Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme

Forty-seven adult patients with glioblastoma multiforme (GBM) were treated in a phase I/II study combining continuous intravenous (IV) infusions of iododeoxyuridine (IdUrd) and hyperfractionated radiation therapy. IdUrd was administered as a continuous infusion (24 h/d) for two separate 14-day infusion periods. The dose of IdUrd was escalated from 500 to 1,200 mg/m2/d. The initial wide-field tumor volume was treated to 45 Gy at 1.5 Gy fractions twice daily over 3 weeks. Following a planned 2-week break, a reduced-field boost of 25 Gy was delivered using 1.25 Gy fractions twice daily over 2 weeks (total dose, 70 Gy over 9 weeks). The IdUrd infusion preceded both the wide-field and reduced-field irradiation by 1 week. All treatment was performed on an outpatient basis. Dose-limiting systemic toxicity to the bone marrow (primarily thrombocytopenia) and gastrointestinal (GI) tract (both stomatitis and diarrhea) established the maximum tolerable dose (MTD) at 1,000 mg/m2/d for a 14-day infusion. Significant local toxicity (within the radiation field) was not seen. The kinetics of IdUrd were linear with dose escalation and reached steady-state plasma concentrations of 1.3 to 3.4 mumol/L. The total body clearance of IdUrd was .82 L/min/m2. The primary metabolite, 5-iodouracil (IUra) approached steady state by day 6 of the infusion when plasma levels were 60 times higher than IdUrd. Plasma levels of uracil and thymine, but not thymidine, were elevated throughout the infusion. With a minimum follow-up of 1 year, ten patients remain alive, while 33 patients died of progressive disease, and four patients died of other causes (including one treatment-related death). The median survival for all 47 patient and for the 40 patients receiving the MTD was 45 and 47 weeks, respectively, with 12% and 14% survivals at 24 months. Using a Cox regression analysis, age (less than or equal to 50 years v greater than 50 years) and pretreatment performance status (PS) (Eastern Cooperative Oncology Group [ECOG]-PS 0 to 1 v PS 2 to 3) were independent, statistically significant (P2 less than .05) predictors of survival, with the ECOG status being a better predictor. Patients with a PS 0 to 1 (28 patients) had a median survival of 64 weeks with 21% survival at 24 months, compared with a median survival of 29 weeks and 0% survival at 12 months in the 19 patients with PS 2 to 3. The overall and subgroup survival data are at least comparable to other combined modality treatment approaches in patients with GBM.     

Phase III trial of accelerated hyperfractionation with or without difluromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme

PURPOSE: To report the results of a prospective Phase III trial for patients with newly diagnosed glioblastoma multiforme (GBM), treated with either accelerated hyperfractionated irradiation with or without difluromethylornithine (DFMO) or standard fractionated irradiation with or without DFMO. METHODS AND MATERIALS: Adult patients with newly diagnosed GBM were registered and randomized following surgery to one of 4 treatment arms: Arm A, accelerated hyperfractionation alone using 2 fractions a day of 1.6 Gy to a total dose of 70.4 Gy in 44 fractions; Arm B, accelerated hyperfractionation as above plus DFMO 1.8 gm/m2 by mouth every 8 h beginning one week before radiation until the last fraction was given; Arm C, single-fraction irradiation of 1.8 Gy/day to 59.4 Gy; Arm D, single-fraction irradiation as in Arm C plus DFMO given as in Arm B. Patients were followed for progression-free survival (PFS) and overall survival (OS), as well as for toxicity. Eligibility required histologically proven GBM, age > or =18, Karnofsky performance status (KPS) > or =60, and no prior chemotherapy or radiotherapy. Adjuvant chemotherapy was not used in this protocol. RESULTS: A total of 231 eligible patients were enrolled. There were 95 men and 136 women with a median age of 57 years, and median KPS of 90. Extent of resection was total in 23, subtotal in 152, and biopsy only in 56 patients. The 4 arms were balanced with respect to age, KPS, and extent of resection. Times to event measurements are from date of diagnosis. Median OS and PFS were 40 and 19 weeks for Arm A; 42 and 22 weeks for Arm B; 37 and 16 weeks for Arm C; and 44 and 19 weeks for Arm D (p = 0.48 for survival; p = 0.32 for PFS). Comparison of the 2 arms treated with DFMO to the 2 arms without DFMO revealed no difference in OS (37 weeks vs. 42 weeks, p = 0.12) or PFS and thus no benefit to the use of DFMO. Comparison of the 2 standard fractionation arms to the 2 accelerated hyperfractionation arms also resulted in no difference in OS (42 weeks vs. 41 weeks, p = 0.75) or PFS, showing no benefit to accelerated hyperfractionated irradiation. CONCLUSION: In this prospective Phase III study, no survival or PFS benefit was seen with accelerated hyperfractionated irradiation to 70.4 Gy, nor was any benefit seen with DFMO as a radiosensitizer. Standard fractionated irradiation to 59.4 Gy remains the treatment of choice for newly diagnosed patients with glioblastoma multiforme.     

Long term follow-up of combined radiochemotherapy for locally advanced bladder carcinoma

BACKGROUND: The 5- and 10-year survival rates and the toxicity of combined radiochemotherapy for 53 consecutive patients with locally advanced bladder carcinoma were studied in a noncomparative trial. METHODS: Between November 1986 and October 1987, 53 consecutive patients (mean age, 68 years) with muscle invasive and/or locally advanced bladder carcinoma were treated by simultaneous chemotherapy and hyperfractionated irradiation. Radiation was administered during the first to fourth week and during the ninth to tenth week as an interrupted treatment protocol. Cisplatin and epirubicin were used as radiosensitizers before radiation. The maximum dose of irradiation was 57.6 grays. RESULTS: Of 53 patients, 45 completed the planned treatment course. Causes for discontinuing therapy in 8 patients were pronounced myelosuppression (n = 2), severe gastrointestinal symptoms (n = 2), nephrotoxicity (n = 1), and severe radioproctitis (n = 1). Two additional patients stopped therapy due to vascular diseases independent of treatment-related toxicity. The overall survival for all 53 patients was 23% after 5 years and 8% after 10 years. Cause specific survival was 36% after 5 years and 29% after 10 years. Four patients are still alive after 10 years without disease progression. One of them received incomplete therapy due to toxicity. All four patients underwent transurethral resections for superficial, local tumor recurrences. CONCLUSIONS: The poor prognosis group of patients with invasive and/or locally advanced bladder carcinoma was found to have a limited disease specific survival after combined radiochemotherapy.     

Accelerated hyperfractionated radiotherapy in supratentorial malignant astrocytomas.

PURPOSE: To determine the safety and effectiveness of accelerated hyperfractionated radiotherapy in the treatment of supratentorial malignant astrocytomas. MATERIALS AND METHODS: Between June 1995-July 1997, 75 patients were enrolled to a prospective phase II study. A total dose of 60 Gy was delivered in 2 Gy b.i.d. fractions with an interval of 6-8 h, 5 days per week, in an overall time of 3 weeks. The treatment protocol was planned to give 40 Gy to a treatment volume covering the contrast-enhancing lesion and oedema (+ 3-cm margin) and additional 20 Gy to the volume encompassing the contrast-enhancing lesion alone with a 1-cm margin based on preoperative magnetic resonance imaging and/or CT findings. The patients had a median age of 46 years and a median Karnofsky performance status score of 80. Histology consisted of anaplastic astrocytoma (AA) in 16 (21%) and glioblastoma multiforme (GBM) in 59 (79%) patients. RESULTS: Median survival was 11 months for all patients; 10 months for GBM patients and 40 months for AA patients. Survival rates at 1 and 3 years were 41%, 11% for all patients; 62, 37% for AA patients and 35, 6% for GBM patients, respectively. Multivariate analysis revealed significant impact of age, histology and neurological functional class on survival. The incidence of grade 3 or worse late neurological toxicity was 5.3%. CONCLUSIONS: Although accelerated hyperfractionated radiotherapy showed no significant advantage on survival, it shortened the treatment period from 6 to 3 weeks. Radiotherapy was well tolerated and the incidence of late toxicity is acceptable.     

Hyperfractionated radiation therapy for oropharyngeal carcinoma in a Japanese population

BACKGROUND: Hyperfractionated radiation therapy is recognized to be a better treatment method, especially regarding local control, than conventional radiation therapy for oropharyngeal carcinoma. However, the survival benefit of hyperfractionated radiation therapy for oropharyngeal carcinoma has not been reported so far. Moreover, patient populations of previous studies were mostly white or African-American, and rarely included Orientals. Thus, the current study is designed to evaluate not only local control but the survival benefit of hyperfractionated radiation therapy for oropharyngeal carcinoma in a Japanese population. METHODS: The eligibility criteria were as follows. The patients were 20 years or older. Performance status ranged from 0 to 2. No patient with double carcinoma was included except those with superficial esophageal carcinoma or advanced carcinoma controlled for at least 2 years after treatment. In our radiation protocol, hyperfractionated radiation therapy was adopted using 1.2 Gy per fraction, two fractions per day (6 h apart), 5 days a week, for a total dose of 66 Gy or more. RESULTS: Complete response was achieved in all 14 patients with oropharyngeal lesions. In five patients with lymph node metastasis, complete response was achieved in four patients and partial response was achieved in the remaining one. The 3-year loco-regional control rate was 77% and the 3-year overall survival rate was 69%. CONCLUSIONS: Treatment with hyperfractionated radiation therapy is considered superior to conventional radiation therapy with acceptable toxicity for Japanese patients with oropharyngeal carcinoma in terms of loco-regional control rate and overall survival rate.     

Permanent iodine implants for recurrent malignant gliomas

Purpose: To determine the efficacy and toxicity of permanent ¹²⁵iodine implants for recurrent malignant gliomas.

Methods and Materials: Between January 1989 and January:, 59 patients with histologically confirmed recurrent malignant gliomas (22 nonglioblastoma malignant gliomas, 37 glioblastoma multiforme at the time of implant) received a permanent ¹²⁵iodine implant. Patients ranged in age from 13–74 years. The median ages for the overall group, nonglioblastoma (nonGBM), and glioblastoma (GBM) groups was 47 years, 39 years, and 53 years, respectively.

Results: With a median follow-up of 40 months, the median survival for the 59 total patients is 1.34 years; nonGBM 2.04 years, GBM 0.9 years. Factors predictive for poor prognosis were GBM histology, age 60 years or more, target volume 17 cc or more, and/or tumor location within the corpus callosum or thalamus. Reoperations have been performed in 24 (40%) patients; 15 (25%) for tumor progression; 3 (5%) for radiation necrosis; 2 (3%) for skull necrosis/infection, and 4 (7%) for other reasons (Ommaya reservoir insertion, catheter removal, hematoma evacuation).

Conclusion: Permanent ¹²⁵iodine implants in selected patients with recurrent malignant gliomas are associated with reasonable long-term survival and a low risk of complications. Given the low incidence of radiation necrosis, future plans are to increase dose rate and/or total dose delivered with the permanent implant.     

Treatment of recurrent glioblastoma multiforme with GliaSite brachytherapy

PURPOSE: In this study, we assess the efficacy of GliaSite brachytherapy in the treatment of patients with recurrent glioblastoma multiforme (GBM). METHODS AND MATERIALS: Between 1999 and 2004, 24 patients with recurrent glioblastoma multiforme were treated with the GliaSite Radiation Therapy System (RTS). The GliaSite is an inflatable balloon catheter that is placed in the resection cavity at the time of surgical resection. Low-dose-rate radiation is then delivered locally by temporarily inflating the balloon with an aqueous solution of organically bound (125)I (Iotrex [sodium 3-((125)I)-iodo-4-hydroxybenzenesulfonate]). Patients at the Johns Hopkins Hospital with recurrent GBM, who were previously treated with surgery and external beam radiotherapy, underwent surgical resection followed by GliaSite balloon implantation. Subsequently, the patients received radiation therapy using the GliaSite to a mean dose of 53.1 Gy. Ten patients were male, and 14 patients were female. The mean age was 48.1 years. All patients had pathologically confirmed recurrent GBM. The median Karnofsky performance status (KPS) was 80. Median follow-up time was 21.8 months. RESULTS: At the time of analysis, 18 patients (75%) had died; 6 patients (25%) were alive. Median survival from diagnosis for all patients was 23.3 months. Median survival after GliaSite brachytherapy was 9.1 months. Patients with a KPS > or =70 had a median survival of 9.3 months, whereas patients with a KPS <70 had a median survival of 3.1 months (p < 0.003). Survival was not significantly different between patients receiving 45 Gy and patients receiving a dose greater than 45 Gy. Acute side effects were minor, consisting of mild nausea and/or headache. One patient developed a wound infection. No incidents of meningitis were observed. Late sequelae were rare, but 2 incidents of symptomatic radiation necrosis were observed. One patient developed transient expressive aphasia. CONCLUSIONS: GliaSite radiotherapy confers a prolongation of survival in patients with recurrent glioblastoma multiforme compared to historical controls with recurrent GBM. GliaSite therapy leads to a favorable survival outcome of 9.3 months in patients with KPS > or =70, but only 3.1 months in patients with KPS <70. Favorable survival is observed for patients within each recursive partitioning analysis class. Treatment with GliaSite is safe and generally well tolerated. Additional data are needed to fully assess the therapeutic benefit of GliaSite brachytherapy for recurrent GBM.     

Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis.

PURPOSE: When an initial retrospective review of malignant glioma patients (MG) undergoing brachytherapy was carried out using the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) criteria, it revealed that glioblastoma multiforme (GBM) cases benefit the most from implant. In the present study, we focused exclusively on these GBM patients stratified by RPA survival class and looked at the relationship between survival and implanted target volume, to distinguish the prognostic value of volume in general and for a given GBM class. METHODS AND MATERIALS: Between 1991 and 1998, 75 MG patients were treated with surgery, external beam radiation, and stereotactic iodine-125 (I-125) implant. Of these, 53 patients (70.7%) had GBMs, with 52 (98%) having target volume (TV) data for analysis. Stratification by RPA criteria showed 12, 26, 13, and 1 patients in classes III to VI, respectively. For analysis purposes, classes V and VI were merged. There were 27 (51.9%) male and 25 (48.1%) female patients. Mean age was 57.5 years (range 14-79). Median Karnofsky performance status (KPS) was 90 (range 50-100). Median follow-up time was 11 months (range 2-79). RESULTS: At analysis, 18 GBM patients (34.6%) were alive and 34 (65.4%) were dead. Two-year and 5-year survivals were 42% and 17.5%, respectively, with a median survival time (MST) of 16 months. Two-year survivals and MSTs for the implanted GBM patients compared to the RTOG database were as follows: 74% vs. 35% and 28 months vs. 17.9 months for class III; 32% vs. 15% and 16 months vs. 11.1 months for class IV; 29% vs. 6% and 11 months vs. 8.9 months for class V/VI. Mean implanted TV was 15.5 cc (range 0.8-78), which corresponds to a spherical implant diameter of 3.1 cm. Plotting survival as a function of 5-cc TV increments suggested a trend toward poorer survival as the implanted volume increases. The impact of incremental changes in TV on survival within a given RPA class of GBMs was compared to the RTOG database. Looking at absolute differences in MSTs: for classes III and IV, there was little effect of different TVs on survival; for class V/VI, a survival benefit to implantation was still seen at the target volume cutoff (TV > 25 cc). Within a given RPA class, no significant differences were found within class III; for class IV, the most significant difference was at 10 cc (p = 0.05); and for class V/VI, at 20 cc (p = 0.06). CONCLUSION: For all GBM patients, an inverse relationship between implanted TV size and median survival is suggested by this study. However, when GBM patients are stratified using the RTOG's RPA criteria, the prognostic effect of implant volume disappears within each RPA survival class. At the critical volume of 25 cc, which approximates an implant of 5-cm diameter (upper implantation limit of many CNS brachytherapy protocols), the "poorest" prognosis GBM patients stratified by RPA still demonstrate a survival benefit with implant. We suggest that any GBM patient meeting brachytherapy recognized size criteria be considered for I-125 implant.     

Hyperfractionated radiotherapy and concomitant cisplatin for locally advanced laryngeal and hypopharyngeal carcinomas: final results of a single institutional program

SUMMARY: ABSTRACT The purpose of this study was to achieve locoregional control of locally advanced laryngeal carcinoma, survival, and organ preservation using split hyperfractionated accelerated radiation therapy and cisplatin concomitantly. This study was a phase II trial of chemoradiotherapy with split hyperfractionated accelerated radiation therapy, 1.6 Gy per fraction given twice per day to a total dose of 64 to 67.2 Gy for a total of 6 weeks with a 2-week gap, and cisplatin 20 mg/m2, days 1 to 5, in continuous perfusion, concomitantly. Seventy-three patients were treated (stage IV, 64%). At a median follow-up of 55 months for living patients, median survival was 44 months, and 5-year overall survival and disease-free survival were 42% and 39%, respectively. Toxicities included mucositis (grade III, 40%; grade IV, 28%), epithelitis (grade III, 28%). Of the 73 patients, 32 (44%) have continued with their larynx free of disease. Split hyperfractionated accelerated radiation therapy and concomitant cisplatin has been demonstrated to be an active treatment for locally advanced laryngeal carcinomas, but more active combinations of chemotherapy and radiotherapy, without increase of toxicity, are necessary to increase the rate of locoregional control, organ preservation, and survival.     

Phase II study of tolerance and efficacy of hyperfractionated radiotherapy and 5-fluorouracil,cisplatin, and paclitaxel (Taxol) in stage III and IV inoperable and/or unresectable head-and-neck squamous cell carcinoma: A-2 protocol

PURPOSE: To determine the toxicity and efficacy of concurrent 5-fluorouracil (5-FU), cisplatin, and paclitaxel (Taxol) and hyperfractionated radiotherapy in locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Twenty-seven patients were entered into this Phase II trial. Eligible patients had Stage III or IV head-and-neck squamous cell carcinoma arising from the oral cavity, hypopharynx, oropharynx, nasopharynx, or larynx. The plan of treatment consisted of hyperfractionated radiotherapy (74.4 Gy at twice daily fractions of 1.2 Gy). Chemotherapy was given on Weeks 1, 5, and 8 as follows: 5-FU at 750 mg/m2 as a constant infusion for 24 h for 3 days; cisplatin at 50 mg/m2 in 250-500 mL D5 0.5 NS or NS infusion during 2-4 h, and paclitaxel at 70 mg/m2 infused in 500 mL NS during 3 h. RESULTS: The overall survival rate of the entire group was 81.5%, 66.7%, and 63% at 1, 2, and 3 years, respectively. The median follow-up was 40.2 months (range 30-62). Of the 27 patients, 19 (70%) had a complete response and an overall survival rate of 100% at 1 year and 94% at 2 and 3 years. The disease-free survival rate of the latter group was 95% at 1 year and 84% at 2 and 3 years. Of the 27 patients, 18 (67%) maintained the complete response until the last follow-up visit or death. Percutaneous endoscopic gastrostomy dependency occurred for a median of 7.1 months. Grade 3 and 4 mucositis occurred in 20 and 3 patients, respectively. Six patients were hospitalized for leukopenic fever. Late toxicities included L'Hermitte syndrome (n = 3), osteoradionecrosis (n =1), hypothyroidism (n = 4), paresthesias (n = 1), aspiration pneumonia (n = 3), and esophageal strictures (8 patients underwent dilation). CONCLUSION: Combining hyperfractionated radiotherapy concurrently with 5-FU, cisplatin, and paclitaxel results in acceptable efficacy and toxicity. However, although a locoregional control benefit is suggested by the preliminary results of this trial, it needs to be confirmed in a prospective randomized trial.     

Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: results of a Phase II study

PURPOSE: To report the results of a Phase II study of hyperfractionated craniospinal radiation therapy, with and without adjuvant chemotherapy for primitive neuroectodermal brain tumors (PNETs) and malignant ependymomas. METHODS AND MATERIALS: Newly diagnosed PNET or malignant ependymomas were treated with hyperfractionated craniospinal radiation therapy. The primary tumor site was treated to a dose of 72 Gy, with 30 Gy given to the rest of the craniospinal axis. The fraction size was 1.0 Gy, given twice a day. Patients with poor risk factors also received adjuvant chemotherapy with CCNU, cisplatin, and vincristine. Patients had follow-up for survival, time to tumor progression, and patterns of relapse. RESULTS: A total of 39 patients (21 males/18 females) were treated between March 12, 1990 and October 29, 1992. The median age was 16 years (range 3-59 years). Tumor types included 25 medulloblastomas, 5 pineoblastomas, 5 cerebral PNETs, 1 spinal cord PNET, and 3 malignant ependymomas. Twenty cases were staged as poor-risk and received adjuvant chemotherapy following radiation. Three-year progression-free survival (PFS) was 60% and 63% for poor-risk and good-risk patients, respectively. Overall 3-year survival for these groups was 70% and 79%, respectively. For the 25 patients with medulloblastoma, there were 16 good-risk and 9 poor-risk patients. Three-year PFSs were 63% and 56%, respectively. The 5-year survival for good-risk medulloblastoma was 69% with 43.7% of these patients having failures outside the primary site. CONCLUSIONS: Survival in patients with good-risk medulloblastoma was no better than that seen in previous studies with single-fraction radiation, and the rate of failure outside the primary site is excessive. Those with poor-risk features had comparable survival to that seen in patients with good risk factors, but these patients were treated with chemotherapy, and the role that hyperfractionated radiation played in their outcome is uncertain.     

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.     

Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer.

PURPOSE: We employed meta-analytic techniques to evaluate early (E) versus late (L) timing of thoracic radiation therapy (RT) in limited-stage small-cell lung cancer (LS-SCLC). In addition, we assessed the impact of radiation fractionation and chemotherapeutic regimen on timing. METHODS: Randomized trials published after 1985 addressing timing of RT relative to chemotherapy in LS-SCLC were included. Trials were analyzed by risk ratio (RR), risk difference, and number-needed-to-treat methods. RESULTS: Overall survival (OS) RRs for all studies were 1.17 at 2 years (95% CI, 1.02 to 1.35; P = .03) and 1.13 at 3 years (95% CI, 0.92 to 1.39; P = .2), indicating a significantly increased 2-year survival for ERT versus LRT patients and suggestive of a similar trend at 3 years. Subset analysis of studies using hyperfractionated RT revealed OS RR for ERT versus LRT of 1.44 (95% CI, 1.17 to 1.77; P = .001) and 1.39 (95% CI, 1.02 to 1.90; P = .04) at 2 and 3 years, respectively, indicating a survival benefit of ERT versus LRT. Studies using once-daily fractionation showed no difference in 2- and 3-year OS RRs for ERT compared with LRT. Studies using platinum-based chemotherapy had OS RRs of 1.30 (95% CI, 1.10 to 1.53; P = .002) and 1.35 (95% CI, 1.07 to 1.70; P = .01) at 2 and 3 years, respectively, favoring ERT. Studies using nonplatinum-based chemotherapy regimens had nonsignificant differences in OS. CONCLUSION: A small but significant improvement in 2-year OS for ERT versus LRT in LS-SCLC was observed, similar to the benefit of adding RT to chemotherapy or prophylactic cranial irradiation. A greater difference was evident for hyperfractionated RT and platinum-based chemotherapy.     

A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023

PURPOSE: This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense accelerated radiation therapy using weekly fractionated stereotactic radiotherapy (FSRT) boost for patients with glioblastoma multiforme (GBM). METHODS AND MATERIALS: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <60 mm were enrolled. A 50-Gy dose of standard radiation therapy (RT) was given in daily 2-Gy fractions. In addition, patients received four FSRT treatments, once weekly, during Weeks 3 to 6. FSRT dosing of either 5 Gy or 7 Gy per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. After the RT course, carmustine (BCNU) at 80 mg/m(2) was given for 3 days, every 8 weeks, for 6 cycles. RESULTS: A total of 76 patients were analyzed. Toxicity included: 3 Grade 4 chemotherapy, 3 acute Grade 4 radiotherapy, and 1 Grade 3 late. The median survival time was 12.5 months. No survival difference is seen when compared with the RTOG historical database. Patients with gross total resection (41%) had a median survival time of 16.6 months vs. 12.0 months for historic controls with gross total resection (p = 0.14). CONCLUSION: This first, multi-institutional FSRT boost trial for GBM was feasible and well tolerated. There is no significant survival benefit using this dose-intense RT regimen. Subset analysis revealed a trend toward improved outcome for GTR patients suggesting that patients with minimal disease burden may benefit from this form of accelerated RT.     

An Approach to Radiosensitizing Cervical Cancer by Use of Chemical Modulators of Nucleoside Metabolism

Although radiation alone is the treatment of choice for patients with cervical cancer that is not surgically respectable, locoregional failures rates approach 50% for locally advanced stages of disease. Therefore, decades of clinical trials using chemoradiotherapy have been performed in an attempt to enhance cure rates. Unfortunately, the addition of chemotherapy has not been shown to unequivocally improve outcome compared with radiation alone. Reasons for this include inadequate radiation doses, radiation treatment delays caused by higher acute toxicities of combined modality therapy, and insufficient understanding of both the optimal sequencing and mechanisms of radiosensitizers. Some of the chemotherapy agents tested include the fluoropyrmidines (5-fluorouracil [5-FU]), the halogenated thymidine analogues (iododeoyxuridine [IdUrd] and bromodeoyxuridine [BrdUrd] and hydroxyurea (HU). This article focuses on clinical results using these compounds, the evolving understanding of these different types of drug-radiation interactions, and potential new strategies for the use of these radiosensitizers in patients with locally advanced cervical cancer.     

Enhancement of X ray induced DNA damage by pre-treatment with halogenated pyrimidine analogs

The use of the halogenated pyrimidine analogs, including bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd), as potential clinical radiosensitizers is an area of renewed clinical research. Cellular radiation effects of these analogs using clinically achievable steady state plasma levels (10(-7)-10(-5) M) were measured in vitro using exponentially growing Chinese hamster V79 cells. Radiation response was determined by clonogenic survival and by the production of DNA single strand (SSB) and double strand breaks (DSB) using filter elution techniques. Replacement of thymidine in DNA by BrdUrd or IdUrd was also determined. Drug exposure of BrdUrd or IdUrd for two population doublings (17 hr) prior to irradiation resulted in a progressive reduction of n and D0 compared to untreated controls over the drug dose range of 10(-7)-10(-5) M. The percent thymidine replacement increased from 1% at 10(-7) M to 5% at 10(-6) M to 23% at 10(-5) M. Using a 17 hr exposure at 10(-5) of BrdUrd or IdUrd, the production of SSB and DSB was increased by greater than or equal to 2X and greater than or equal to 1.5X respectively. No differences in the kinetics of repair of SSB and DSB were found following 3 hr of post-irradiation repair. We conclude that in this in vitro model, there appears to be a direct relationship between percent thymidine replacement, reduction of radiation survival parameters (n, D0), and the production of DNA strand breaks in the clinically achievable dose range of these halogenated pyrimidine analogs. These filter elution assays may be adapted to in vivo studies and possibly may allow for monitoring of radiation-induced DNA damage and repair in clinical tumor specimens treated with these radiosensitizers.     

鼻咽癌外照射加腔内近距离超分割推量照射的远期疗效分析

背景与目的:鼻咽癌的后装治疗一般采用鼻咽腔内治疗的方法进行推量照射,适用于局部早期鼻咽癌.福建省肿瘤医院率先开展鼻咽旁插植技术,无颅底破坏的局部晚期鼻咽癌采用后装治疗推量照射.本文分析腔内后装推量照射的远期疗效,探讨常规外照射的合适剂量配合后程超分割后装推量照射的临床价值.方法:1998年1月～2002年12月体外照射加腔内后装超分割推量放射治疗鼻咽癌患者352例,体外常规放射治疗50～70 Gy后进行腔内近距离超分割推量照射,外照射后咽旁间隙肿瘤残留者配合咽旁区插植放疗.采用个体化鼻咽腔内施源器,超分割照射每次2.5～3.0 Gy,2次/天,间隔6 h,总剂量5～32 Gy,中位剂量17 Gy.结果:本组l、2、3、5年生存率分别为97.0%、91.3%、87.6%、84.7%.总体5年生存率Ⅰ、Ⅱ期88.2%,Ⅲ、Ⅳ期79.2%(log-rank检验,P=0.016);总体局控率Ⅰ、Ⅱ期94.1%,Ⅲ、Ⅳ期91.7%(log-rank检验,P＞0.05).后组颅神经损伤32例(9.4%).结论:鼻咽腔内后装联合咽旁间隙捅植近距离放射治疗鼻咽癌取得良好的局控率和生存率,局部晚期鼻咽癌取得与早期鼻咽癌类似的局控率,咽旁间隙受累者咽旁插植增加颈动脉鞘区照射剂量,后组颅神经损伤发生率较高.     

Re-irradiation with radiosurgery for recurrent glioblastoma multiforme

Local tumor control remains a significant challenge in patients with glioblastoma multiforme (GBM). Despite aggressive radiation therapy approaches, most recurrences are within the high-dose field, limiting the ability to safely re-irradiate recurrence using conventional techniques. Fractionated stereotactic radiosurgery (fSRS) is a technique whose properties make it useful for re-irradiation. We retrospectively reviewed the charts of 14 patients with recurrent GBM treated with salvage radiosurgery. Seven patients were male and seven were female with a median age of 58 (range: 39-76). All patients had prior cranial radiation therapy to a median dose of 60 Gy (58-69). There were 18 lesions treated with a median tumor volume of 6.97 cm3 (0.54-50.0 cm3). fSRS was delivered in 1-3 fractions to a median dose of 24 Gy (18-30 Gy). Median follow-up for the cohort was 8 months (3-22 months). On follow-up MRI, 8 of 18 lesions had a radiographic response. The median time-to-progression following primary irradiation was 8 months (1-28 months) while the median time-to-progression (TTP) following fSRS was 5 months (1-16 months). Median local control following re-irradiation was 5 months and actuarial local control was 21% at 1-year. Overall survival following primary irradiation was 79% at 12 months and 46% at 2 years. Overall survival following re-irradiation was 79% at 6 months and 30% at 1 year. No significant treatment-related toxicity was seen in follow-up. These results indicate that re-irradiation for recurrent GBM using fSRS is well-tolerated and can offer a benefit in terms of progression-free survival (PFS).     

Epidermal growth factor receptor amplification does not have prognostic significance in patients with glioblastoma multiforme

PURPOSE: There have been conflicting reports in the literature regarding the prognostic significance of epidermal growth factor receptor (EGFR) amplification in patients with glioblastoma multiforme (GBM). The purpose of this study is to determine the prognostic significance of EGFR amplification in patients with GBM treated at the Cleveland Clinic Foundation. METHODS AND MATERIALS: A retrospective review of GBM patients treated with surgery at the Cleveland Clinic Foundation was performed. Amplification of EGFR was evaluated with fluorescence in situ hybridization in a total of 107 patients diagnosed between December 1995 and May 2003. In addition to EGFR status, various prognostic factors were evaluated to determine the factors that influenced survival and radiographic response rate. The median follow-up was 9 months. RESULTS: The overall median survival was 9.8 months, with a 1-year survival of 40%. Of the 107 patients in whom EGFR status was evaluated, 36 (33.6%) were found to have EGFR amplification. On multivariate analysis, median survival was found to be significantly improved for patients with age < 60 (12.6 months vs. 8 months, p = 0.0061), patients with Karnofsky Performance Status > or = 70 (12.1 months vs. 4.4 months, p < 0.0001), patients who had undergone subtotal resection or gross total resection (11.1 months vs. 4.1 months, p = 0.002), and patients who received a radiation dose > or = 60 Gy compared with no radiation (12.7 months vs. 3 months, p < 0.0001). There was no association of EGFR amplification with survival. When stratified by age (< 60 vs. > or = 60), EGFR status still did not reach statistical significance in predicting for survival. For the 81 patients who had radiographic follow-up, the 1-year overall local control was 14%. On univariate analysis, only treatment with radiation (< 60 Gy vs. > or = 60 Gy vs. no radiation, p = 0.03) was found to predict for improved local control. Treatment with radiation did not remain statistically significant on multivariate analysis. CONCLUSION: Epidermal growth factor receptor amplification was not found to be a significant prognostic indicator of overall survival or radiographic local control in patients with GBM treated with surgery at the Cleveland Clinic Foundation. Further studies are needed to fully delineate the significance of this molecular marker in patients with GBM.     

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study)

PURPOSE: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. METHODS AND MATERIALS: Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). RESULTS: Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. CONCLUSIONS: Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.