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Accelerated Radiotherapy, Carbogen, and Nicotinamide in Glioblastoma Multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933

From the Hôpital Cantonal Universitaire, Geneva, Inselspital, Bern, Ospedale San Giovanni, Bellinzona, and Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Centre Hospitalier Lyon-Sud, Lyon, and Centre Hospitalier Regional et Universitaire, Grenoble, France; Academish Ziekenhuis, VUB, and EORTC headquarters, Brussels, Belgium; Academisch Medisch Centrum, Amsterdam, the Netherlands; Norrlands Universitetssjukhus, Umeà, Sweden; and Gray Lab, Mount Vernon Hospital, Northwood, United Kingdom.

Address reprint requests to Raymond Miralbell, MD, Division de Radio-oncologie, Hôpital Cantonal Universitaire, 1211 Genève 14, Switzerland; email raymond.miralbell{at}hcuge.ch

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme.

PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg.

RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively.

CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
GLIOBLASTOMA multiforme (GBM) is among the most malignant brain tumors, with median survival times seldom longer than 9 months and practically no patient surviving 5 years after treatment.¹ Although postoperative radiotherapy has been shown to improve survival compared with surgery alone, the benefit is rather modest.^2,3 GBM is generally considered radioresistant, even though in vitro studies have shown a wide range of intrinsic radiosensitivities.⁴ Several hypotheses have been formulated to explain the radioresistance of malignant gliomas, including a large proportion of clonogenic cells with a rapid turnover rate,⁵ a high fraction of hypoxic tumor cells that are biologically more aggressive and radioresistant,^6,7 and a possible high repair capacity of sublethal or potentially lethal radiation damage.⁸ Accelerated radiotherapy, using several fractions a day in order to reduce the overall treatment time, may be effective in overcoming rapid tumor proliferation.⁹ Breathing carbogen (95% O₂ plus 5% CO₂) before and during irradiation has been shown to promote reoxygenation of chronically hypoxic cells.¹⁰ In addition, nicotinamide may overcome the unfavorable effects of acute hypoxia, which results from the intermittent blood flow brought about by temporary closure of blood vessels.^10,11 An enhancement ratio of 1.8 was seen with high-dose nicotinamide and carbogen in two rodent adenocarcinomas¹⁰ and almost a factor of 2 was subsequently observed in one of these tumors using a clinically relevant schedule of accelerated radiotherapy with carbogen and nicotinamide (ARCON).¹¹ A lesser but still significantly improved radioresponse with an ARCON schedule was shown in human glioblastoma xenografts (Sun et al, manuscript submitted for publication).

The present report represents an attempt to overcome the potential effects of proliferation and both acute and chronic hypoxia as causes of tumor radioresistance as proposed by Rojas and Denekamp.¹² The study was designed as a prospective three-step phase I/II trial, testing the combination of accelerated radiotherapy and either carbogen, nicotinamide, or both. The goals were to evaluate feasibility, toxicity, and outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
The study design called for the treatment of groups of patients in three sequential steps (not randomized): accelerated radiotherapy and carbogen (step 1, ARCO), accelerated radiotherapy and nicotinamide (step 2, ARN), and ARCON (step 3). Patients from 14 European Organization for Research and Treatment of Cancer (EORTC) centers were included in the study, according to the following inclusion criteria: histologically confirmed diagnosis of GBM, operation within 4 weeks before the start of irradiation, age between 16 and 70 years, Eastern Cooperative Oncology Group/World Health Organization performance index of 0 to 2, expected survival time of at least 8 weeks, and no previous anticancer therapy. No central pathology review of the tumor specimens was performed. All patients participating in the study signed an informed consent form approved by the ethics committee of each participating institution. Treatment was to be discontinued at any time in case of patient refusal, noncompliance, rapidly progressive disease, or life-threatening toxicity. In an effort to increase compliance, patients on steps 1 and 3 were asked to breathe carbogen for about 10 minutes a few days before commencing radiotherapy.

In every case, 60 Gy was delivered in two 1.5-Gy fractions daily, with at least a 6-hour interval between each fraction, 5 days per week over a 4-week period. Megavoltage equipment was always used. The treatment volume included the entire enhanced tumor, as defined by the preoperative contrast-enhanced computed tomography (CT) scan with a 2- to 3-cm margin in all directions. The reference point for dose prescription was at the intersection of the central axes of the radiation beams. There was a maximum permissible range of ±5% in dose distribution within the target volume. Whenever possible, the doses to the optic chiasm and brainstem were less than 55 Gy. Carbogen breathing was started 5 minutes before each fraction and lasted until the end of each irradiation session. Carbogen was administered with a flow of 10 L/min. Nicotinamide was given daily as a single dose of 85 mg/kg at least 1.5 hours before the morning fraction of radiotherapy.

Patients were monitored weekly during therapy for acute toxicity. Renal and liver function tests (blood biochemistry) were performed before the start of treatment and within 2 months after treatment completion. Acute toxicity was graded according to Radiation Therapy Oncology Group (RTOG)/EORTC criteria and scored weekly during treatment and within 2 months after the end of therapy. Late effects were scored according to the RTOG/EORTC Late Radiation Morbidity Scoring System.

Tumor response and outcome were assessed using clinical, CT, and/or magnetic resonance imaging (MRI) investigations 1, 4, 9, and 12 months after therapy and every 6 months thereafter. Complete response after surgical resection was defined as the absence of any image suggesting residual tumor on postoperative CT or MRI. In patients with residual disease on postoperative imaging, the response after radiotherapy was considered to be complete if the patient was neurologically stable or improved and off corticosteroids and if there was no residual enhancing tumor on consecutive CT or MRI examinations at least 1 month apart. Partial response required a 50% reduction in size of the enhancing tumor, corticosteroids stable or reduced, and neurologic stability or improvement. Patients were coded as having progression if enhancing tumor size increased by 25%, any new tumor appeared, or neurogic status worsened despite stable or increased corticosteroid dosage. Patients not categorized as in complete response, partial response, or progression were considered to have stable disease. No specific treatment recommendations were given for patients for whom treatment failed.

In this study, the analysis of the data is purely descriptive and does not include any statistical inference. The acute toxicities described in Table 2 were based on the worst grade observed for individual patients during therapy. Overall survival was computed from the date of registration to the date of death. Patients alive at the time of the analysis were censored at the last reported follow-up. Time to progression was computed from the date of registration to the date of first documented progression. Patients who died or were last seen without progression evidence were censored at the date of death or last follow-up. Probabilities of survival and progression, as well as median values, were estimated by the Kaplan-Meier method. Patients were further distributed in prognostic classes according to the RTOG recursive partitioning analysis model, based on age, performance status, surgical resection, and neurologic function.¹³ Survival was estimated for each class to assess whether the present results were consistent with the RTOG results.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

Table 1 shows the patient distribution in the three treatment steps according to age, tumor site, extent of surgery, performance status before and after surgery, and neurologic status before and after surgery. Age was homogeneously distributed among the successive treatment steps. Frontal tumors, known to have a better prognosis, were underrepresented in step 1 (ARCO) compared with the other two treatment arms. Surgical resection was complete in 43 (40%) and subtotal in 29 (27%) patients. A tumor biopsy was performed in the remaining 35 patients (33%). There were slightly more complete resections in the step 2 (ARN) group. Performance status before and after surgery was as follows: grade 0, 38% and 44%; grade 1, 52% and 45%; and grade 2, 9% and 11%. After surgery, the performance status had improved in nine patients and deteriorated in four patients. Neurologic status was impaired in 72 patients (67%) before surgery and improved after surgery in 22 patients and deteriorated in five patients.

Grade 1 to 4 acute toxicity was reported in 73% of patients (Table 2). Skin toxicity was observed in 59% of patients, but grade 2 or worse was only recorded in the ARN and ARCON arms. Mucous membrane toxicity was rare (4% of patients) but was only observed in the ARN and ARCON arms. Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients on ARN and 32% of patients on ARCON but in only 8% of patients on ARCO. Among patients with available liver tests at treatment completion, results were abnormal in the following patients: ALT/AST, greater than 50 units in six (n = 4, ARCO; n = 2, ARCON) of 72 patients; bilirubin, greater than 18 µmol/L in four (n = 1, ARCO; n = 3, ARCON) of 61 patients. Liver test follow-up information was not required per protocol but was retrospectively requested for those patients who developed severe liver toxicity.

Neurologic symptoms and increased cerebral edema were reported in 52% and 27% of patients, respectively. The dose of corticosteroids had to be increased homogeneously in all treatment steps (44% of cases). Epilepsy was observed in seven patients, all of whom were in the ARCON arm. Drowsiness increased in 21% of cases, more frequently among patients receiving nicotinamide (ARN and ARCON). Most of the late complications were neurologic. Late brain damage was reported in 22 patients, but the adverse reactions occurred before disease progression in only seven patients, all of whom were receiving nicotinamide with or without carbogen (mild lethargy in two, severe neurologic dysfunction in five). Eleven patients presented with slight induration or moderate fibrosis of the irradiated subcutaneous tissue of the scalp. The time to occurrence of late complications was not different among the three treatment arms.

The planned treatment was administered without any interruption in 72% of patients (86% in the ARCO step, but 68% in both the ARN and ARCON treatment arms). Radiotherapy was stopped before 60 Gy in six patients, either because of tumor progression (three cases), death (one case, sudden; one case, hyperglicemic coma), or neurologic toxicity (one case). Among the 101 patients who received the complete dose of radiotherapy, temporary treatment interruptions (median, 7 days; range, 2 to 12 days) were reported in nine cases; three of these interruptions were due to toxicity. One patient refused to continue therapy and did not give a more precise motive. In the remaining five patients, the treatment was protracted for unknown reasons.

Carbogen was stopped in five patients during radiotherapy administration. In three patients, this interruption was mainly caused by psychologic intolerance; oral dryness and dyspnea were the reasons for stopping in the other two patients. Nicotinamide was stopped in 15 cases as a result of toxicity. Gastrointestinal intolerance was the reason for stopping in 12 patients including three with severe, but transient, liver toxicity. Dizziness, skin rash, and neurologic toxicity were the reasons for stopping in the three remaining patients.

Response status was evaluated 1 month after the end of radiotherapy. Among patients who had a total resection, 58% were still in complete remission. Among patients who underwent less than complete resection (or biopsy), 5% were complete responders, 12% were partial responders, and 31% presented with stable disease. Figure 1 displays the overall survival curves for the three treatment steps. With a median follow-up of 110 weeks, death was reported in 97 of the 107 eligible patients. Median survival times for patients treated with ARCO, ARN, and ARCON were estimated at 10.1, 9.7, and 11.1 months, respectively. Estimated median survival figures, according to the RTOG recursive partitioning analysis classes, ranged from 14.8 months for patients in class III to 3.9 months for patients in class VI and are consistent with the reference results of the RTOG database as shown in Table 3. Tumor progression was reported in 94 cases (local in 88 and local with CNS seeding in six). Estimated median times to progression for patients treated with ARCO, ARN, and ARCON were 6.7, 4.8, and 5.8 months, respectively.

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan Meier overall survival curves for treatment steps 1 (ARCO), 2 (ARN), and 3 (ARCON).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Prolonged survival in GBM is almost exclusively observed in young patients with good performance status who have resectable tumors and receive more than 54 Gy of postoperative radiotherapy.¹³ Unfortunately, recent progress in radiotherapy thus far has not led to significant prolongation of survival. Potential improvements related to more precise target volume definition and more effective time-dose-fractionation schedules have yielded rather disappointing results. In the early 1990s, the EORTC performed an accelerated radiotherapy dose escalation study in which no substantial gain in overall survival was achieved by significantly shortening the overall treatment time.¹⁴ This result was interpreted as an indication that the radioresistance of GBM was unlikely to be explained solely by rapid tumor cell turnover during treatment. The notion that tumor hypoxia might be a more important determining factor than rapid repopulation required investigation in GBM. The present study was designed to address the question as to whether patient outcome could be improved by simultaneously counteracting both repopulation and hypoxia.

The feasibility of the planned therapy programs was good for patients treated in step 1 (ARCO) but only fair for patients who received the nicotinamide-containing regimens. Nicotinamide-related upper gastrointestinal toxicity was the main reason for treatment interruption in 14% of patients in both the step 2 and 3 arms. Nicotinamide toxicity has also been reported as the main reason for treatment interruption by other authors using similar treatment approaches for GBM. Fatigante et al¹⁵ reported that four (15%) of 28 patients required interruption of nicotinamide because of intractable vomiting or allergic flush. Pickles et al¹⁶ and Van der Maazen et al¹⁷ also observed that eight of 19 and five of 16 patients, respectively, were unable to complete the treatment as planned. Tumor cell repopulation may have occurred in the nine patients reported in the present series in whom radiotherapy was temporarly interrupted.

With the exception of neurologic symptoms, acute toxicity was moderate in all treatment arms. Acute skin reactions, although not more frequent, were more marked in patients treated with nicotinamide (ARN and ARCON). As mentioned above, upper gastrointestinal reactions were also more frequent in these patients. Fatigante et al¹⁵ also reported acute, predominantly gastrointestinal, side effects in 19 of 28 patients receiving nicotinamide. They observed, as we did, that gastralgia, nausea, and vomiting occurred following only a few doses of the drug and were thus unlikely to be related to a dose-cumulative toxic effect. Although these authors did not report on nicotinamide-related liver toxicity, Pickles et al¹⁶ and Van der Maazen et al¹⁷ observed different degrees of hepatotoxicity in eight of 16 and four of 16 assessable patients, respectively. In the present study, among two thirds of patients evaluated, less than 10% presented a serum increase of liver enzymes or billirubin. Furthermore, among the 10 patients in this study who developed liver abnormalities, nicotinamide had been given to only five patients, suggesting a role for antiepileptics in causing liver function abnormalities.

Neurologic symptoms in the peri- and early postradiotherapy periods were reported in one half of the patients, 13% of whom required hospitalization because of grade 3 or 4 symptoms. Initiation of corticosteroids or increases in corticosteroid dosage were observed in a substantial but similar proportion of cases in all three treatment arms. In contrast, Buati et al¹⁸ reported an increased corticosteroid requirement in only 5% of 70 patients treated with the same radiotherapy schedule as that used in the present study but without sensitizing agents. In the EORTC dose-escalation study,¹⁴ corticosteroids had to be initiated or increased during treatment in 10 (23%) of 43 patients treated to doses less than 54 Gy but in six (43%) of 14 treated to 60 Gy (2 Gy/fraction three times a day). The patients in the present study thus had a rate of corticosteroid increase similar to that of the high-dose group in the former EORTC trial, despite a much faster treatment delivery in the earlier study. Moreover, in patients receiving carbogen and nicotinamide associated with 50-Gy monofractionated radiotherapy, Van der Maazen et al¹⁷ observed that only two of 16 patients were able to discontinue corticosteroids. Furthermore, of 11 patients who completed a similar treatment program with a somewhat lower tumor dose (<54 Gy), six developed grade 2 and two developed grade 3 early neurologic toxicity.¹⁶ These data suggest the possibility that the addition of nicotinamide and/or carbogen, and not only the accelerated radiotherapy schedule, might account for the frequent acute neurologic toxicity and the high incidence of increased corticosteroid requirement in the present study. Epilepsy was seen exclusively among patients treated in step 3. Reasons for this effect are unknown to us. Drowsiness seemed to be related to the intake of nicotinamide, as it was observed most often in patients treated in steps 2 and 3.

Tumor control and survival did not seem to be improved by any of the treatment steps when compared with published results using standard radiotherapy. A median survival of 10 months was also reported by Fatigante et al,¹⁵ who investigated treatment approaches similar to those of the present study. Only surgical resection was associated with a better prognosis in their series, with no apparent survival benefit when carbogen and/or nicotinamide was added to accelerated radiotherapy. In the present study, late neurologic side effects were mostly observed in patients with disease progression. Routine assessment of the cause of clinical deterioration (tumor progression v treatment toxicity or both) was not undertaken. However, the proportion of events coded as late neurologic side effects was similar among the three treatment steps.

The results of the present study regarding tumor response, tumor progression, overall survival, and late side effects should be interpreted with caution. Patients were not randomized, treatment groups were not evenly distributed, samples sizes were small, and follow-up times were different. An improper assessment of phase I/II trials has been blamed for the failure of subsequent phase III trials to show a benefit compared with standard treatments. Curran et al¹³ defined prognostic classes of malignant glioma patients using a recursive partitioning model of pretreatment and treatment variables in over 1,500 patients entered on RTOG clinical trials. These classes provide reliable "historical" controls, with which results of phase I/II studies may be compared. A validation of the predictive value of this model was undertaken by Scott et al,¹⁹ using data from the randomized phase III RTOG trial 90-06. This trial compared 60 Gy in 30 2-Gy daily fractions (control arm) with 72 Gy in 60 1.2-Gy fractions twice a day (study arm). The experimental treatment was based on the apparently superior results obtained using this regimen in the prior RTOG phase I/II trial 83-02.²⁰ A reanalysis of this trial by recursive partitioning analysis classes indicated that 72 Gy did not in fact produce results that were superior to those estimated from the database. Hence, this type of analysis would have correctly predicted that RTOG 90-06 had little chance of producing a positive result. Indeed, the results of the present study, analyzed according to the same classes, did not show any significant difference in survival when compared with the RTOG database.

In summary, the feasibility of ARCO was good, but feasibility became only fair when nicotinamide was associated with accelerated radiotherapy with or without carbogen. This was most likely related to the higher acute toxicity rate (mainly upper gastrointestinal) in patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, which suggests a higher-than-expected acute neurologic toxicity. Late neurologic events were similar in the three treatment steps and were most frequently observed in patients with disease progression. Although this trial was not randomized, overall survival was similar in the three treatment steps and not different when compared with appropriate historical controls. Thus, the results of the present study do not support the development of a randomized phase III trial to test the utility of carbogen and nicotinamide in association with radiotherapy in this setting.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Centers Participating in EORTC Trial 22933: Academisch Medisch Centrum, Amsterdam, the Netherlands; Ospedale San Giovanni, Bellinzona, Switzerland; Inselspital, Bern, Switzerland; Academish Ziekenhuis, VUB, Brussels, Belgium; Centre G.F. Leclerc, Dijon, France; Hôpital Cantonal Universitaire, Geneva, Switzerland; Centre Hospitalier Regional et Universitaire, Grenoble, France; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Centre Léon Berard, Lyon, France; Ospedale Maggiore della Carita, Novara, Italy; Norrlands Universitetssjukhus, Umeà, Sweden; Ospedale di Circolo, Fondazione Macchi, Varese, Italy; and Universitätsspital, Zurich, Switzerland.

	ACKNOWLEDGMENTS

 
Supported by a grant from Fondation Cancer (Belgium) and by grants no. 5U10CA11488-24 through 2U10CA11488-28 from the National Cancer Institute (Bethesda, MD)

	NOTES

 
The contents of this article are solely the responsibility of the authors and do not necessary represent the official views of the National Cancer Institute.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Black PM: Brain tumors. N Engl J Med324:1555-1564, 1991[Medline]

2. Walker MD, Alexander E, Hunt WE, et al: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic glioma: A cooperative clinical trial. J Neurosurg49:333-343, 1978[Medline]

3. Kristiansen K, Hagen S, Kollevold T, et al: Combined modality therapy in operated astrocytoma grade III and IV. Cancer47:649-652, 1981[Medline]

4. Taghian A, Ramsay J, Allalunis-Turner J, et al: Intrinsic radiation sensitivity may not be the major determinant of the poor clinical outcome of glioblastoma multiforme. Int J Radiat Oncol Biol Phys25:243-249, 1993[Medline]

5. Shibuya M, Ito S, Miwa T, et al: Proliferative potential of brain tumors: Analysis with Ki-67 and anti-DNA polymerase alpha monoclonal antibodies, bromodeoxyuridine labeling, and nuclear organizer region counts. Cancer71:199-206, 1993[Medline]

6. Kayama T, Yoshimoto T, Fujimoto S, et al: Intratumoral oxygen pressure in malignant brain tumors. J Neurosurg74:55-59, 1991[Medline]

7. Rampling R, Cruickshank G: Direct measurements of the pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int J Radiat Oncol Biol Phys29:427-431, 1994[Medline]

8. Keim H, Potthoff PC, Schmidt K, et al: Survival and quality of life after continuous accelerated radiotherapy of glioblastomas. Radiother Oncol9:21-26, 1987[Medline]

9. Thames DH, Peters LJ, Withers RH, et al: Accelerated fractionation vs hyperfractionation: Rationales for several treatments per day. Int J Radiat Oncol Biol Phys9:127-138, 1983[Medline]

10. Kjellen E, Joiner MC, Collier JM, et al: A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated x-ray treatments. Radiother Oncol22:81-91, 1991[Medline]

11. Rojas A, Hirst VK, Calvert AS, et al: Carbogen and nicotinamide as radiosensitizers in a murine mammary carcinoma using conventional and accelerated radiotherapy. Int J Radiat Oncol Bio Phys34:357-365, 1996[Medline]

12. Rojas A: ARCON: Accelerated radiotherapy with carbogen and nicotinamide. Br J Radiol24:174-178, 1992 (suppl)

13. Curran WJ Jr, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst85:704-710, 1993[Abstract/Free Full Text]

14. González-González D, Menten J, Bosch DA, et al: Accelerated radiotherapy in glioblastoma multiforme: A dose searching prospective study. Radiother Oncol32:98-105, 1994[Medline]

15. Fatigante L, Ducci F, Cartei F, et al: Carbogen and nicotinamide combined with unconventional radiotherapy in glioblastoma multiforme: A new modality treatment. Int J Radiat Oncol Biol Phys37:499-504, 1997[Medline]

16. Pickles T, Grahem P, Syndikus I, et al: Tolerance of nicotinamide and carbogen with radiation therapy for glioblastoma. Radiother Oncol40:245-247, 1996[Medline]

17. Van der Maazen RWM, Thijssen HOM, Kaanders JHAM, et al: Conventional radiotherapy combined with carbogen breathing and nicotinamide for malignant gliomas. Radiother Oncol35:118-122, 1995[Medline]

18. Buatti JM, Marcus RB Jr, Mendenhall WM, et al: Accelerated hyperfractionated radiotherapy for malignant gliomas. Int J Radiat Oncol Biol Phys34:785-792, 1996[Medline]

19. Scott CB, Scarantino C, Urtasun R, et al: Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG 90-06. Int J Radiat Oncol Biol Phys40:51-55, 1998[Medline]

20. Werner-Wasik M, Scott CB, Nelson DF, et al: Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas: Radiation Therapy Oncology Group study 83-02. Cancer77:1535-1543, 1996[Medline]

Submitted January 6, 1999; accepted June 2, 1999.

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