batzdorf, U.; Brooks, W. H.; Hunt, W. E.; MacCarty, C. S.; Mahaley, M. S., Jr.; Mealey, J., Jr.; Owens, G.; Ransohoff,J., II; Robertson,J. T.; Shapiro,W. R.; Smith, K. R., Jr.; Wilson, C. B.; Strike, T. A. Randomizedcomparisonsof radiotherapyand nitrosoureasfor the treatmentof malignantgliomaafter surgery.N. Engl. J. Med. 303:13231329; 1980. 33. Walker, M. D.; Strike, T. A.; Sheiine,G. E. An analysis of dose-effectrelationshipin the radiotherapyof malignant gliomas.Int. J. Radiat. Oncol. Biol. Phys. 5:1725-1731; 1979. 34. Williams, M. V.; Denekamp,J.; Fowler, J. F. A review of

a/lJ ratiosfor experimentaltumors:Implicationsfor clinical studiesof alteredfractionation. Iut. J. Radiat. Oncol. Biol. Phys. 1187-96; 1985. 35. Winger, M. J.; MacDon~d, D. R.; Cairncross,J. G. Supratentorial anaplastic gliomas in adults. J. Neurosurg. 71:487-493; 1989.