Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial

PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.     

Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy.

EORTC protocol 22791 compared once daily fractionation (CF) of 70 Gy in 35-40 fractions in 7-8 weeks, to pure hyperfractionation (HF) of 80.5 Gy in 70 fractions in 7 weeks using 2 fractions of 1.15 Gy per day, in T2-T3 oropharyngeal carcinoma (excluding base of tongue), N0,N1 of less than 3 cm. From 1980 to 1987, 356 patients were entered. In the final analysis (June 1990), the local control was significantly higher (p = 0.02 log-rank) after HF compared with CF. At 5 years, 59% of patients are local disease-free in the HF arm compared to 40% in the CF arm. The superiority of HF was demonstrated in patients staged T3N0,T3N1 but not in T2. The Cox model confirmed that the treatment regimen was an independent significant prognostic factor for locoregional control (p = 0.007 log-rank). This improvement of locoregional control was responsible for a trend to an improved survival (p = 0.08 log-rank). There was no difference in late normal tissue damage between the two treatment modalities.     

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx

AIMS AND BACKGROUND: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. METHODS AND STUDY DESIGN: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). RESULTS: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. CONCLUSIONS: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.     

Five year results of a randomized trial comparing hyperfractionated to conventional radiotherapy over four weeks in locally advanced head and neck cancer.

BACKGROUND AND PURPOSE: Fractionation strategies delivered over 4 weeks are of clinical and radiobiological interest because treatment is completed before radiotherapy (RT) induced clonogen proliferation commences in earnest approximately 3 to 4 weeks into a course of RT. We wished to test the clinical hypothesis that an increased total dose delivered over 4 weeks with smaller than standard doses per fraction in locally advanced squamous cell carcinoma (SCC) may result in relative protection of late responding tissues and an increased tumor control compared to a conventional daily course in the same overall time. MATERIALS AND METHODS: Between 1988 and 1995 a randomized controlled trial employing RT alone was undertaken at the Princess Margaret Hospital that included 331 eligible patients with T3 or T4 N0 or any N-positive oropharynx, hypopharynx, or larynx primary SCC. RT was randomly assigned to one of two 4 week schedules, either 51 Gy in 20 equal daily fractions, termed conventional fractionation (CF), or 58 Gy in 40 equal fractions given twice per day as a hyperfractionated (HF) experimental arm. RESULTS: The 5-year local relapse rate was reduced in the HF (41%) compared to the CF arm (49%). This difference was marginally not significant (p=0.082) when the effect was not adjusted. When the effect of the treatment was adjusted by Cox model for clinical factors that included N-category, ECOG performance status, site of disease, T-category, age, hemoglobin, and gender the HF achieved a significant effect (p=0.02). Survival (40% vs. 30%) was also improved with HF compared to CF arm. This difference was only marginally not significant (p=0.069) but again achieved statistical significance when the model was adjusted for clinical factors (p=0.01). Similar results were observed for disease free survival. Although reversible acute toxicity was increased with HF, the overall 5-year rate of grade 3 and 4 late toxicity for the CF was 10.5% compared to 7.7% in the higher dose HF arm. CONCLUSIONS: HF delivered in 4 weeks permits enhanced RT doses achieving improved tumor control, without increased late toxicity, compared to daily fractionated radiotherapy in the same overall time.     

A randomized clinical trial comparing systemic radiotherapy versus chemotherapy versus local radiotherapy in small cell lung cancer

Between 1982 and 1987 a prospectively randomized trial of sequential hemibody irradiation (SHBI) (A), a non-cross-resistant chemotherapy drug combination (B) and local and/or locoregional radiotherapy (C) in small cell lung cancer (SCLC) was conducted. Previously untreated patients with extensive SCLC were randomized into three arms: A = 31 patients, B = 37, C = 31. In the chemotherapy combination, the following were used: etoposide, doxorubicin, methotrexate (VAM) and procarbacine, vincristine, cyclophosphamide, lomustine (POCC) and prophylactic cranial irradiation (30 Gy). The results show that the median survival was significantly (P < 0.01) better in chemotherapy (44 weeks) compared with 17 and 20 weeks in arms A and C, respectively. One year and 2 year survival rates were better for the chemotherapy arm. No differences were found between groups A and C. In comparing the total hospitalization time expressed as a percentage of overall survival, an advantage for group B was shown. In conclusion, high dose SHBI cannot be recommended as a standard therapy for extensive SCLC.     

鼻咽癌超分割伴后程加速放疗临床Ⅲ期研究初步分析

目的：比较超分割伴后程加速放疗和常规放疗治疗鼻咽癌的疗效和急性反应。方法：1998年3月至2001年8月，163例低分化鳞癌的住院鼻咽癌患者进行放射治疗。随机分组81例入超分割伴后程加速组，1．2GyBid，间隔≥6小时，至48Gy／40次既第4周后，改为1．5Gy Bid达6周总剂量78Gy／60次。82例人常规放疗组，为7周70Gy／35次。结果：中位随访期37个月(19～59个月)。超分割后程伴加速组和常规组2年和4年的局部控制率分别为94．7％、87．9％和89．9%、79．2％(P=0．1627)；2年和4年的无瘤生存率分别为81．6％、71．7％和83．8％、64．7％(P=0．5438)；2年和4年的总生存率分别为95．6％、88．2％和96．2％、79．2％(P=0．5424)。Ⅲ度黏膜反应发生率分别为42％和15．9％，Ⅳ度黏膜反应的比例相仿(6％和5％)。结论：本研究发现在超分割基础上的后程加速超分割放疗与常规放疗相比有提高局控率的趋势，但生存率并未提高。急性粘膜反应较常规放疗有所增加。     

Long-term results of hyperfractionated radiotherapy in patients with stage III-IV oropharyngeal carcinoma

Radiotherapy was given to 139 patients with oropharyngeal carcinoma (stage III-IV) divided into two groups. Group I included 82 patients who received three daily equal fractions (1 Gy), at 4 hr interval, of a mean total focal dose of 80 Gy. Patients in group II (57) received a mean total dose of 68 Gy in 5 weekly standard fractions. Fractionated treatment was carried out in both groups in three stages at 17-day intervals. Complete remission was achieved in 50 (60.9%) patients in group I and in 31 (54.4%)--group II. Total 5-year and recurrence-free survival was 37.3 +/- 5.4 and 32.4 +/- 5.2% (group I) and 12.5 +/- 4.7 and 10.4 +/- 4.4% in group II, respectively. Radiation injury rates were nearly identical in both groups: 14% for standard radiotherapy and 12% for multiple fractions. The data point to high effectiveness of the latter.     

Health-related quality-of-life outcomes following IMRT versus conventional radiotherapy for oropharyngeal squamous cell carcinoma

PURPOSE: To compare health-related quality-of-life (HRQOL) outcomes of patients with oropharyngeal squamous cell carcinoma treated using intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT). PATIENTS AND METHODS: Patients with oropharyngeal squamous cell carcinoma were extracted from the database of an ongoing longitudinal Outcome Assessment Project. Eligible criteria included (1) treated with definitive radiation, and (2) provided 12-month posttreatment HRQOL data. Excluded were 7 patients who received IMRT before October 1, 2002, during this institution's developmental phase of the IMRT technique. The HRQOL outcomes of patients treated with IMRT were compared with those of patients who received CRT. RESULTS: Twenty-six patients treated using IMRT and 27 patients treated using CRT were included. Patients in the IMRT group were older and had more advanced-stage diseases and more patients received concurrent chemotherapy. However, the IMRT group had higher mean Head and Neck Cancer Inventory scores (which represent better outcomes) for each of the four head-and-neck cancer-specific domains, including eating, speech, aesthetics, and social disruption, at 12 months after treatment. A significantly greater percentage of patients in the CRT group had restricted diets compared with those in the IMRT group (48.0% vs. 16.0%, p = 0.032). At 3 months after treatment, both groups had significant decreases from pretreatment eating scores. However, the IMRT group had a significant improvement during the first year, but the CRT group had only small improvement. CONCLUSIONS: Proper delivery of IMRT can improve HRQOL for patients with oropharyngeal cancer compared with CRT.     

There is no role for hyperfractionated radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy

Purpose: In June 1992, POG began accrual to a phase III study, POG-9239, designed to compare the time to disease progression, overall survival, and toxicities observed in children with newly diagnosed brainstem tumor treated with 100 mg/m² of infusional cisplatin and randomized to either conventional vs. hyperfractionated radiotherapy.

Methods and Materials: Patients eligible for study were those between 3 and 21 years of age with previously untreated tumors arising in the pons. Histologic confirmation of diagnosis was not mandatory, provided that the clinical and MRI scan findings were typical for a diffusely infiltrating pontine lesion. Treatment consisted of a six-week course of local field radiotherapy with either once a day treatment of 180 cGy per fraction to a total dose of 5400 cGy (arm 1) or a twice a day regimen of 117 cGy per fraction to a total dose of 7020 cGy (the second of the three hyperfractionated dose escalation levels of POG-8495) (arm 2). Because of previously reported poor results with conventional radiotherapy alone, cisplatin was included as a potential radiosensitizer in an attempt to improve progression-free and ultimate survival rates. Based on results of the phase I cisplatin dose escalation trial, POG-9139, 100 mg/m² was chosen for this trial and was delivered by continuous infusion over a 120-hour period, beginning on the first day of radiotherapy and repeated during weeks 3 and 5. One hundred thirty eligible patients were treated on protocol, 66 on arm 1 and 64 on arm 2.

Results: The results we report are from time of diagnosis through October 1997. For patients treated on arm 1, the median time to disease progression (defined as time to off study) was 6 months (range 2–15 months) and the median time to death 8.5 months (range 3–24 months); survival at 1 year was 30.9% and at 2 years, 7.1%. For patients treated on arm 2, the corresponding values were 5 months (range 1–12 months) and 8 months (range 1–23 months), with 1- and 2-year survival rates at 27.0% and 6.7%, respectively. Evaluation of response by MRI at 4 or 8 wks post treatment was available in 108 patients and revealed a complete response in 1 patient of each Rx arm, a partial response (> 50% decrease in size) in 18 patients of arm 1 and 15 patients of arm 2, minimal to no response (stable) in 25 patients of arm 1 and 23 patients of arm 2, and progressive disease in 13 patients of arm 1 and 12 patients of arm 2. The pattern of failure was local in all patients. Morbidity of treatment was similar in both Rx arms, with no significant toxicity (including hearing loss) reported. Autopsy was performed in 6 patients, and confirmed the presence of extensive residual tumor in these cases.

Conclusion: The major conclusion from this trial is that the hyperfractionated method of Rx 2 did not improve event-free survival (p = 0.96) nor did it improve survival (p = 0.65) over that of the conventional fractionation regimen of Rx 1, and that both treatments are associated with a poor disease-free and survival outcome.     

Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma

PURPOSE: Intracavitary brachytherapy plays an important role in the treatment of cervical carcinoma. Previous results have shown controversy between the effect of dose rate on tumor control and the occurrence of complications. We performed a prospective randomized clinical trial to compare the clinical outcomes between low-dose-rate (LDR) and high-dose-rate (HDR) intracavitary brachytherapy for treatment of invasive uterine cervical carcinoma. METHODS AND MATERIALS: A total of 237 patients with previously untreated invasive carcinoma of the uterine cervix treated at King Chulalongkorn Memorial Hospital were randomized between June 1995 and December 2001. Excluding ineligible, incomplete treatment, and incomplete data patients, 109 and 112 patients were in the LDR and HDR groups, respectively. All patients were treated with external beam radiotherapy and LDR or HDR intracavitary brachytherapy using the Chulalongkorn treatment schedule. RESULTS: The median follow-up for the LDR and HDR groups was 40.2 and 37.2 months, respectively. The actuarial 3-year overall and relapse-free survival rate for all patients was 69.6% and 70%, respectively. The 3-year overall survival rate in the LDR and HDR groups was 70.9% and 68.4% (p = 0.75) and the 3-year pelvic control rate was 89.1% and 86.4% (p = 0.51), respectively. The 3-year relapse-free survival rate in both groups was 69.9% (p = 0.35). Most recurrences were distant metastases, especially in Stage IIB and IIIB patients. Grade 3 and 4 complications were found in 2.8% and 7.1% of the LDR and HDR groups (p = 0.23). CONCLUSION: Comparable outcomes were demonstrated between LDR and HDR intracavitary brachytherapy. Concerning patient convenience, the lower number of medical personnel needed, and decreased radiation to health care workers, HDR intracavitary brachytherapy is an alternative to conventional LDR brachytherapy. The high number of distant failure suggests that other modalities such as systemic concurrent or adjuvant chemotherapy might lower this high recurrence, especially in Stage IIB and IIIB.     

放疗联合顺铂治疗晚期鼻咽癌的临床研究

目的：观察放疗同时应用顺铂治疗鼻咽癌时放射增敏作用以及预防转移和提高生存情况。方法：75例晚期（Ⅲ,Ⅳ期）鼻咽癌被随机分为两组：单纯放疗组（RT）37例,顺铂联合放疗组（RT＋P）38例,鼻咽部均采用^60Co或6MVx线常规外照射,总量为68－72Gy。颈部淋巴结转移灶采用^60Co和12－9Mev电子线,肿瘤总量为60－74Gy(颈髓≤40Gy).RT P组在放疗的开始日同时应用顺铂,每次40mg静滴,并给予适当水化和止吐药物。每周2次（周一,三给药）,连用4周,结果：疗终鼻咽肿瘤全消率两组无差异,颈淋巴结转移灶全消率RT＋P组高于RT组（P＜0．05）。低分化鳞癌N2病灶全消时的平均放射剂量RT＋P组低于RT组（P＜0．05）。3年内鼻咽癌复发,颈部淋巴结复发及远处转移RT＋P组均低于RT组,分别是10．5％,7．9％,15．8％和29．7％,27．0％,48．6％,均有显性差异。3,5年生存率RT＋P组＜RT组分别是40．5％,24．3％和68．4％,47．4％（P＜0．05）。结论：放疗同时给予适量顺铂,具有一定增敏作用,并能抑制或延迟肿瘤复发及远处转移,从而提高晚期鼻咽癌患的生存期。     

Radiotherapy for muscle-invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose-escalated partial bladder radiotherapy

PURPOSE: To investigate whether delivering an increased radiation dose to the tumor-bearing region of the bladder alone would improve local disease control without increasing treatment toxicity. METHODS AND MATERIALS: A total of 149 patients with unifocal T2-T3N0M0 bladder carcinoma were randomized between whole bladder conformal radiotherapy (WBRT, 52.5 Gy in 20 fractions, n = 60) and partial bladder conformal RT (PBRT) to tumor alone with 1.5-cm margins within either 4 weeks (PBRT4, 57.5 Gy in 20 fractions, n = 44) or 3 weeks (PBRT3, 55 Gy in 16 fractions, n = 45). The response was assessed cystoscopically after 4 months. RESULTS: The 5-year overall and CFS rate was 58% and 47%, respectively, for the whole population. The CR rate was 75% for WBRT, 80% for PBRT4, and 71% for PBRT3 (p = 0.6), with a 5-year local control rate of 58%, 59%, and 34%, respectively (p = 0.18). Solitary new tumors arose within the bladder, outside the irradiated volume, in 6 (7%) of 89 patients who underwent PBRT. The 5-year overall survival and cystectomy-free survival rate was 61% and 49% for WBRT, 60% and 50% for PBRT4, and 51% and 41% for PBRT3 (p = 0.81 and p = 0.59). The treatment toxicity was mild and equivalent across the three trial arms. CONCLUSION: The reduction in treatment volume allowed delivery of an increased radiation dose without a reduction in local tumor control or the development of excess toxicity. However, this dose-escalated partial bladder approach did not result in significantly improved overall survival.     

鼻咽癌后程三维适形放疗加时间调节化疗的临床前瞻性随机研究

目的观察鼻咽癌后程三维适形放疗加时间调节化疗与常规放化疗的疗效和副作用。方法将86例患者用信封法随机分为后程三维适形放疗加时间调节化疗组(CCR组)和常规放化疗组(RCR组)。两组均先进行2个周期顺铂+氟尿嘧啶+亚叶酸钙不同给药方法的诱导化疗,之后加不同方式的放疗。RCR组用药量同CCR组,鼻咽病灶放疗剂量均为70Gy7周。结果完全缓解率、有效率CCR组和RCR组分别为45.5%、95.5%和23.8%、71.4%。两组差异有统计学意义(P<0.05)。两组1、3年生存率差异无统计学意义(P>0.05)。RCR组相对于CCR组口腔炎、恶心呕吐、腹泻更多见(P<0.05),骨髓毒性反应的差异亦有统计学意义(P<0.05)。结论鼻咽癌后程三维适形放疗加时间调节化疗治疗较常规放化疗有较好效果,且副反应较低。     

Malignant astrocytoma: hyperfractionated and standard radiotherapy with chemotherapy in a randomized prospective clinical trial

A prospective randomized trial of 157 patients with malignant astrocytoma (Grade III or IV) was carried out at a single institution. The minimization technique ensured balanced distribution of prognostic factors between the treatment groups. All received oral lomustine (CCNU, 80 mg/m2) six weekly and hydroxyurea (HU, 3.5 gm/m2 over 5 days) three weekly, for one year or until recurrence, with doses adjusted for myelosuppression. Patients were randomized to daily (5000 rad in 25 fractions (fr) in 5 weeks) or Q3h (every 3 hours) Cobalt 60 irradiation (3600-4000 rad in 36-40 fr of 100 rad each, given 4 fr per day at 3-hour intervals over two weeks) Steroid therapy (up to 16 mg day dexamethasone) was permitted. Complications were moderate and equivalent in the two groups. No significant survival or toxicity differences were seen between the two groups. Age, initial performance status, and extent of surgical resection were found to be significant (P less than 0.01) prognostic factors for survival. Median survival of the whole group was 48 weeks with a minimum follow-up of one year. There was no advantage to large radiation fields. The hyperfractionation and daily regimens had similar efficacy and toxicity. Hyperfractionation with chemotherapy offers a useful alternative approach in the management of this disease.     

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m² of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1–3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p?=?0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p?=?0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p?=?0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p?=?0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p?=?0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p?=?0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.