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.     

Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or ≤ 20 cm, respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients

Purpose: To compare survivorship, and acute and delayed toxicities following radiation therapy (RT) of radiosurgery-ineligible glioblastoma multiforme (GBM) patients treated with tumor volume-influenced, high-dose accelerated, hyperfractionated RT plus bischloroethyl-nitrosourea (BCNU), using prior RTOG malignant glioblastoma patients as historical controls.

Methods and Materials: One hundred four of 108 patients accrued from June 1994 through May 1995 from 26 institutions were analyzable. Patients were histologically confirmed with GBM, and previously untreated. Treatment assignment (52 patients/arm) was based on tumor mass (TM), defined as the product of the maximum diameter and greatest perpendicular dimension of the titanium-gadolinium-enhanced postoperative MRI: Arm A, 64 Gy, TM > 20 cm²; or Arm B, 70.4 Gy, TM ≤ 20 cm². Both Arms A and B received BCNU (80 mg/m², under hyperhydration) days 1–3, 56–58, then 4 cycles, each 8 weeks, for a total of 6 treatment series.

Results: During the 24 months immediately post-treatment, the overall median survival was 9.1 months in Arm A (64 Gy) and 11.0 months in Arm B (70.4 Gy). Median survival in recursive partitioning analysis (RPA) Class III/IV was 10.4 months in Arm A and 12.2 months in Arm B, while RPA Class V/VI was 7.6 months in Arm A and 6.1 months in Arm B. There were no grade 4 neurological toxicities in Arm A; 2 grade 4 neurological toxicities were observed in Arm B (1 motor deficit, 1 necrosis at 157 days post-treatment).

Conclusion: This strategy of high-dose, accelerated hyperfractionated radiotherapy shortens overall RT treatment times while allowing dose escalation, and it provides the potential for combination with currently available, as well as newer, chemotherapy agents. Survival is comparable with previously published RTOG data, and toxicities are within acceptable limits.     

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.     

A Randomized Study of Short Course (One Week) Radiation Therapy with or without Temozolomide in Elderly and/or Frail Patients with Newly Diagnosed Glioblastoma (GBM)

Objective: Short-course radiotherapy (25 Gy in 5 fractions) has been shown to be non-inferior to standard course radiotherapy in elderly and frail patients (60 Gy in 30 fractions). The purpose of this study was to determine the effects of temozolomide combined with short-course radiotherapy on the outcome of elderly and frail patients. Methods: Between January 2017 and November 2018, 90 patients (65 years old and KPS score of 50-70; 65 years old and KPS score of 80-100; and 65 years old and KPS score of 50-70) were assessed for eligibility. Nine patients were excluded because they did not meet the inclusion criteria, six patients declined to participate, and four patients were unable to complete the quality-of-life questionnaire. The remaining 71 patients were divided into two arms at random in a 1:1 ratio. Short-course radiotherapy with concurrent temozolomide and adjuvant temozolomide was given to Arm 1, while short-course radiotherapy alone was given to Arm 2. Results: In terms of overall survival and progression-free survival, radiotherapy with concurrent temozolomide and adjuvant temozolomide outperformed short-course radiotherapy alone. The median overall survival in arm 1 was 146 days and 121 days in arm 2 (P=0.146). The median progression-free survival in arm 1 was 109.50 days, while it was 77 days in arm 2 (P=0.028). With a median follow-up time of 6 months, the quality of life at 4 weeks and 12 weeks after treatment was not different between the two arms. Conclusion: We concluded that adding temozolomide to short-course radiotherapy significantly improved progression-free survival and showed an increasing trend in overall survival without compromising the quality of life.     

A phase 2 randomised study of ramucirumab (IMC-1121B) with or without dacarbazine in patients with metastatic melanoma

BackgroundTo evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM).MethodsEligible patients received ramucirumab (10 mg/kg) + dacarbazine (1000 mg/m²) (Arm A) or ramucirumab only (10 mg/kg) (Arm B) every 3 weeks. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), overall response and safety.FindingsOf 106 randomised patients, 102 received study treatment (Arm A, N = 52; Arm B, N = 50). Baseline characteristics were similar in both arms. Median PFS was 2.6 months (Arm A) and 1.7 months (Arm B); median 6-month PFS rates were 30.7% and 17.9% and 12-month PFS rates were 23.7% and 15.6%, respectively. In Arm A, 9 (17.3%) patients had partial response (PR) and 19 (36.5%), stable disease (SD); PR and SD in Arm B were 2 (4.0%) and 21 (42.0%), respectively. Median OS was 8.7 months in Arm A and 11.1 months in Arm B. Patients in both arms tolerated the treatment with limited Grade 3/4 toxicities.InterpretationRamucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm.     

Clinical prognostic factors in patients with locally advanced (stage III) nonsmall cell lung cancer treated with hyperfractionated radiation therapy with and without concurrent chemotherapy: single-Institution Experience in 600 Patients

BACKGROUND:

Influence of potential clinical prognostic factors on overall survival (OS), local progression‐free survival (PFS), and distant metastasis‐free survival (MFS) in patients with locally advanced nonsmall cell lung cancer treated with hyperfractionated radiation therapy (HFX RT) with or without concurrent chemotherapy was investigated.

METHODS:

Three phase 3 and 2 phase 2 studies have been designed and executed with a total of 600 patients. HFX RT alone was given in 127 and HFX RT‐chemotherapy was given in 473 patients. HFX RT doses were either 64.8 grays (Gy) or 69.6 Gy using 1.2 Gy twice daily, or 67.6 Gy using 1.3 Gy twice daily. Chemotherapy consisted of concurrent carboplatin and etoposide in 409 patients and concurrent carboplatin and paclitaxel in 64 patients. Sex, age, Karnofsky performance score (KPS), weight loss (>5%), stage, histology, interfraction interval, and treatment (the addition of concurrent chemotherapy) were investigated as potential prognostic factors.

RESULTS:

The median OS, median local PFS, and median distant MFS times were 19, 21, and 23 months, respectively. Five‐year OS, local PFS, and distant MFS rates were 19%, 29%, and 35%, respectively. Univariate and multivariate analysis showed that only age did not influence OS and local PFS, whereas female sex, lower KPS, less pronounced weight loss, lower stage, squamous histology, shorter interfraction interval, and treatment independently predicted better OS and local PFS. Only age and treatment did not influence distant MFS, whereas histology was of borderline significance.

CONCLUSIONS:

This study identified independent prognosticators of treatment outcome. These results may have implications for future studies in this disease. Cancer 2011. © 2011 American Cancer Society.     

常规与后加速超分割及常规加腔内照射治疗食管癌的远期疗效

目的　观察和比较常规分割、后程加速超分割及常规分割加腔内照射三种方式治疗局部中晚期食管癌的疗效及放射反应。方法　对 111例局部中晚期食管癌首治病例进行前瞻性随机分组研究。常规分割照射组 (常规组 ) 4 0例 :2 .0Gy/次 ,1次 /d ,5d/周 ,共 6 0Gy,30分次 ,6周完成。后程加速超分割组 (后超组 ) 4 1例 :前 3周常规分割 ,30Gy ,15分次 ,3周完成 ;后 2周加速超分割照射 ,1.5Gy/次 ,2次 /d ,5d/周 ,共 30Gy ,2 0分次 ,2周完成。常规外照射加腔内照射组 (腔内组 ) 30例 :常规外照射达 34～ 36Gy时与腔内照射同期进行 (腔内照射当天停外照射 1次 ) ,腔内照射 5 .0Gy/次 ,1次 /周 ,共 2次 ,外照射总量为 5 0Gy。结果　常规组和后超组及腔内组的 1、3、5年生存率分别为 5 7.5 %、2 2 .5 %、14 .1%和 5 7.5 %、2 9.3%、2 4 .4 %及 5 3.3%、2 6 .7%、2 3.3% ,急性放射性食管炎的发生率分别为 2 2 .5 %和 4 1.5 %及 5 0 .0 % ,出血、穿孔的发生率分别为 7.7%和 7.3%及 16 .7%。结论　虽然后程加速超分割放射治疗有提高生存率的趋势 ,但与常规分割照射组及常规外照射加腔内放射治疗组的生存率差异无显著性意义 ,但其是否在治疗中晚期食管癌方面占有绝对优势尚有待大样本前瞻性随机临床研究和长期观察     

A randomized phase I/II trial of hyperfractionated radiation therapy with total doses of 60.0 Gy to 79.2 Gy: possible survival benefit with greater than or equal to 69.6 Gy in favorable patients with Radiation Therapy Oncology Group stage III non-small-cell lung carcinoma: report of Radiation Therapy Oncology Group 83-11

A phase Ilate/II trial of hyperfractionated (HFX) radiation therapy for non-small-cell carcinoma of the lung (NSCCL) was conducted by the Radiation Therapy Oncology Group (RTOG) between 1983 and 1987. Fractions of 1.2 Gy were administered twice daily with greater than or equal to 4 hours between fractions. Patients were randomized to receive minimum total doses of 60.0, 64.8, and 69.6 Gy. After acceptable risks of acute and late effects were found, 74.4 Gy and 79.2 Gy arms were added, and the lowest total dose arms were closed. No significant differences in the risks of acute or late effects in normal tissues were found among the 848 patients analyzed in the five arms; risks of severe or life-threatening pneumonitis were 2.6% for 60.0 to 64.8 Gy, 5.7% for 69.6 to 74.4 Gy, and 8.1% for 79.2 Gy. Among 350 patients who had the same criteria as Cancer and Leukemia Group B (CALGB) protocol 84-33 (American Joint Committee on Cancer Staging [AJCCS], 1984, stage III; Karnofsky performance status [KPS] 70 to 100; less than 6% weight loss), there was a dose response for survival: survival with 69.6 Gy (median, 13.0 months; 2 years, 29%) was significantly (P = .02) better than the lower total doses. There were no differences in survival among the three highest total-dose arms. Comparisons with results in similar patients treated with 60 Gy in 30 fractions of 2.0 Gy 5 days per week for 6 weeks suggest benefit from HFX radiation therapy with 69.6 Gy. Improvement in survival with HFX radiation therapy at 69.6 Gy total dose without increase in normal tissue effects, justifies phase III comparison with standard fractionation alone and combined with systemic chemotherapy in this common presentation of NSCCL.     

Survival Results from a Phase I Study of Etanidazole (SR2508) and Radiotherapy in Patients with Malignant Glioma

Purpose: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status.Patients and Methods: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS ≥ 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m² × 4–5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (≤ 49 or > 49 years), KPS (≤ 80 or > 80) and implant versus non-implant were also performed.Results: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age ≤ 49 were factors found not to be associated with a statistically improved survival.Conclusion: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.     

Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy

Ultrafractionation of radiation therapy is a novel regimen consisting of irradiating tumors several times daily, delivering low doses (<0.75 Gy) at which hyperradiosensitivity occurs. We recently demonstrated the high efficiency of ultrafractionated radiotherapy (RT) on glioma xenografts and report here on a phase II clinical trial to determine the safety, tolerability, and efficacy of an ultrafractionation regimen in patients with newly and inoperable glioblastoma (GBM). Thirty-one patients with histologically proven, newly diagnosed, and unresectable supratentorial GBM (WHO grade IV) were enrolled. Three daily doses of 0.75 Gy were delivered at least 4 hours apart, 5 days per week over 6–7 consecutive weeks (90 fractions for a total of 67.5 Gy). Conformal irradiation included the tumor bulk with a margin of 2.5 cm. The primary end points were safety, toxicity, and tolerability, and the secondary end points were overall survival (OS) and progression-free survival (PFS). Multivariate analysis was used to compare the OS and PFS with the EORTC-NCIC trial 26981-22981/CE.3 of RT alone vs radiation therapy and temozolomide (TMZ). The ultrafractionation radiation regimen was safe and well tolerated. No acute Grade III and/or IV CNS toxicity was observed. Median PFS and OS from initial diagnosis were 5.1 and 9.5 months, respectively. When comparing with the EORTC/NCIC trial, in both PFS and OS multivariate analysis, ultrafractionation showed superiority over RT alone, but not over RT and TMZ. The ultrafractionation regimen is safe and may prolong the survival of patients with GBM. Further investigation is warranted and a trial associating ultra-fractionation and TMZ is ongoing.     

局限期SCLC超分割或大分割放疗同步化疗预后比较

目的 比较超分割或大分割放疗同步化疗对局限期SCLC的生存影响。方法 超分割和大分割组分别入组患者92、96例。超分割组采用45 Gy分30次,2 次/d。大分割组采用55 Gy分22次,1 次/d。采用Kaplan-Meier法计算生存率,Cox模型多因素预后分析。结果 超分割和大分割组患者1、2、5年PFS率分别为82%、61%、59%和85%、69%、69%(P=0.27),OS率分别为85%、41%、27%和77%、34%、27%(P=0.37)。多因素分析显示化疗开始到放疗开始时间≤43 d是PFS的有利因素(P=0.005),化疗开始到放疗结束时间≤63 d、PCI是OS有利因素(P=0.044、0.000)。超分割组和大分割组2、3级急性放射性食管炎发生率分别为28%、9%和16%、2%(P=0.009)。结论 采用加速超分割或大分割方案联合同步化疗的PFS及OS均显著提高。控制化疗开始至放疗开始、结束时间≤43 d、≤63 d有利于提高PFS和OS。但2、3级急性放射性食管炎的发生率超分割组显著高于大分割组。     

Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB–IVA cervical cancer with or without immunomodulator Z-100: a JGOG study

BackgroundBased on the result of our previous study showing better overall survival (OS) at the lower dose (0.2 µg) of immunomodulator Z-100 than higher dose (40 µg) in patients with locally advanced cervical cancer who received radiotherapy, we conducted a placebo-controlled double-blind randomized trial.Patients and methodsPatients of stages IIB–IVA squamous cell carcinoma of the uterine cervix were randomly assigned to receive Z-100 at 0.2 µg (Z) or placebo (P). The study agent was given subcutaneously twice a week during the radiotherapy, followed by maintenance therapy by administering once every 2 weeks until disease progression. Primary end point was OS, and secondary end points were recurrence-free survival, and toxicity.ResultsA total of 249 patients were randomized. Death events occurred extremely slower than expected, and Independent Data Monitoring Committee recommended to analyze the survival result prematurely. The 5-year OS rate was 75.7% [95% confidence interval (CI) 66.4% to 82.8%] for Arm Z and 65.8% (95% CI 56.2% to 73.8%) for Arm P (P = 0.07); hazard ratio was 0.65 (95% CI 0.40–1.04). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There was no trend in recurrence-free survival between the two arms. Side-effects were not different between two arms.ConclusionZ-100 showed a trend of improvement on OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Validation of potential survival benefit of immune modulation should be made.Trial registrationumin.ac.jp/ctr Identifier: C000000221.     

Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma

Objectives The optimal treatment for elderly patients (age >70 years) with glioblastoma (GBM) remains controversial. We conducted a prospective trial in 43 consecutive elderly patients with GBM treated with hypofractionated radiotherapy (RT) followed by adjuvant temozolomide. Patients and methods Forty-three patients 70 years of age or older with a newly diagnosed GBM and a Karnofsky performance status (KPS) ≥ 60 were treated with hypofractionated RT (6 fractions of 5 Gy each for a total of 30 Gy over 2 weeks) followed by up to 12 cycles of adjuvant temozolomide (150–200 mg/m² for 5 days during each 28 day cycle). The HRQOL was assessed with the EORTC Quality of Life Questionnaire C30. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), toxicity and quality of life. Results The median OS was 9.3 months and the median PFS was 6.3 months. The 6 and 12 month survival rates were 86% and 35%, respectively. The 6 and 12 month PFS rates were 55% and 12%, respectively. In multivariate analysis KPS was the only significant independent predictive factor of survival (P = 0.008). Neurological deterioration occurred during or after RT in 16% of patients and was resolved in most cases with the use of steroids. Grade 3–4 hematologic toxicity occurred in 28% of patients during the adjuvant chemotherapy treatment with temozolomide. The treatment had no negative effect on HRQOL, however, fatigue (P = 0.02) and constipation (P = 0.01) scales worsened over time. Conclusions Hypofractionated RT followed by temozolomide may provide survival benefit maintaining a good quality of life in elderly patients with GBM. It may represent a reasonable therapeutic approach especially in patients with less favourably prognostic factors.     

A pilot study of hypofractionated radiation therapy with temozolomide for adults with glioblastoma multiforme

To evaluate the safety and efficacy of hypofractionated radiotherapy (RT) with a standard temozolomide (TMZ) regimen for adults with newly diagnosed glioblastoma multiforme (GBM), twenty-six consecutive adults (range 39–79 years) who met our enrollment criteria received short courses of hypofractionated RT (45 Gy in 15 fractions over three weeks) with concomitant TMZ at 75 mg/m²/d. After 28 days, TMZ was maintained at 150–200 mg/m²/d on five days for 12 cycles or until tumor progression or unacceptable toxicity. The primary end point was determined by overall survival (OS) and toxicity. Secondary assessed end points were: progression-free survival (PFS) at six months, health-related quality of life (HRQOL), and pseudo-progression. We assessed HRQOL by use of the Karnofsky performance status (KPS) and the Functional Assessment of Cancer Therapy–Brain (FACT-Br) Subscale. All 26 patients were evaluated for OS, PFS, and HRQOL. At a median follow-up of 20 months, the median OS was 15.6 months (95% confidence interval 9.0–22.2 months) with acceptable toxicity. PFS rate at six months was 65%. KPS and FACT-Br Subscale scores did not decline after this procedure. Pseudo-progression occurred in two (8%) patients. Adult patients with GBM benefitted from favorable OS and PFS rate as a result of the hypofractionated RT with TMZ. An additional advantage is that this procedure may reduce the course of treatment. Further studies using this procedure are warranted.     

Comparison of accelerated hyperfractionated radiotherapy and conventional radiotherapy for supratentorial malignant glioma

Between 1988 and 1993, 71 patients with glioblastoma or anaplastic astrocytoma were treated either with accelerated hyperfractionation radiotherapy (1.5 Gy twice daily to a total dose of 69 Gy, n = 35) or with conventional fractionation radiotherapy (1.8 Gy daily to 64.8 Gy, n = 36). Two patients in each group did not complete radiotherapy, leaving 67 evaluable. All patients received the chemotherapeutic regime ACNU intraarterially (50 mg/m2) or intravenously (100 mg/m2) prior to and after radiotherapy. Between 1990 and 1992, 19 patients also received intravenous interferon-beta (3 x 10(6) U, three times weekly) during radiotherapy. The median survival time was 14.5 months for the accelerated hyperfractionation group and 14 months for the conventional fractionation group. The median time to progression was 12 months for the accelerated hyperfractionation group and 9.5 months for the conventional fractionation group. There was no significant difference in either survival (P = 0.89) or progression-free survival (P = 0.25) between the accelerated hyperfractionation and conventional fractionation groups. Interferon therapy was associated with poorer survival. Brain necrosis developed in four out of 10 patients receiving accelerated hyperfractionation radiotherapy plus interferon-beta, but in none of nine patients receiving conventional fractionation radiotherapy plus interferon (P = 0.033). In conclusion, our study failed to demonstrate any possible benefit of accelerated hyperfractionation radiotherapy for malignant glioma. The incidence of brain necrosis may be increased by combining accelerated hyperfractionation radiotherapy and interferon-beta.      

Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma

From April 1986 to May 1989, 112 patients seen at a single institution with previously untreated squamous cell oropharynx carcinoma, Stages III and IV, were randomly assigned to 66 Gy in 33 fractions of 2 Gy each (conventional RT) versus 70.4 Gy in 64 fractions of 1.1 Gy given twice a day with a minimal interfraction interval of 6 hours (hyperfractionated RT). The overall time for both arms was 6 1/2 weeks. Patients were stratified by site (base of the tongue vs others), T stage (T1/T2 vs T3 vs T4), N stage (N0/N1 vs N2 vs N3), and lymphnode size (less than 6 cm vs greater than 6 cm). As of January 1990, an analysis was performed in 98 patients (8 patients in the conventional arm and 6 in the hyperfractionation not included). The groups were balanced by age, performance status, stage, and site of the primary disease. The median follow-up time was 25 months. The probability of complete loco-regional response was 62% in the hyperfractionation arm and 52% for the conventional fractionation (p = 0.28). There was no difference in the control of lymphnodal disease (hyperfractionated = 55%, conventional = 57%; p = 0.92), but the disease control in the oropharynx only was significantly improved in the hyperfractionation arm (84% vs 64%, p = 0.02). Overall survival rate at 42 months was 27% for the hyperfractionation arm and 8% for the conventional (p = 0.03). Survival rates for hyperfractionated versus conventional RT were 40% versus 18% (p = 0.06), respectively, for Stage III patients and 16% versus 0% (p = 0.15), respectively, for Stage IV. There was significant improvement in survival in favor of the hyperfractionation arm in patients with lesions outside the base of the tongue (31% vs 15%, p = 0.02), for those with a 50-70% Karnofsky status (19% vs 0%, p = 0.006) and for patients with N0/N1 disease (38% vs 15%, p = 0.03). Acute toxicities were of similar magnitude, although both skin and mucosal reactions appeared earlier on the hyperfractionation scheme. To date, no differences in late toxicity have been observed. We conclude that in a subset group of patients with locally advanced carcinoma of the oropharynx, hyperfractionated radiotherapy appears to provide improved survival without adding to increased toxicity.     

Improved results with accelerated hyperfractionated radiotherapy of advanced head and neck cancer

A retrospective study on local tumor control, survival, and complications of conventional irradiation vs. accelerated hyperfractionated irradiation in patients with selected head and neck cancer sites was undertaken. A total of 1,007 consecutive patients treated with radiation alone for cure from 1974-1997 were analyzed. Excluded were female patients, patients with T1 stage of the vocal cord, and patients also treated with brachytherapy implants. There were 637 patients treated with conventional fractionation once daily (QD) in 1974-1997, at a median 2.1 Gy/fraction, to a total median dose of 71.4 Gy in a median overall time of 54 days. As was common before the mid-1980s, 39% and 22% of patients had overall times exceeding 8 and 9 weeks, respectively; 370 patients were treated with accelerated hyperfractionation twice daily (BID) from 1987-1997, at a median of 1.6 Gy/fraction, with an interfraction interval of 4-6 h, to a total median dose of 68 Gy in 40 days. Both schedules were well-balanced with respect to their pretreatment characteristics. Patients were not randomized into QD or BID. The 10-year actuarial probability of local control was 37% vs. 56% for QD and BID, respectively (P < 0.001), which reflects an increase of 19% or a 51% reduction in the local failure rate. Multivariate analysis revealed that T-stage, QD or BID schedule, and overall treatment time were significant independent factors for achieving local tumor control. The 10-year actuarial probability of cause-specific disease-free survival was 25% and 30% for QD and BID, respectively (P = 0.012). Acute morbidity was slightly higher with the BID schedule: patients requiring tube or parenteral feeding were 2.4% for BID and 0.5% for QD (P = 0.01). The 10-year actuarial probability of RTOG/EORTC Grades 3-5 late effects was 13% for both QD and BID. The lack of increase in late complications was most probably due to the lower total dose and dose per fraction in the BID schedule. This study has shown that accelerated hyperfractionated irradiation using two doses of 1.6 Gy each treatment day for less than 6 weeks in advanced head and neck cancer in male patients provides significantly better local tumor control and cause-specific disease-free survival, without increased late morbidity, than conventional fractionation delivered at the previously relaxed overall times of 7 weeks, but sometimes exceeding 8 or 9 weeks. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 80-91, 2000.     

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.     

后程加速超分割放疗联合腔内加热治疗食管癌前瞻性研究

目的探讨食管癌后程加速超分割放疗联合腔内加热的疗效。方法91例食管癌患者进入单纯后程加速超分割放疗(单放组)和后程加速超分割放疗联合腔内加热(热放组)的前瞻性随机对照研究，其中单放组44例，热放组47例。放疗前2／3疗程常规分割，1．8Gy／次，共41．4Gy，23分次，4～5周完成；后1／3疗程缩野加速超分割放疗，1．5Gy／次，2次／d，间隔6h，共27Gy，18分次；总剂量68．4Gy，41分次。热放组在常规分割期间每周腔内加热1次，共4次。结果单放组和热放组治疗结束时CR率分别为47．7％和72．3％，PR率分别为52．3％和27．8％(P=0．016)。中位生存时间单放组和热放组分别为30．3和30．6个月。1、2、3年生存率单放组和热放组分别为77．3％、57．4％、37．3％和80．5％、68．6%、46．3％(P=0．526)，1、2、3年局部控制率分别为86．3％、70．5％、56．5%、和92．4％、72．5％、65．5％(P=0．686)。单放组与热放组的3级急性放射性食管炎发生率分别为18．2％和27．6％(P=0．498)，3级急性放射性气管炎分别为11．4％和19．2%(P=0．191)。结论食管癌后程加速超分割放疗联合腔内加热的即期疗效优于单纯后程加速超分割放疗，腔内加热没有明显增加后程加速超分割放疗的毒性反应。     

Long-term outcome of irradiation with or without chemotherapy for esophageal squamous cell carcinoma: a final report on a prospective trial

ABSTRACT: PurposeTo investigate the long-term outcome of esophageal squamous cell carcinoma (SCC) treated by irradiation with or without concurrent chemotherapy.Methods and materialsA prospective clinical trial was carried out from 1998 to 2000. One hundred and eleven patients were randomly enrolled to receive either late course accelerated hyperfractionated irradiation (LCAF) or LCAF with concurrent chemotherapy (LCAF + CT). For LCAF, 41.4 Gy in 23 fractions was first delivered at five fractions per week, followed by 27 Gy in 18 fractions at two 1.5 Gy fractions a day. Concurrent chemotherapy of cis-platinum and 5-fluorouracil was administered for four cycles. Overall survival (OS), locoregional recurrence and distant metastasis were observed. Late toxicity was scored by RTOG criteria, and quality of life (QOL) was also evaluated. RESULTS: The median follow-up time was 24 months for all patients and 138 months for 17 living patients. Median survival time was 25 months and 32 months in LCAF and LCAF + CT (p = 0.653), respectively. For an entire group of patients, overall survivals were 34%, 27% and 22%; locoregional recurrence rates were 30%, 36% and 41%; and distant metastasis rates were 26%, 28% and 29% at 5-yr, 8-yr and 10-yr, respectively. Incidences of [GREATER-THAN OR EQUAL TO] Grade 3 late toxicity were 29% at 10-yr. There were no statistically significant differences between LCAF and LCAF + CT with respect to the parameters mentioned above. Cumulative incidence of late toxicities of [GREATER-THAN OR EQUAL TO] Grade 3 increased sharply after the attained age of 70 years. Eighty-eight percent of patients lived with good KPS ([GREATER-THAN OR EQUAL TO]90) and 94% could eat regular or soft diet. CONCLUSION: The long-term outcome of esophageal SCC patients who received LCAF or LCAF + CT was good. The locoregional and distant failures occurred more often in the first three years after treatment, but could continuously occur up to 10 years. The late toxicity was acceptable. Late toxicities [GREATER-THAN OR EQUAL TO] Grade 3 were more likely to occur in elderly patients. QOL was good in living patients.